Consumer medicine information

Keytruda

Pembrolizumab

BRAND INFORMATION

Brand name

Keytruda

Active ingredient

Pembrolizumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Keytruda.

What is in this leaflet

This leaflet answers some common questions about KEYTRUDA. It does not contain all the available information.

It does not take the place of talking to your doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of you using KEYTRUDA against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor.

Keep this leaflet. You may need to read it again.

What KEYTRUDA is used for

KEYTRUDA is used to treat:

  • a kind of skin cancer called melanoma in adults.
  • a kind of lung cancer called non-small cell lung cancer in adults.
  • a kind of head and neck cancer called head and neck squamous cell carcinoma in adults.
  • a kind of cancer called classical Hodgkin Lymphoma in adults.
  • a kind of cancer called primary mediastinal B-cell lymphoma in adults and children.
  • a kind of cancer called urothelial carcinoma, including bladder cancer in adults.
  • a kind of cancer in adults and children that can occur in any part of the body and is shown by laboratory tests to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • a kind of cancer called colon or rectal cancer in adults that is shown by a laboratory test to be MSI-H or dMMR
  • a kind of uterine cancer called endometrial carcinoma
  • a kind of kidney cancer called renal cell carcinoma in adults.

It is not known if KEYTRUDA is safe and effective in children with MSI-H or dMMR cancers of the brain or spinal cord (central nervous system cancers).

KEYTRUDA contains the active substance pembrolizumab.

Adults may get KEYTRUDA if their cancer has spread or cannot be taken out by surgery.

Adults get KEYTRUDA after they had surgery to remove melanoma to help prevent their cancer from coming back.

KEYTRUDA may be given in combination with other anti-cancer medicines. It is important that you also read the Consumer Medicine Information for these other medicines. If you have any questions about these specific medicines, please ask your doctor.

This medicine is available only with a doctor's prescription.

KEYTRUDA works by helping your immune system fight your cancer.

Ask your doctor if you have any questions about why KEYTRUDA has been prescribed for you.

Before you are given KEYTRUDA

KEYTRUDA can be used in children with primary mediastinal B-cell lymphoma.

Before you are given KEYTRUDA

Tell your doctor if you:

  • have a disease of your immune system like Crohn's, ulcerative colitis or lupus
  • had an organ transplant (like a kidney transplant) or a bone marrow (stem cell) transplant that used donor stem cells (allogeneic)
  • have pneumonia or swelling of your lungs (called pneumonitis)
  • have liver damage

Pregnancy

  • If you are pregnant, think you may be pregnant or are planning to have a baby, tell your doctor.
  • KEYTRUDA can cause harm or death to your unborn baby.
  • You must use effective contraception while you are being treated with KEYTRUDA and for at least 4 months after the last dose of KEYTRUDA if you are a woman who could become pregnant.

Breast-feeding

  • If you are breastfeeding, tell your doctor.
  • Do not breastfeed while taking KEYTRUDA.

Taking other medicines

Tell your doctor if you

  • are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop
  • take other medicines that make your immune system weak. Examples of these may include steroids, such as prednisone.

How KEYTRUDA is given

  • Your doctor will give you KEYTRUDA through an IV for about 30 minutes.
  • Most people get KEYTRUDA every 3 weeks or every 6 weeks, depending on the dose you are given.
  • Your doctor will decide how many treatments you need.

If you miss a dose

  • Call your doctor right away to reschedule your appointment.
  • It is very important that you do not miss a dose of this medicine.

While you are being treated with KEYTRUDA

Things you must do

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given KEYTRUDA.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given KEYTRUDA.

Side Effects

Like all medicines, KEYTRUDA can cause side effects, although not everybody gets them. Your doctor will discuss these with you and will explain the risks and benefits of your treatment.

When you get KEYTRUDA, you can have some serious side effects.

These side effects can sometimes become life-threatening and can lead to death. These side effects may happen anytime during treatment or even after your treatment has ended. You may experience more than one side effect at the same time.

If you have any of the following symptoms, call or see your doctor right away.

  • Signs and symptoms of lung problems
    - shortness of breath
    - chest pain
    - coughing
  • Signs and symptoms of problems with your intestines
    - diarrhoea or more bowel movements than usual
    - your stools are black, tarry, sticky or have blood or mucus
    - severe stomach pain or tenderness
  • Signs and symptoms of liver problems
    - nausea or vomiting
    - feeling less hungry
    - pain on the right side of your stomach
    - your skin looks yellow
    - the whites of your eyes look yellow
    - dark urine
    - you bleed or bruise more easily than normal
  • Signs and symptoms of kidney problems
    - changes in the amount or colour of your urine
  • Signs and symptoms of hormone gland problems (especially the thyroid, pituitary, and adrenal glands)
    - rapid heart beat
    - weight loss
    - increased sweating
    - weight gain
    - hair loss
    - feeling cold
    - constipation
    - your voice gets deeper
    - muscle aches
    - dizziness or fainting
    - headaches that will not go away or unusual headache
  • Signs and symptoms of blood sugar problems
    - feeling more hungry or thirsty
    - needing to urinate more often
    - weight loss
  • Signs and symptoms of skin problems
    - rash
    - itching
    - skin blistering, peeling or sores
    - ulcers in mouth or in lining of nose, throat, or genital area
  • Signs and symptoms of problems in other organs
    - muscle pain or weakness
    - changes in eyesight
    - stomach area pain with nausea and vomiting (pancreatitis)
    - confusion, fever, memory problems, or seizures (encephalitis)
    - swollen lymph nodes, rash or tender lumps on skin, cough, or eye pain (sarcoidosis)
    - shortness of breath, irregular heartbeat, feeling tired, or chest pain (myocarditis)
    - inflammation of the heart muscle, which may present as shortness of breath, irregular heartbeat, feeling tired, or chest pain (pericarditis)
    - inflammation of the covering of the heart and accumulation of fluid around the heart (pericardial effusion)
    - inflammation of the nerves that may cause pain, weakness, and paralysis in the arms and legs (peripheral neuropathy)
    - pain, numbness, tingling, or weakness in the arms or legs; bladder or bowel problems including needing to urinate more frequently, urinary incontinence, difficulty urinating and constipation (myelitis)
  • Signs and symptoms of infusion (IV) reactions
    - shortness of breath
    - itching or rash
    - dizziness
    - fever
  • There are possible side effects of treatment with KEYTRUDA in people who have received a transplant
    - Rejection of a transplanted organ.
    People who have had an organ transplant may have an increased risk of organ transplant rejection. Your doctor should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had.
    - Complications, including graft-versus-host-disease (GVHD), in people with bone marrow (stem cell) transplant that uses donor stem cells (allogeneic).
    These complications can be severe and can lead to death. They may occur if you had this kind of transplant in the past or if you get it in the future. Your doctor will monitor you for the following signs and symptoms: skin rash, liver inflammation, abdominal pain, and diarrhoea.

The following side effects have been reported in clinical trials:

Very common (may affect more than 1 in 10 people)

  • diarrhoea, nausea
  • itching, rash
  • joint pain
  • back pain
  • feeling tired
  • cough
  • patches of skin which have lost colour
  • stomach pain
  • decreased sodium levels in the blood
  • fever
  • infections of the upper respiratory tract
  • a decreased number of white blood cells (which are important in fighting infection) in patients with primary mediastinal B-cell lymphoma

The following side effects have been reported in more than 1 in 5 people when KEYTRUDA was given in combination with chemotherapy:

  • hair loss
  • feeling tired
  • diarrhoea
  • decrease in white blood cell count
  • joint pain
  • rash
  • swelling of the lining of the digestive system (for example mouth, intestines)
  • mouth sores
  • decrease in red blood cell count
  • nausea
  • constipation
  • vomiting

Common side effects when KEYTRUDA is given in combination with lenvatinib include:

  • feeling tired
  • high blood pressure
  • joint and muscle pain
  • diarrhoea
  • decreased appetite
  • low levels of thyroid hormone
  • nausea
  • mouth sores
  • vomiting
  • weight loss
  • stomach-area (abdominal) pain
  • headache
  • constipation
  • urinary tract infection
  • hoarseness
  • bleeding
  • low magnesium level
  • blisters or rash on the palms of your hands and soles of your feet
  • shortness of breath
  • cough
  • rash

The most common side effects when KEYTRUDA is given in combination with axitinib are:

  • diarrhoea
  • fatigue
  • high blood pressure
  • liver problems
  • low levels of thyroid hormone
  • decreased appetite
  • blisters or rash on the palms of your hands and soles of your feet
  • nausea
  • mouth sores or swelling of the lining of the mouth, nose, eyes, throat, intestines, or vagina
  • hoarseness
  • rash
  • cough
  • constipation

The most common side effects when KEYTRUDA is given to children are:

  • fever
  • vomiting
  • fatigue
  • constipation
  • stomach pain
  • nausea

Less common side effects can happen.

Also, your doctor may do blood tests to check for side effects.

KEYTRUDA may cause other side effects that are not listed. For more information, ask your doctor.

If you have any side effect that bothers you or that does not go away, tell your doctor.

Ask your doctor to answer any questions you may have.

Storage

It is unlikely that you will be asked to store KEYTRUDA yourself. It will usually be stored in the pharmacy or on the ward.

Product Description

What it looks like

KEYTRUDA powder for injection comes as a white to off-white powder in a glass vial. KEYTRUDA concentrated injection comes as a clear to slightly opalescent, colourless to slightly yellow solution in a glass vial.

Ingredients

Active ingredient:

  • pembrolizumab

Inactive ingredients:

  • Histidine
  • Histidine hydrochloride monohydrate
  • Sucrose
  • Polysorbate 80
  • Water for Injections

Supplier

KEYTRUDA is supplied in Australia by:

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera
Road, Macquarie Park NSW 2113,
AUSTRALIA

This leaflet was prepared 22 February 2021.

Australian Register Numbers:

AUST R 226597 - KEYTRUDA 50mg Powder for injection

AUST R 263932 - KEYTRUDA 100mg/4mL concentrated injection

RCN000013027

Published by MIMS April 2021

BRAND INFORMATION

Brand name

Keytruda

Active ingredient

Pembrolizumab

Schedule

S4

 

1 Name of Medicine

Pembrolizumab (rch).

2 Qualitative and Quantitative Composition

One vial contains 100 mg of pembrolizumab in 4 mL of solution.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Keytruda 100 mg/4 mL concentrated injection is a sterile, preservative-free, clear to slightly opalescent, colourless to slightly yellow solution.
Not for direct infusion or injection (see Section 4.2 Dose and Method of Administration).

4 Clinical Particulars

4.1 Therapeutic Indications

Melanoma.

Keytruda (pembrolizumab) is indicated as monotherapy for the treatment of unresectable or metastatic melanoma in adults.
Keytruda (pembrolizumab) is indicated for the adjuvant treatment of adult and adolescent (12 years and older) patients with stage IIB, IIC, or III melanoma who have undergone complete resection.

Non-small cell lung cancer (NSCLC).

Keytruda (pembrolizumab), in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic non-squamous NSCLC, with no EGFR or ALK genomic tumour aberrations.
Keytruda (pembrolizumab), in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.
Keytruda (pembrolizumab) is indicated as monotherapy for the first-line treatment of patients with NSCLC expressing PD-L1 [tumour proportion score (TPS) ≥ 1%] as determined by a validated test, with no EGFR or ALK genomic tumour aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.
Keytruda (pembrolizumab) is indicated as monotherapy for the treatment of patients with advanced NSCLC whose tumours express PD-L1 with a ≥ 1% TPS as determined by a validated test and who have received platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumour aberrations should have received prior therapy for these aberrations prior to receiving Keytruda.
Keytruda (pembrolizumab) is indicated as monotherapy for the adjuvant treatment of patients with Stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC who have undergone complete resection and platinum-based chemotherapy.
Keytruda (pembrolizumab), in combination with platinum containing chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment, is indicated for the treatment of patients with resectable Stage II, IIIA, or IIIB (T3-4N2) NSCLC.

Head and neck squamous cell cancer (HNSCC).

Keytruda (pembrolizumab), as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of patients with metastatic or unresectable recurrent HNSCC, and whose tumours express PD-L1 [Combined Positive Score (CPS) ≥ 1] as determined by a validated test.
Keytruda (pembrolizumab) is indicated as monotherapy for the treatment of patients with metastatic or unresectable recurrent HNSCC with disease progression on or after platinum-containing chemotherapy and whose tumours express PD-L1 [Combined Positive Score (CPS) ≥ 1] as determined by a validated test.

Classical Hodgkin lymphoma (cHL).

Keytruda (pembrolizumab) is indicated as monotherapy for the treatment of adult and paediatric patients with relapsed or refractory classical Hodgkin Lymphoma (cHL):
1. following autologous stem cell transplant (ASCT); or
2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.
The approval of this indication in paediatric patients is on the basis of objective response rate from patients aged 11 years and older from single arm trial data and extrapolation from adult data (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Primary mediastinal B-cell lymphoma (PMBCL).

Keytruda (pembrolizumab) is indicated for the treatment of adult and paediatric patients with refractory primary mediastinal B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. The approval of this indication is on the basis of objective response rate (ORR) and duration of response from non-randomised studies. See Section 5.1 Pharmacodynamic Properties, Clinical trials.

Urothelial carcinoma.

Keytruda (pembrolizumab), in combination with enfortumab vedotin, is indicated for the first-line treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC).
Keytruda (pembrolizumab) is indicated as monotherapy for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for any platinum-containing chemotherapy. This indication is approved based on overall response rate and duration of response in a single-arm study. Improvements in overall survival, progression-free survival, or health-related quality of life have not been established.
Keytruda (pembrolizumab) is indicated as monotherapy for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have received platinum-containing chemotherapy.
Keytruda (pembrolizumab) is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in-situ (CIS) with or without papillary tumours who are ineligible for or have elected not to undergo cystectomy. This indication was approved via the provisional approval pathway based on complete response rate and duration of response. Continued approval of this indication depends on verification and description of benefit in confirmatory trials.

Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer.

Keytruda (pembrolizumab) is indicated for the treatment of adult and paediatric patients with unresectable or metastatic solid tumours that are MSI-H or dMMR, as determined by a validated test, that have progressed following prior treatment and when there are no satisfactory alternative treatment options.

Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer.

Keytruda (pembrolizumab) is indicated for the treatment of patients with unresectable or metastatic colorectal cancer (CRC) that is MSI-H or dMMR as determined by a validated test.

Biliary tract carcinoma (BTC).

Keytruda (pembrolizumab), in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract carcinoma (BTC).

Endometrial carcinoma.

Keytruda (pembrolizumab), in combination with carboplatin and paclitaxel, followed by Keytruda as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma.
Keytruda (pembrolizumab), in combination with lenvatinib, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Cervical cancer.

Keytruda (pembrolizumab), in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with high-risk, locally advanced cervical cancer (FIGO 2014 Stage IB2-IIB and node-positive, or Stage III-IVA).
Keytruda (pembrolizumab) in combination with platinum chemotherapy and paclitaxel, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumours express PD-L1 [Combined Positive Score (CPS) ≥ 1] as determined by a validated test.

Renal cell carcinoma (RCC).

Keytruda (pembrolizumab), in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
Keytruda in combination with Lenvima (lenvatinib) is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
Keytruda (pembrolizumab), as monotherapy, is indicated for the adjuvant treatment of patients with RCC with a clear cell component who are at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions (see Section 5.1, Clinical trials, Renal cell carcinoma).

Cutaneous squamous cell carcinoma (cSCC).

Keytruda (pembrolizumab) is indicated as monotherapy for the treatment of adult patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation. This indication was approved via the provisional approval pathway based on objective response rate and duration of response from a single-arm study. Improvements in overall survival, progression-free survival, or health-related quality of life have not been established. Full registration for this indication depends on submission of further clinical data to confirm the clinical benefit of the medicine.

Gastric cancer.

Keytruda (pembrolizumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GOJ) adenocarcinoma that is not HER2-positive.
Keytruda (pembrolizumab), in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GOJ) adenocarcinoma, whose tumours express PD-L1 [Combined Positive Score (CPS) ≥ 1] as determined by a validated test.

Oesophageal cancer.

Keytruda (pembrolizumab), in combination with platinum and fluoropyrimidine based chemotherapy, is indicated for the first-line treatment of patients with locally advanced or metastatic carcinoma of the oesophagus or HER2-negative gastroesophageal junction (GOJ) adenocarcinoma (tumour centre 1 to 5 centimetres above the GOJ) that is not amenable to surgical resection or definitive chemoradiation.

Tumour mutational burden-high (TMB-H) cancer.

Keytruda (pembrolizumab) is indicated for the treatment of adult and paediatric patients with unresectable or metastatic tumour mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] solid tumours, as determined by a validated test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication was approved via the provisional approval pathway, based on the pooling of data on objective response rate and response duration across multiple different tissue types in a single-arm trial. The assumption that TMB-H status is predictive of the treatment effect of Keytruda for every tissue type has not been verified. Full registration for this indication depends on verification and description of clinical benefit in confirmatory trials.

Triple negative breast cancer.

Keytruda (pembrolizumab) is indicated for the treatment of patients with high risk early stage triple negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery.
Keytruda (pembrolizumab), in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumours express PD-L1 (CPS ≥ 10) as determined by a validated test and who have not received prior chemotherapy for metastatic disease.

4.2 Dose and Method of Administration

Treatment must be initiated and supervised by specialised healthcare professionals experienced in the treatment of cancer.

Patient selection.

For safe and effective use of Keytruda in some indications, in vitro diagnostic (IVD) companion diagnostic (CDx) testing for biomarkers (such as PD-L1, MSI-H/dMMR, and TMB-H is essential (see Section 4.1 Therapeutic Indications). Testing used in clinical practice should be adequately comparable to the testing used in the pivotal studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Because subclonal dMMR mutations and microsatellite instability may arise in high grade gliomas during temozolomide therapy, it is recommended to test for TMB-H, MSI-H, and dMMR in the primary tumour specimens obtained prior to initiation of temozolomide chemotherapy in patients with high grade gliomas.

Recommended dosing.

The recommended dosage and duration of treatment for Keytruda-containing treatment is presented in Table 1. When assessing disease progression to determine if treatment should cease, consider the possibility of pseudoprogression (i.e. an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage). Clinically stable patients with initial evidence of disease progression can under some circumstances remain on treatment until disease progression is confirmed (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Dose modifications.

No dose reductions of Keytruda are recommended. Withhold or discontinue Keytruda to manage adverse reactions as described in Table 2.

Geriatric dosing.

No dose adjustment is necessary in this population (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Dosing in renal impairment.

No dose adjustment is needed for patients with mild or moderate renal impairment. Keytruda has not been studied in patients with severe renal impairment [see Section 5.2 Pharmacokinetic Properties, Special populations].

Dosing in hepatic impairment.

No dose adjustment is needed for patients with mild hepatic impairment. Keytruda has not been studied in patients with moderate or severe hepatic impairment [see Section 5.2 Pharmacokinetic Properties, Special populations].

Preparation and administration.

Protect from light. Do not freeze. Do not shake.
Equilibrate the vial of Keytruda to room temperature.
Prior to dilution, the vial of liquid can be out of refrigeration (temperatures at or below 25°C) for up to 24 hours.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Keytruda is a clear to slightly opalescent, colourless to slightly yellow solution. Discard the vial if visible particles are observed.
Withdraw the required volume up to 4 mL (100 mg) of Keytruda and transfer into an intravenous bag containing 0.9% sodium chloride or 5% glucose (dextrose) to prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Mix diluted solution by gentle inversion.
Do not freeze the infusion solution.
The product does not contain preservative. The diluted product should be used immediately. If not used immediately, diluted solutions of Keytruda may be stored at room temperature for a cumulative time of up to 6 hours. Diluted solutions of Keytruda may also be stored under refrigeration at 2°C to 8°C; however, the total time from dilution of Keytruda to completion of infusion should not exceed 96 hours. If refrigerated, allow the vials and/or IV bags to come to room temperature prior to use.
Translucent to white proteinaceous particles may be seen in the diluted solution, and are not of concern, as particles will be removed by the filter during administration. Administer infusion solution intravenously over 30 minutes using a sterile, non-pyrogenic, low protein binding 0.2 to 5 micrometer in-line or add-on filter.
Do not co-administer other drugs through the same infusion line.
Product is for single use in one patient only. Discard any residue.

4.3 Contraindications

None.

4.4 Special Warnings and Precautions for Use

Assessment of PD-L1 status.

When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations.

Immune-mediated adverse reactions.

Immune-mediated adverse reactions, including severe and fatal cases, have occurred in patients receiving Keytruda. In clinical trials, most immune-mediated adverse reactions occurred during treatment, were reversible and managed with interruptions of Keytruda, administration of corticosteroids and/or supportive care. Immune-related adverse reactions have occurred after discontinuation of treatment with Keytruda. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.
For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold Keytruda and consider administration of corticosteroids. Upon improvement to grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Restart Keytruda if the adverse reaction remains at grade 1 or less following corticosteroid taper. If another episode of a severe adverse reaction occurs, permanently discontinue Keytruda [see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)].
Immune-mediated pneumonitis. Pneumonitis (including fatal cases) has been reported in patients receiving Keytruda [see Section 4.8 Adverse Effects (Undesirable Effects)].
Monitor patients for signs and symptoms of pneumonitis. If pneumonitis is suspected, evaluate with radiographic imaging and exclude other causes. Administer corticosteroids for grade 2 or greater events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), withhold Keytruda for moderate (grade 2) pneumonitis, and permanently discontinue Keytruda for severe (grade 3), life-threatening (grade 4) or recurrent moderate (grade 2) pneumonitis [see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Immune-mediated adverse reactions above].
Immune-mediated colitis. Colitis has been reported in patients receiving Keytruda [see Section 4.8 Adverse Effects (Undesirable Effects)].
Monitor patients for signs and symptoms of colitis and exclude other causes. Administer corticosteroids for grade 2 or greater events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), withhold Keytruda for moderate (grade 2) or severe (grade 3) colitis, and permanently discontinue Keytruda for life-threatening (grade 4) colitis [see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Immune-mediated adverse reactions above]. The potential risk of gastrointestinal perforation should be taken into consideration.
Immune-mediated hepatitis (Keytruda) and hepatotoxicity (Keytruda in combination with axitinib).

Immune-mediated hepatitis.

Hepatitis has been reported in patients receiving Keytruda [see Section 4.8 Adverse Effects (Undesirable Effects)].
Monitor patients for changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and symptoms of hepatitis and exclude other causes. Administer corticosteroids (initial dose of 0.5-1 mg/kg/day [for grade 2 events] and 1-2 mg/kg/day [for grade 3 or greater events] prednisone or equivalent followed by a taper) and, based on severity of liver enzyme elevations, withhold or discontinue Keytruda [see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Immune-mediated adverse reactions above].

Hepatotoxicity in combination with axitinib.

Keytruda in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of grades 3 and 4 ALT and AST elevations compared to Keytruda alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt Keytruda and axitinib and consider administering corticosteroids as needed [see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)].
With the combination of Keytruda and axitinib, grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. The median time to onset of increased ALT was 2.3 months (range: 7 days to 19.8 months). Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥ 3 times ULN (grades 2-4, n = 116), ALT resolved to grades 0-1 in 94%. Among the 92 patients who were rechallenged with either Keytruda (3%) or axitinib (31%) administered as a single agent or with both (50%), 55% had no recurrence of ALT > 3 times ULN. There were no grade 5 hepatic events.
Immune-mediated nephritis. Nephritis has been reported in patients receiving Keytruda. Nephritis appears to be more common when pembrolizumab is used in combination with pemetrexed and platinum chemotherapy than when pembrolizumab is used alone [see Section 4.8 Adverse Effects (Undesirable Effects)].
Monitor patients for changes in renal function and exclude other causes. Administer corticosteroids for grade 2 or greater events (initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), withhold Keytruda for moderate (grade 2), and permanently discontinue Keytruda for severe (grade 3) or life-threatening (grade 4) nephritis [see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Immune-mediated adverse reactions above].
Immune-mediated endocrinopathies. Adrenal insufficiency (primary and secondary) has been reported in patients receiving Keytruda. Hypophysitis has also been reported in patients receiving Keytruda [see Section 4.8 Adverse Effects (Undesirable Effects)].
Monitor patients for signs and symptoms of adrenal insufficiency and hypophysitis (including hypopituitarism) and exclude other causes. Administer corticosteroids to treat adrenal insufficiency and other hormone replacement as clinically indicated, withhold Keytruda for moderate (grade 2), withhold or discontinue Keytruda for severe (grade 3) or life-threatening (grade 4) adrenal insufficiency or hypophysitis [see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Immune-mediated adverse reactions above].
Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving Keytruda [see Section 4.8 Adverse Effects (Undesirable Effects)]. Monitor patients for hyperglycaemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold Keytruda in cases of severe hyperglycaemia until metabolic control is achieved.
Thyroid disorders, including hyperthyroidism, hypothyroidism and thyroiditis, have been reported in patients receiving Keytruda and can occur at any time during treatment, therefore monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically. Withhold or discontinue Keytruda for severe (grade 3) or life-threatening (grade 4) hyperthyroidism [see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Immune-mediated adverse reactions above].
For patients with severe (grade 3) or life-threatening (grade 4) endocrinopathy that improves to grade 2 or lower and is controlled with hormone replacement, continuation of Keytruda may be considered.
Severe skin reactions. Immune-mediated severe skin reactions have been reported in patients treated with Keytruda. Monitor patients for suspected severe skin reactions and exclude other causes. Based on the severity of the adverse reaction, withhold or permanently discontinue Keytruda and administer corticosteroids [see Section 4.2 Dose and Method of Administration].
Cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and bullous pemphigoid, have been reported in patients treated with Keytruda. Some cases of SJS and TEN have had a fatal outcome. For signs or symptoms of SJS or TEN, withhold Keytruda and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue Keytruda [see Section 4.2 Dose and Method of Administration].
Other immune-mediated adverse reactions. The following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients treated with Keytruda in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010: uveitis, myositis/polymyositis, Guillain-Barre syndrome, pancreatitis, encephalitis, sarcoidosis, myasthenic syndrome/myasthenia gravis (including exacerbation), myelitis, vasculitis, hypoparathyroidism, gastritis, haemolytic anaemia, and pericarditis. The following were reported in other clinical studies with Keytruda or in post-marketing use: myocarditis and pericardial effusion, peripheral neuropathy, sclerosing cholangitis, exocrine pancreatic insufficiency, arthritis, and aplastic anaemia.
Cases of these immune-mediated adverse reactions, some of which were severe, have been reported in clinical trials or in post-marketing use.
Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with Keytruda. Treatment with Keytruda may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with Keytruda versus the risk of possible organ rejection in these patients.
Patients with pre-existing autoimmune disease (AID). In patients with pre-existing autoimmune disease (AID), data from observational studies suggest that the risk of immune-mediated adverse reactions following immune checkpoint inhibitor therapy may be increased as compared with the risk in patients without pre-existing AID. In addition, flares of the underlying AID occurred, but the majority were mild and manageable.

Increased mortality in patients with multiple myeloma when Keytruda is added to a thalidomide analogue and dexamethasone.

In two randomised clinical trials in patients with multiple myeloma, the addition of Keytruda to a thalidomide analogue plus dexamethasone, a use for which no PD-1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Infusion-related reactions.

Severe infusion reactions, including hypersensitivity and anaphylaxis, have been reported in 6 (0.2%) of 2799 patients receiving Keytruda in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006 and KEYNOTE-010. For severe infusion reactions, stop infusion and permanently discontinue Keytruda [see Section 4.2 Dose and Method of Administration]. Patients with mild or moderate infusion reaction may continue to receive Keytruda with close monitoring; premedication with antipyretic and antihistamine may be considered.

Patients excluded from clinical trials.

Patients with the following conditions were excluded from clinical trials: active CNS metastases; ECOG PS ≥ 2 (except for urothelial carcinoma and advanced RCC); HIV, hepatitis B or hepatitis C infection; active systemic autoimmune disease; interstitial lung disease; prior pneumonitis requiring systemic corticosteroid therapy; a history of severe hypersensitivity to another monoclonal antibody; receiving immunosuppressive therapy and a history of severe immune-related adverse reactions from treatment with ipilimumab, defined as any grade 4 toxicity or grade 3 toxicity requiring corticosteroid treatment (> 10 mg/day prednisone or equivalent) for greater than 12 weeks. Patients with active infections were excluded from clinical trials and were required to have their infection treated prior to receiving pembrolizumab. Patients with active infections occurring during treatment with pembrolizumab were managed with appropriate medical therapy. Patients with clinically significant renal (creatinine > 1.5 x ULN) or hepatic (bilirubin > 1.5 x ULN, ALT, AST > 2.5 x ULN in the absence of liver metastases) abnormalities at baseline were excluded from clinical trials, therefore, information is limited in patients with severe renal and moderate to severe hepatic impairment.
After careful consideration of the potential increased risk, pembrolizumab may be used with appropriate medical management in these patients.

Patient alert card.

The prescriber must discuss the risks of Keytruda therapy with the patient. The patient should be provided with the patient alert card.

Effects on fertility.

Fertility studies have not been conducted with pembrolizumab. There were no notable effects on male and female reproductive organs observed in general repeat-dose toxicity studies conducted with pembrolizumab in Cynomolgus monkeys, involving IV administration at doses up to 200 mg/kg once a week for 1 month or once every two weeks for 6 months. No findings of toxicological significance were observed and the no observed adverse effect level (NOAEL) in both studies was ≥ 200 mg/kg, which produced exposure multiples of 19 and 94 times the exposure in humans at doses of 10 and 2 mg/kg, respectively. The exposure multiple between the NOAEL and a human dose of 200 mg was 74.

Use in pregnancy.

(Category D)
There are no clinical data on the use of pembrolizumab in pregnancy. Animal reproduction studies have not been conducted with pembrolizumab; however, blockade of the PD-1 pathway has been shown in mouse models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss. These results indicate a potential risk, based on its mechanism of action, that administration of Keytruda during pregnancy could cause fetal harm, including increased rates of abortion or stillbirth. Human IgG4 (immunoglobulin) is known to cross the placental barrier and pembrolizumab is an IgG4; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Keytruda is not recommended during pregnancy unless the clinical benefit outweighs the potential risk to the fetus. Patients who could become pregnant should use effective contraception during treatment with Keytruda and for at least 4 months following the last dose of Keytruda.

Use in lactation.

There is no information regarding the presence of pembrolizumab in human milk, the absorption and effects on the breast-fed infant, or the effects on milk production. Human IgG is excreted in human milk. Because of the lack of data to support safety for the breastfed child, patients should be advised not to breast-feed during treatment and for at least 4 months after the last dose.

Paediatric use.

In KEYNOTE-051, 173 paediatric patients (65 children ages 6 months to less than 12 years and 108 adolescents ages 12 years to 17 years) with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours were administered Keytruda 2 mg/kg every 3 weeks. The cHL population (n = 30) included patients 6 to 17 years of age. Patients received Keytruda for a median of 4 doses (range 1-52 doses), with 147 patients (85%) receiving Keytruda for 2 doses or more. The concentrations of pembrolizumab in paediatric patients were comparable to those observed in adult patients at the same dose regimen of 2 mg/kg every 3 weeks.
The safety profile in these paediatric patients was similar to that seen in adults treated with pembrolizumab. The most common adverse reactions (reported in at least 20% of paediatric patients) were pyrexia (33%), vomiting (30%), headache (25%), abdominal pain (23%), anaemia (21%), and cough (20%). The majority of adverse reactions reported for monotherapy were of grades 1 or 2 severity. Eighty (46%) patients had 1 or more grades 3 to 5 adverse reactions of which 5 (2.9%) patients had 1 or more adverse reactions that resulted in death. The frequencies are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. No new immune-mediated AEs causally associated with pembrolizumab are identified in this population.
Efficacy for paediatric patients with melanoma, relapsed or refractory cHL, PMBCL, MSI-H/dMMR cancers, or TMB-H cancers is extrapolated from the results in the respective adult populations and supported by data from KEYNOTE-051 [see Section 5.1 Pharmacodynamic Properties, Clinical trials]. Efficacy has not been established in other paediatric malignancies.

Use in the elderly.

No overall differences in safety or efficacy were reported between elderly patients (65 years and over) and younger patients (less than 65 years). There is limited data regarding the safety of combination therapy with pembrolizumab and axitinib in patients ≥ 75 years of age with advanced RCC.

Effect on laboratory tests.

Thyroid and liver (hepatic transaminase and bilirubin levels) function tests should be performed at the start of treatment, periodically during treatment and as indicated based on clinical evaluation [see Section 4.2 Dose and Method of Administration].

Complications of allogeneic haematopoietic stem cell transplant (HSCT).

Allogeneic HSCT after treatment with Keytruda in classical Hodgkin lymphoma.

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic haematopoietic stem cell transplantation (HSCT) after being treated with Keytruda.
Of 14 patients in KEYNOTE-013 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 6 patients reported acute GVHD and 1 patient reported chronic GVHD, none of which were fatal. Two patients experienced hepatic VOD, one of which was fatal. One patient experienced engraftment syndrome post-transplant.
Of 32 patients in KEYNOTE-087 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 16 patients reported acute GVHD and 7 patients reported chronic GVHD, two of which were fatal. No patients experienced hepatic VOD. No patients experienced engraftment syndrome post-transplant.
Of 14 patients in KEYNOTE-204 who proceeded to allogeneic HSCT after treatment with pembrolizumab, 8 patients reported acute GVHD and 3 patients reported chronic GVHD, none of which were fatal. No patients experienced hepatic VOD. One patient experienced engraftment syndrome post-transplant.
Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune mediated adverse reactions, and intervene promptly.

Allogeneic HSCT prior to treatment with Keytruda.

In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with Keytruda. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after treatment with Keytruda. Consider the benefit of treatment with Keytruda versus the risk of possible GVHD in patients with a history of allogeneic HSCT.

Use of pembrolizumab in urothelial carcinoma patients who have received prior platinum-containing chemotherapy.

Physicians should consider the delayed onset of pembrolizumab effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In urothelial cancer, a higher number of deaths within 2 months was observed in pembrolizumab compared to chemotherapy (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Factors associated with early deaths were fast progressive disease on prior platinum therapy and liver metastases.

Use of pembrolizumab in combination with chemotherapy for first-line treatment of patients with NSCLC.

In general, the frequency of adverse reactions for pembrolizumab combination therapy is observed to be higher than for pembrolizumab monotherapy or chemotherapy alone, reflecting the contributions of each of these components (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)). A direct comparison of the safety of pembrolizumab when used in combination with pemetrexed and platinum chemotherapy to pembrolizumab monotherapy is not available.
Efficacy and safety data from patients ≥ 75 years are limited. For patients ≥ 75 years, pembrolizumab combination therapy should be used with caution after careful consideration of the potential benefit/risk on an individual basis (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal pharmacokinetic drug interaction studies have been conducted with Keytruda. Since pembrolizumab is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.
The use of systemic corticosteroids or immunosuppressants before starting Keytruda should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of Keytruda. However, systemic corticosteroids or other immunosuppressants can be used after starting Keytruda to treat immune-mediated adverse reactions [see Section 4.4 Special Warnings and Precautions for Use]. Corticosteroids can also be used as premedication, when Keytruda is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 4.4 Special Warnings and Precautions for Use, Effects on fertility.
(Category D)
See Section 4.4 Special Warnings and Precautions for Use, Use in pregnancy.
 See Section 4.4 Special Warnings and Precautions for Use, Use in lactation.

4.7 Effects on Ability to Drive and Use Machines

Keytruda may have an influence on the ability to drive and use machines. Fatigue has been reported following administration of Keytruda [see Section 4.8 Adverse Effects (Undesirable Effects)].

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience.

Advanced melanoma and NSCLC (pooled analysis).

The safety of Keytruda was evaluated in 2799 patients with unresectable or metastatic melanoma or metastatic NSCLC in controlled and uncontrolled studies. The median treatment duration was 4.2 months (range 1 day to 30.4 months) including 1153 patients treated for greater than or equal to six months and 600 patients treated for greater than or equal to one year.
Keytruda was discontinued for treatment-related adverse reactions in 5% of patients. Treatment-related serious adverse events (SAEs) reported up to 90 days after the last dose occurred in 10% of patients receiving Keytruda. Of these treatment-related SAEs, the most common were: pneumonitis, colitis, diarrhoea, and pyrexia. The most common treatment-related adverse reactions (reported in > 10% of patients) were: fatigue, pruritus, rash, diarrhoea, and nausea. The safety profile was generally similar for patients with melanoma and NSCLC.
The incidences of immune-mediated adverse reactions in this pooled population of patients with advanced melanoma or NSCLC (n=2799) are presented by CTCAE grade in Table 3.
Incidences of pneumonitis in individual studies in patients with melanoma or non-small cell lung cancer treated with Keytruda as monotherapy ranged from 1.6% to 5.8%.

Endocrinopathies.

The median time to onset of adrenal insufficiency was 5.3 months (range 26 days to 16.6 months). The median duration was not reached (range 4 days to 1.9+ years). Adrenal insufficiency led to discontinuation of Keytruda in 1 (< 0.1%) patient. Adrenal insufficiency resolved in 5 patients. The median time to onset of hypophysitis was 3.7 months (range 1 day to 11.9 months). The median duration was 4.7 months (range 8+ days to 12.7+ months). Hypophysitis led to discontinuation of Keytruda in 4 (0.1%) patients. Hypophysitis resolved in 7 patients. The median time to onset of hyperthyroidism was 1.4 months (range 1 day to 21.9 months). The median duration was 2.1 months (range 3 days to 15.0+ months). Hyperthyroidism led to discontinuation of Keytruda in 2 (< 0.1%) patients. Hyperthyroidism resolved in 71 patients. The median time to onset of hypothyroidism was 3.5 months (range 1 day to 18.9 months). The median duration was not reached (range 2 days to 27.7+ months). One (< 0.1%) patient discontinued Keytruda due to hypothyroidism.

Pneumonitis.

The median time to onset of pneumonitis was 3.3 months (range 2 days to 19.3 months). The median duration was 1.5 months (range 1 day to 17.2+ months). Pneumonitis led to discontinuation of Keytruda in 36 (1.3%) patients. Pneumonitis resolved in 55 patients.

Colitis.

The median time to onset of colitis was 3.5 months (range 10 days to 16.2 months). The median duration was 1.3 months (range 1 day to 8.7+ months). Colitis led to discontinuation of Keytruda in 15 (0.5%) patients. Colitis resolved in 41 patients.

Hepatitis.

The median time to onset of hepatitis was 1.3 months (range 8 days to 21.4 months). The median duration was 1.8 months (range 8 days to 20.9+ months). Hepatitis led to discontinuation of Keytruda in 6 (0.2%) patients. Hepatitis resolved in 15 patients.

Nephritis.

The median time to onset of nephritis was 5.1 months (range 12 days to 12.8 months). The median duration was 3.3 months (range 12 days to 8.9+ months). Nephritis led to discontinuation of Keytruda in 3 (0.1%) patients. Nephritis resolved in 5 patients. In patients with non-squamous NSCLC treated with pembrolizumab in combination with pemetrexed and platinum chemotherapy (n = 405), the incidence of nephritis was 1.7% (all grades) with 1.0% grade 3 and 0.5% grade 4.

Melanoma.

Advanced melanoma.

Table 4 summarises the adverse events that occurred in at least 10% of patients with melanoma treated with Keytruda in KEYNOTE-006. The most common adverse events (reported in at least 15% of patients) were arthralgia and cough. (See Table 5.)
Table 6 summarises the adverse events that occurred in at least 10% of patients treated with Keytruda in KEYNOTE-002. The most common adverse event (reported in at least 20% of patients) was pruritus. (See Table 7.)
Overall, the safety profile was similar across all doses and between patients previously treated with ipilimumab and patients naïve to treatment with ipilimumab.

Resected melanoma.

Among the 509 patients with resected melanoma treated with adjuvant pembrolizumab in KEYNOTE-054 (mean duration of treatment 9 months), adverse events that were reported in at least 5% of patients, and at least 5% more frequently with pembrolizumab than placebo, were hypothyroidism (14.7% vs 2.8%), hyperthyroidism (10.4% vs 1.2%) and pruritus (19.4% vs 11.6%).
The overall safety profile of pembrolizumab for the adjuvant treatment of melanoma was generally similar to that described for unresectable or metastatic melanoma and NSCLC, with immune-related adverse reactions the predominant significant toxicity. Discontinuation due to adverse events was 14% with adjuvant pembrolizumab treatment, most commonly due to pneumonitis, colitis, and diarrhoea. Compared to placebo, pembrolizumab was associated with increases in grade 3-5 adverse events (31.0% vs. 19.1%) and serious adverse events (25.1% vs. 16.3%). A fatal event of immune-mediated myositis occurred in the pembrolizumab arm.
Among the 969 patients with resected melanoma enrolled in KEYNOTE-716, the adverse reactions were generally similar to those occurring in patients with unresectable or metastatic melanoma and NSCLC.

Non-small cell lung carcinoma (NSCLC).

In combination with chemotherapy for advanced NSCLC.

Table 8 summarises the adverse events that occurred in at least 20% of patients treated with Keytruda, pemetrexed, and platinum chemotherapy in KEYNOTE-189. Adverse events occurring in previously untreated patients with NSCLC receiving Keytruda in combination with carboplatin and either paclitaxel or nab-paclitaxel in KEYNOTE-407 were generally similar to those occurring in patients in KEYNOTE-189 with the exception of alopecia (46%) and arthralgia (21%).

Monotherapy for advanced NSCLC.

Table 9 summarises the adverse events that occurred in at least 10% of previously untreated patients with NSCLC receiving Keytruda in KEYNOTE-042. The most common adverse events (reported in at least 15% of patients) were dyspnoea and cough. Adverse events occurring in previously untreated patients with NSCLC receiving Keytruda in KEYNOTE-024 and previously treated patients in KEYNOTE-010 were generally similar to those occurring in patients in KEYNOTE-042.

Adjuvant therapy for resected NSCLC.

Among the 580 patients with resected NSCLC treated with Keytruda in KEYNOTE-091, the adverse reactions were generally similar to those occurring in other patients with NSCLC receiving Keytruda as monotherapy with the exception of hypothyroidism (21%) and hyperthyroidism (11%).

Neoadjuvant followed by adjuvant therapy for resectable NSCLC.

Adverse events occurring in patients with resectable NSCLC receiving Keytruda in combination with platinum containing chemotherapy, given as neoadjuvant treatment and continued as monotherapy adjuvant treatment in KEYNOTE-671, were generally similar to those occurring in patients in other clinical trials across tumour types receiving Keytruda in combination with chemotherapy. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were not eligible for this study.

Neoadjuvant phase of KEYNOTE-671.

A total of 396 patients received at least 1 dose of Keytruda in combination with platinum-containing chemotherapy as neoadjuvant treatment and 399 patients received at least 1 dose of placebo in combination with platinum-containing chemotherapy as neoadjuvant treatment.
Serious adverse events occurred in 34% of patients who received Keytruda in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥ 2%) serious adverse events were pneumonia (4.8%), venous thromboembolism (3.3%), and anaemia (2%). Fatal adverse events occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%).
Permanent discontinuation of any study drug due to an adverse event occurred in 18% of patients who received Keytruda in combination with platinum-containing chemotherapy as neoadjuvant treatment; the most frequent (≥ 1%) adverse events that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anaemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%).
Of the 396 Keytruda-treated patients and 399 placebo-treated patients who received neoadjuvant treatment, 6% (n = 25) and 4.3% (n = 17), respectively, did not receive surgery due to adverse events. The most frequent (≥ 1%) adverse event that led to cancellation of surgery in the Keytruda arm was interstitial lung disease (1%).
Of the 325 Keytruda-treated patients who received surgery, 3.1% (n = 10) experienced delay of surgery (surgery more than 8 weeks from last neoadjuvant treatment if patient received less than 4 cycles of neoadjuvant therapy or more than 20 weeks after first dose of neoadjuvant treatment if patient received 4 cycles of neoadjuvant therapy) due to adverse events. Of the 317 placebo-treated patients who received surgery, 2.5% (n = 8) experienced delay of surgery due to adverse events.
Of the 325 Keytruda-treated patients who received surgery, 7% (n = 22) did not receive adjuvant treatment due to adverse events. Of the 317 placebo-treated patients who received surgery, 3.2% (n = 10) did not receive adjuvant treatment due to adverse events.

Adjuvant phase of KEYNOTE-671.

A total of 290 patients in the Keytruda arm and 267 patients in the placebo arm received at least 1 dose of adjuvant treatment.
Of the patients who received single agent Keytruda as adjuvant treatment, 14% experienced serious adverse events; the most frequent serious adverse event was pneumonia (3.4%). One fatal adverse event of pulmonary haemorrhage occurred. Permanent discontinuation of adjuvant Keytruda due to an adverse event occurred in 12% of patients; the most frequent (≥ 1%) adverse reactions that led to permanent discontinuation of adjuvant Keytruda were diarrhoea (1.7%), interstitial lung disease (1.4%), AST increased (1%), and musculoskeletal pain (1%).

Head and neck cancer.

The safety of Keytruda, as a single agent and in combination with platinum (cisplatin or carboplatin) and 5-FU chemotherapy, was investigated in KEYNOTE-048, a multicentre, open label, randomised (1:1:1), active controlled trial in patients with previously untreated, recurrent or metastatic HNSCC [see Clinical Studies (14.4)]. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. A total of 576 patients received Keytruda 200 mg every 3 weeks either as a single agent (n = 300) or in combination with platinum and 5-FU (n = 276) every 3 weeks for 6 cycles followed by Keytruda, compared to 287 patients who received cetuximab weekly in combination with platinum and 5-FU every 3 weeks for 6 cycles followed by cetuximab.
The median duration of exposure to Keytruda was 3.5 months (range: 1 day to 24.2 months) in the Keytruda single agent arm and was 5.8 months (range: 3 days to 24.2 months) in the combination arm. Seventeen percent of patients in the Keytruda single agent arm and 18% of patients in the combination arm were exposed to Keytruda for ≥ 12 months. Fifty-seven percent of patients receiving Keytruda in combination with chemotherapy started treatment with carboplatin.
Keytruda was discontinued for adverse reactions in 12% of patients in the Keytruda single agent arm. The most common adverse reactions resulting in permanent discontinuation of Keytruda were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of Keytruda occurred in 31% of patients; the most common adverse reactions leading to interruption of Keytruda (≥ 2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%).
Keytruda was discontinued for adverse reactions in 16% of patients in the combination arm. The most common adverse reactions resulting in permanent discontinuation of Keytruda were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to the interruption of Keytruda occurred in 45% of patients; the most common adverse reactions leading to interruption of Keytruda (≥ 2%) were neutropenia (14%), thrombocytopenia (10%), anaemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%).
Tables 10 and 11 summarise adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-048.

Classical Hodgkin lymphoma.

KEYNOTE-204.

The safety of Keytruda for the treatment of patients with cHL was investigated in KEYNOTE-204, an open-label, randomised, active-controlled trial in which 300 patients received Keytruda 200 mg or brentuximab vedotin (BV) 1.8 mg/kg every 3 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The median duration of exposure to Keytruda was 10.0 months (range: 1 day to 26.7 months). Keytruda was discontinued due to adverse reactions in 14% of patients and treatment was interrupted due to adverse reactions in 30%. Thirty-eight percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 30% of patients receiving Keytruda. The most frequent serious adverse reactions (≥ 1%) included pneumonia, pneumonitis, interstitial lung disease, pyrexia, myocarditis, acute kidney injury, and febrile neutropenia. Three patients died from causes other than disease progression; one from pneumonia, one from hypovolemic shock, and one due to unknown cause. Tables 12 and 13 summarise adverse reactions and laboratory abnormalities, respectively, in patients in KEYNOTE-204.
Clinically relevant adverse reactions in < 10% of patients who received Keytruda included herpes virus infection (9%), pneumonia (8%), oropharyngeal pain (8%), hyperthyroidism (5%), hypersensitivity (4.1%), infusion reactions (3.4%), altered mental state (2.7%), and in 1.4% each, uveitis, myocarditis, thyroiditis, febrile neutropenia, sepsis, and tumour flare.

KEYNOTE-087.

Among the 210 patients with cHL who received Keytruda in KEYNOTE-087 (see Section 5.1 Pharmacodynamic Properties, Clinical trials), the median duration of exposure to Keytruda was 8.4 months (range: 1 day to 15.2 months). Serious adverse reactions occurred in 16% of patients who received Keytruda. Serious adverse reactions that occurred in ≥ 1% of patients included pneumonia, pneumonitis, pyrexia, dyspnoea, graft versus host disease (GVHD) and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock.
Permanent discontinuation of Keytruda due to an adverse reaction occurred in 5% of patients and dosage interruption due to an adverse reaction occurred in 26%. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 14 and 15 summarise adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-087.
Clinically relevant adverse reactions in < 10% of patients who received Keytruda included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each).
Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all grades, 2.4% grade 3-4).

Primary mediastinal B-cell lymphoma.

In patients with PMBCL, a higher incidence of pyrexia (28%) possibly due to B-symptoms, and neutropenia (26%) have been noted. The incidence of grade 3 or 4 neutropenia was 17%, and febrile neutropenia was 2%. A causal relationship with Keytruda has not been established, and the neutropenia may have been due to prior myelotoxic therapy. Other adverse events were generally similar to those occurring in patients with melanoma or NSCLC.

Urothelial carcinoma.

Combination therapy.

The safety of Keytruda in combination with enfortumab vedotin was investigated in KEYNOTE A39 in patients with locally advanced or metastatic urothelial cancer [see Section 5.1 Pharmacodynamic Properties, Clinical trials]. A total of 440 patients received Keytruda 200 mg on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21 day cycle compared to 433 patients who received gemcitabine on Days 1 and 8 and investigator's choice of cisplatin or carboplatin on Day 1 of each 21-day cycle. Among patients who received Keytruda and enfortumab vedotin, the median duration of exposure to Keytruda was 8.5 months (range: 9 days to 28.5 months).
Fatal adverse reactions occurred in 3.9% of patients treated with Keytruda in combination with enfortumab vedotin including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).
Serious adverse reactions occurred in 50% of patients receiving Keytruda in combination with enfortumab vedotin. Serious adverse reactions in ≥ 2% of patients receiving Keytruda in combination with enfortumab vedotin were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhoea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).
Permanent discontinuation of Keytruda occurred in 27% of patients. The most common adverse reactions (≥ 2%) resulting in permanent discontinuation of Keytruda were pneumonitis/ILD (4.8%) and rash (3.4%).
Dose interruptions of Keytruda occurred in 61% of patients. The most common adverse reactions (≥ 2%) resulting in interruption of Keytruda were rash (17%), peripheral neuropathy (7%), COVID-19 (5%), diarrhoea (4.3%), pneumonitis/ILD (3.6%), neutropenia (3.4%), fatigue (3%), alanine aminotransferase increased (2.7%), hyperglycemia (2.5%), pneumonia (2%), and pruritus (2%).
Tables 16 and 17 summarise adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in combination with enfortumab vedotin in KEYNOTE A39.
Clinically relevant adverse reactions (< 20%) include pyrexia (18%), dry skin (17%), vomiting (12%), pneumonitis/ILD (10%), hypothyroidism (10%), blurred vision (6%), infusion site extravasation (2%), and myositis (0.5%).

Cisplatin ineligible patients with urothelial carcinoma (KEYNOTE-052).

The safety of Keytruda was investigated in study KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible. Patients received Keytruda 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression. The median duration of exposure to Keytruda was 2.8 months (range: 1 day to 15.8 months).
The most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, decreased appetite, constipation, rash and diarrhoea. Keytruda was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with Keytruda experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of Keytruda occurred in 22% of patients; the most common (≥ 1%) were liver enzyme increase, diarrhoea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥ 2%) were urinary tract infection, haematuria, acute kidney injury, pneumonia, and urosepsis.
Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose ≥ 40 mg oral prednisone equivalent.
Table 18 summarises the incidence of adverse reactions occurring in at least 10% of patients receiving Keytruda.

Previously treated urothelial carcinoma (KEYNOTE-045).

The safety of Keytruda for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in study KEYNOTE-045. KEYNOTE-045 was a multicentre, open-label, randomised (1:1), active-controlled trial in which 266 patients received Keytruda 200 mg every 3 weeks or investigator's choice of chemotherapy (n = 255), consisting of paclitaxel (n = 84), docetaxel (n = 84) or vinflunine (n = 87) [see Section 5.1 Pharmacodynamic Properties, Clinical trials]. Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients who received Keytruda and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy.
Keytruda was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of Keytruda was pneumonitis (1.9%). Adverse reactions leading to interruption of Keytruda occurred in 20% of patients; the most common (≥ 1%) were urinary tract infection (1.5%), diarrhoea (1.5%), and colitis (1.1%). The most common adverse reactions (occurring in at least 20% of patients who received Keytruda) were fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea and rash. Serious adverse reactions occurred in 39% of Keytruda-treated patients. The most frequent serious adverse reactions (≥ 2%) in Keytruda-treated patients were urinary tract infection, pneumonia, anaemia, and pneumonitis.
Table 19 summarises the incidence of adverse reactions occurring in at least 10% of patients receiving Keytruda. Table 20 summarises the incidence of laboratory abnormalities that occurred in at least 20% of patients receiving Keytruda.

BCG-unresponsive high-risk NMIBC.

The safety of Keytruda was investigated in KEYNOTE-057, a multicentre, open-label, single-arm trial that enrolled 148 patients with high-risk non-muscle invasive bladder cancer (NMIBC), 96 of whom had BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumours. Patients received Keytruda 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression.
The median duration of exposure to Keytruda was 4.3 months (range: 1 day to 25.6 months).
Keytruda was discontinued due to adverse reactions in 10% of patients. The most common adverse (> 1%) reaction resulting in permanent discontinuation of Keytruda was pneumonitis (1.4%). Adverse reactions leading to interruption of Keytruda occurred in 24% of patients; the most common (≥ 2%) were diarrhoea (2%) and urinary tract infection (2%). Serious adverse reactions occurred in 27% of Keytruda-treated patients. The most frequent serious adverse reactions (≥ 2%) in Keytruda-treated patients were pneumonia (3%), colitis (2%), pulmonary embolism (2%), and urinary tract infection (2%). Tables 21 and 22 summarise adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-057.

MSI-H/dMMR cancer.

Adverse events occurring in patients with MSI-H/dMMR cancer, including previously untreated CRC, were generally similar to those occurring in patients with melanoma or NSCLC.

Endometrial carcinoma.

In combination with chemotherapy (KEYNOTE-868/NRG-GY018).

In patients with endometrial carcinoma receiving Keytruda plus chemotherapy (paclitaxel and carboplatin), adverse events were generally similar to those observed with Keytruda alone or chemotherapy alone with the exception of rash maculo-papular (13% all Grades; 2% Grades 3-4).

In combination with lenvatinib (KEYNOTE-775).

The safety of Keytruda in combination with lenvatinib was investigated in KEYNOTE-775, a multicentre, open-label, randomised (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with endometrial carcinoma that is not MSI-H or dMMR received Keytruda 200 mg every 3 weeks in combination with lenvatinib 20 mg orally once daily (n = 342) or received doxorubicin or paclitaxel (n = 325).
For patients with not MSI-H or dMMR tumour status, the median duration of study treatment was 7.2 months (range: 1 day to 26.8 months) and the median duration of exposure to Keytruda was 6.8 months (range: 1 day to 25.8 months).
Fatal adverse reactions among these patients occurred in 4.7% of those treated with Keytruda and lenvatinib, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal haemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.
Serious adverse reactions occurred in 50% of these patients receiving Keytruda and lenvatinib. Serious adverse reactions (≥ 3%) were hypertension (4.4%) and urinary tract infections (3.2%).
Discontinuation of Keytruda due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of Keytruda (≥ 1%) was increased ALT (1.2%).
Dose interruptions of Keytruda due to an adverse reaction occurred in 48% of these patients. The most common adverse reactions leading to interruption of Keytruda (≥ 3%) were: diarrhoea (8%), increased ALT (4.4%), increased AST (3.8%), and hypertension (3.5%).
Tables 23 and 24 summarise adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in combination with lenvatinib in KEYNOTE-775.

Gastric or GOJ adenocarcinoma.

In combination with chemotherapy for gastric or gastroesophageal junction (GOJ) adenocarcinoma (KEYNOTE-859).

The safety of Keytruda was evaluated in 1572 patients with gastric or GOJ cancer enrolled in KEYNOTE-859, which included 785 patients treated with Keytruda 200 mg and FP (n=106) or CAPOX (n=674) every 3 weeks, and 787 patients who received placebo and FP (n=107) or CAPOX (n=679) every 3 weeks [see Section 5.1 Pharmacodynamic Properties, Clinical trials]. Patients with HER2-positive tumours were excluded from this study.
The median duration of exposure to Keytruda was 6.2 months (range: 1 day to 33.7 months).
Serious adverse events occurred in 45% of patients receiving Keytruda. Serious adverse events in > 2% of patients included pneumonia (4.1%), diarrhoea (3.9%), haemorrhage (3.9%), and vomiting (2.4%). Fatal adverse events occurred in 8% of patients receiving Keytruda, including infection (2.3%) and thromboembolism (1.3%). Permanent discontinuation of Keytruda due to adverse reactions occurred in 15% of patients. Adverse reaction resulting in permanent discontinuation of Keytruda in ≥ 1% were infections (1.8%) and diarrhoea (1.0%). Dosage interruptions of Keytruda due to an adverse reaction occurred in 65% of patients. Adverse reactions leading to interruption of Keytruda (≥ 2%) were neutropenia (21%), thrombocytopenia (13%), diarrhoea (5.5%), fatigue (4.8%), infection (4.8%), anaemia (4.5%), increased AST (4.3%), increased ALT (3.8%), increased blood bilirubin (3.3%), white blood cell count decreased (2.2%), nausea (2%), palmar-plantar erythrodysaesthesia syndrome (2%), and vomiting (2%).
The adverse events occurring in at least 20% of patients and with a difference of ≥ 5% incidence between patients treated with Keytruda versus placebo were vomiting (34% vs 27%). Grade 3-5 adverse events were generally similar between arms, except for events consistent with known toxicities of pembrolizumab [see Section 4.4 Special Warnings and Precautions for Use].
The laboratory abnormalities occurring in at least 20% of patients and with a difference of ≥ 5% incidence were lymphopenia (57% vs. 51%), increased AST (57% vs. 48%), increased alkaline phosphatase (48% vs. 41%), increased ALT (40% vs. 29%), hypokalemia (35% vs. 27%), and hypomagnesemia (29% vs. 22%).

In combination with chemotherapy and trastuzumab for HER2-positive gastric or gastroesophageal junction adenocarcinoma (KEYNOTE-811).

The safety of Keytruda was evaluated in 696 patients with HER2-positive gastric or GOJ cancer enrolled in KEYNOTE-811, which included 350 patients treated with Keytruda 200 mg, trastuzumab, and CAPOX (n=297) or FP (n=53) every 3 weeks, compared to 346 patients treated with placebo, trastuzumab, and CAPOX (n=298) or FP (n=48) every 3 weeks [see Section 5.1 Pharmacodynamic Properties, Clinical trials].
The median duration of exposure to Keytruda was 9.1 months (range: 1 day to 30.3 months).
Keytruda was discontinued in 13% of patients and placebo was discontinued in 10% of patients due to adverse events. The most common adverse events resulting in permanent discontinuation of Keytruda were pneumonitis (1.7%), pneumonia (1.1%) and colitis (0.9%). Adverse events leading to interruption of Keytruda occurred in 70% of patients. The most common adverse reactions leading to interruption of Keytruda (≥ 10%) were neutrophil count decreased (12%).
The adverse events occurring in at least 20% of patients and with a difference of ≥ 5% incidence between patients treated with Keytruda versus placebo were diarrhoea (52% vs 46%).
The laboratory abnormalities occurring in at least 20% of patients and with a difference of ≥ 5% incidence between patients treated with Keytruda versus placebo were anaemia (71% vs. 66%), neutropenia (64% vs. 59%), decreased white blood cells (59% vs. 54%), lymphopenia (58% vs. 51%), hypocalcemia (55% vs. 45%), increased blood bilirubin (31% vs. 25%), and increased creatinine (26% vs. 17%). There were no grade 3-4 laboratory abnormalities with an incidence > 2% higher amongst patients treated with Keytruda versus standard of care.

Cervical cancer.

High-risk, locally advanced cervical cancer.

The safety of Keytruda in combination with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) was investigated in KEYNOTE-A18, a placebo-controlled, randomised (1:1), multicentre, double-blind trial including 1058 patients with high-risk, locally advanced cervical cancer. A total of 528 patients received Keytruda in combination with chemoradiotherapy compared to 530 patients who received placebo in combination with chemoradiotherapy.
Keytruda was discontinued for adverse reactions in 9% of patients, with no single adverse reaction accounting for the majority. Serious adverse reactions occurred in 33% of patients receiving Keytruda in combination with chemoradiotherapy. Serious adverse reactions occurring in ≥ 1% of patients included urinary tract infection (3.2%), anaemia (3%), pyrexia (2.7%), diarrhoea (1.9%), hydronephrosis (1.1%), sepsis (1.1%), and vaginal haemorrhage (1.1%). Fatal adverse reactions occurred in 0.9% of patients receiving Keytruda in combination with chemoradiotherapy, including 1 case each (0.2%) of immune-mediated gastritis, large intestinal perforation, urosepsis, sepsis, and vaginal haemorrhage.
Table 25 and Table 26 summarise adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-A18.

Persistent, recurrent, or metastatic cervical cancer.

The safety of Keytruda in combination with chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) with or without bevacizumab was investigated in KEYNOTE-826, a multicentre, double-blind, randomised, placebo-controlled trial in 616 patients with persistent, recurrent, or first-line metastatic cervical cancer (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Keytruda was discontinued due to adverse reactions in 15% of patients and treatment was interrupted due to adverse reactions in 66% of patients. Serious adverse reactions occurred in 50% of patients receiving Keytruda plus chemotherapy, with or without bevacizumab. The most frequently occurring serious adverse reactions (≥ 3%) included febrile neutropenia, urinary tract infection, anaemia, acute kidney injury and sepsis. Fatal adverse reactions were reported in 4.6% of patients receiving Keytruda plus chemotherapy, with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection.
Tables 27 and 28 summarise adverse reactions and laboratory abnormalities, respectively, in patients on Keytruda in KEYNOTE-826.

Renal cell carcinoma.

In combination with axitinib (KEYNOTE-426).

The most common adverse reactions that occurred in at least 20% of previously untreated patients with RCC receiving Keytruda and axitinib in KEYNOTE-426 were diarrhoea, fatigue/ asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation. Incidences of grades 3-5 adverse reactions were 76% for Keytruda combination therapy and 71% for sunitinib alone. See Tables 29 and 30.

In combination with lenvatinib for advanced renal cell carcinoma (KEYNOTE-581).

Table 31 summarises the adverse events that occurred in at least 20% of patients treated with Keytruda and lenvatinib in KEYNOTE-581.

Monotherapy for resected renal cell carcinoma (KEYNOTE-564).

In patients receiving Keytruda as monotherapy for adjuvant treatment of RCC, adverse events were generally similar to those occurring in patients with melanoma or NSCLC.

Cutaneous squamous cell carcinoma (cSCC).

Adverse events occurring in patients with recurrent or metastatic cSCC or LA cSCC were generally similar to those occurring in patients with melanoma or NSCLC.

Oesophageal cancer.

In patients with oesophageal cancer, adverse reactions occurring in at least 20% of patients and at a higher incidence (≥ 2%) of grades 3-5 severity for Keytruda in combination with chemotherapy (cisplatin and 5-FU) compared to placebo and chemotherapy (cisplatin and 5-FU) were: vomiting (7% vs. 5%), stomatitis (6% vs. 3.8%), neutrophil count decreased (24.1% vs 17.3%), and white blood cell count decreased (9.2% vs. 4.9%).

TMB-H cancer.

The safety of Keytruda was investigated in 105 adult patients with TMB-H cancer enrolled in KEYNOTE-158 (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The median duration of exposure to Keytruda was 4.9 months (range: 0.03 to 35.2 months). Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumours who received Keytruda as a single agent.

Triple-negative breast cancer (TNBC).

KEYNOTE-522: Controlled study of neoadjuvant and adjuvant treatment of patients with high risk early stage TNBC.

In patients with high risk early stage TNBC receiving Keytruda in combination with chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide), given as a neoadjuvant treatment and continued as monotherapy adjuvant treatment, adverse events and laboratory abnormalities occurring in at least 20% are presented in Table 32 and Table 33, respectively.

KEYNOTE-355: Controlled study of combination therapy in patients with locally recurrent unresectable or metastatic TNBC.

In patients with TNBC receiving Keytruda in combination with chemotherapy (paclitaxel, nab paclitaxel, or gemcitabine and carboplatin), adverse events and laboratory abnormalities occurring in at least 20% are presented in Table 34 and Table 35, respectively.

Biliary tract carcinoma (BTC).

In patients with BTC receiving Keytruda plus chemotherapy (gemcitabine and cisplatin) in KEYNOTE-966, the median duration of exposure to Keytruda was 6 months (range: 1 day to 28 months). In the Keytruda plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of ≥ 5% incidence in adverse events between patients treated with Keytruda versus placebo for pyrexia (26% vs. 20%), rash (21% vs. 13%), pruritus (15% vs. 10%) and hypothyroidism (9% vs. 2.6%). There were no clinically meaningful differences in incidence of grade 3-4 toxicity between arms. Keytruda was discontinued due to adverse events in 15% of patients. The most common adverse event resulting in permanent discontinuation of Keytruda (≥ 1%) was pneumonitis (1.3%). Adverse events leading to the interruption of Keytruda occurred in 55% of patients. The most common adverse events or laboratory abnormalities leading to interruption of Keytruda (≥ 2%) were decreased neutrophil count (18%), decreased platelet count (10%), anaemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%).

Post-marketing experience.

The following adverse reactions have been identified during post-approval use of Keytruda. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic disorders.

Autoimmune haemolytic anaemia.

Eye disorders.

Vogt-Koyanagi-Harada syndrome.

Gastrointestinal disorders.

Coeliac disease.

Immune system disorders.

Haemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, infusion-related reactions (including cytokine release syndrome).

Musculoskeletal and connective tissue disorders.

Arthritis (including immune-mediated arthritis), Sjogren's syndrome, tenosynovitis, polymyalgia rheumatica and myositis (including polymyositis).

Nervous system disorders.

Optic neuritis.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no information on overdosage with Keytruda. The maximum tolerated dose of Keytruda has not been determined. In clinical trials, patients received up to 10 mg/kg with a similar safety profile to that seen in patients receiving 2 mg/kg.
In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies.
ATC code: L01XC18.

Mechanism of action.

PD-1 is an immune-checkpoint receptor that limits the activity of T lymphocytes in peripheral tissues. The PD-1 pathway is an immune control checkpoint that may be engaged by tumour cells to inhibit active T-cell immune surveillance. Keytruda is a high affinity antibody against PD-1, which exerts ligand blockade of the PD-1 pathway, including PD-L1 and PD-L2, on antigen presenting or tumour cells. By inhibiting the PD-1 receptor from binding to its ligands, Keytruda reactivates tumour-specific cytotoxic T lymphocytes in the tumour microenvironment and reactivates anti-tumour immunity.
In preclinical murine models, combinations of an anti-mouse PD-1 antibody plus a tyrosine kinase inhibitor (TKI) have demonstrated enhanced anti-tumour activity compared to either agent alone.
Based on the modelling of dose/exposure relationships for efficacy and safety for pembrolizumab, there are no clinically significant differences in efficacy and safety between the doses of 200 mg or 2 mg/kg every 3 weeks or 400 mg every 6 weeks.
In peripheral blood of patients who received Keytruda 2 mg/kg every 3 weeks or 10 mg/kg every 2 weeks or 3 weeks, an increased percentage of activated (i.e. HLA-DR+) CD4+ and CD8+ T-cells was observed after treatment at all doses and schedules without an increase in the circulating T-lymphocyte number.

Clinical trials.

Melanoma.

KEYNOTE-006: Controlled trial in melanoma patients naïve to treatment with ipilimumab.

The safety and efficacy of Keytruda were investigated in KEYNOTE-006, a multicentre, controlled, phase III study for the treatment of unresectable or metastatic melanoma in patients who were naïve to ipilimumab and who received no or one prior systemic therapy. Patients were randomised (1:1:1) to receive Keytruda at a dose of 10 mg/kg every 2 (n = 279) or 3 weeks (n = 277) or ipilimumab (n = 278). Randomisation was stratified by line of therapy, ECOG performance status, and PD-L1 expression status. The study excluded patients with autoimmune disease or those receiving immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; and HIV, hepatitis B or hepatitis C infection. Patients with BRAF V600E mutant melanoma were not required to have received prior BRAF inhibitor therapy.
Patients were treated with Keytruda until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Assessment of tumour status was performed at 12 weeks, then every 6 weeks through week 48, followed by every 12 weeks thereafter.
Of the 834 patients in KEYNOTE-006, 60% were male, 44% were ≥ 65 years (median age was 62 years [range 18-89]) and 98% were white. Sixty-six percent had no prior systemic therapies and thus received study therapy as first-line treatment whereas 34% had one prior therapy and thus received study therapy as second-line treatment. Thirty-one percent had an ECOG PS of 1 and 69% had an ECOG PS of 0. Eighty percent of patients were PD-L1 positive (PD-L1 membrane expression in ≥ 1% of tumour and associated immune cells as assessed prospectively by an immunohistochemistry assay with the 22C3 anti-PD-L1 antibody) and 18% were PD-L1 negative. Sixty-five percent of patients had M1c stage, 32% had elevated LDH and 9% had brain metastases. BRAF mutations were reported in 302 (36%) patients. Among patients with BRAF mutant tumours, 139 (46%) were previously treated with a BRAF inhibitor. Baseline characteristics were well-balanced across treatment arms.
The primary efficacy outcome measures were overall survival (OS) and progression free survival (PFS; as assessed by Integrated Radiology and Oncology Assessment [IRO] review using Response Evaluation Criteria in Solid Tumours [RECIST 1.1]). Secondary efficacy outcome measures were overall response rate (ORR) and response duration. Table 36 summarises key efficacy measures.
The final analysis was performed after all patients had at least 21 months of follow-up. The final OS analysis was performed after 383 patient events (119 for Keytruda 10 mg/kg every 3 weeks, 122 for Keytruda 10 mg/kg every 2 weeks and 142 for ipilimumab). The OS HRs vs. ipilimumab were 0.68 (95% CI: 0.53, 0.86; p < 0.001) for patients treated with Keytruda 10 mg/kg every 3 weeks and 0.68 (95% CI: 0.53, 0.87; p < 0.001) for patients treated with Keytruda 10 mg/kg every 2 weeks. The OS rate at 18 months and 24 months were 62% and 55% respectively for Keytruda 10 mg/kg every 3 weeks, 60% and 55% respectively for Keytruda 10 mg/kg every 2 weeks, and 47% and 43% respectively for ipilimumab. At the final analysis, a long-term PFS analysis was performed based on 566 patient events (183 for Keytruda 10 mg/kg every 3 weeks, 181 for Keytruda 10 mg/kg every 2 weeks and 202 for ipilimumab). The PFS HRs vs. ipilimumab were 0.61 (95% CI: 0.50, 0.75) for patients treated with Keytruda 10 mg/kg every 3 weeks and 0.61 (95% CI: 0.50, 0.75) for patients treated with Keytruda 10 mg/kg every 2 weeks. (See Figures 1 and 2.) The percentage of responders with an ongoing response at 18 months was 68% for Keytruda 10 mg/kg every 3 weeks, 71% for Keytruda 10 mg/kg every 2 weeks and 70% for ipilimumab.

Sub-population analysis by BRAF mutation status.

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who were BRAF wild type, BRAF mutant without prior BRAF treatment and BRAF mutant with prior BRAF treatment. The PFS hazard ratios (HRs) (pooled Keytruda [10 mg/kg every 2 or 3 weeks] vs. ipilimumab) were 0.61 (95% CI: 0.49, 0.76) for BRAF wild type, 0.52 (95% CI: 0.35, 0.78) for BRAF mutant without prior BRAF treatment, and 0.76 (95% CI: 0.51, 1.14) for BRAF mutant with prior BRAF treatment. The OS HRs for pooled Keytruda vs. ipilimumab were 0.68 (95% CI: 0.52, 0.88) for BRAF wild type, 0.70 (95% CI: 0.40, 1.22) for BRAF mutant without prior BRAF treatment, and 0.66 (95% CI: 0.41, 1.04) for BRAF mutant with prior BRAF treatment. ORR for pooled Keytruda vs. ipilimumab was 38% vs. 14% for BRAF wild type, 41% vs. 15% for BRAF mutant without prior BRAF treatment, and 24% vs. 10% for BRAF mutant with prior BRAF treatment.

Sub-population analysis by PD-L1 status.

A subgroup analysis was performed as part of the final analysis of KEYNOTE-006 in patients who were PD-L1 positive vs. PD-L1 negative. The PFS HRs (pooled Keytruda [10 mg/kg every 2 or 3 weeks] vs. ipilimumab) were 0.53 (95% CI: 0.44, 0.65) for PD-L1 positive patients and 0.87 (95% CI: 0.58, 1.30) for PD-L1 negative patients. The OS HRs for pooled Keytruda vs. ipilimumab were 0.63 (95% CI: 0.50, 0.80) for PD-L1 positive patients and 0.76 (95% CI: 0.48, 1.19) for PD-L1 negative patients.

KEYNOTE-002: Controlled trial in melanoma patients previously treated with ipilimumab.

The safety and efficacy of Keytruda were investigated in KEYNOTE-002, a multicentre, controlled study for the treatment of unresectable or metastatic melanoma in patients previously treated with ipilimumab and if BRAF V600 mutation positive, a BRAF or MEK inhibitor. Patients were randomised (1:1:1) to receive Keytruda at a dose of 2 (n = 180) or 10 mg/kg (n = 181) every 3 weeks or chemotherapy (n = 179; including dacarbazine, temozolomide, carboplatin, paclitaxel, or carboplatin + paclitaxel). The study excluded patients with autoimmune disease or those receiving immunosuppression; a history of severe or life-threatening immune-mediated adverse reactions from treatment with ipilimumab, defined as any grade 4 toxicity or grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; previous severe hypersensitivity to other monoclonal antibodies; a history of pneumonitis or interstitial lung disease; HIV, hepatitis B or hepatitis C infection.
Patients were treated with Keytruda until disease progression or unacceptable toxicity. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Assessment of tumour status was performed at 12 weeks, then every 6 weeks through week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced independently verified progression of disease after the first scheduled disease assessment were able to crossover and receive 2 mg/kg or 10 mg/kg of Keytruda every 3 weeks in a double-blind fashion.
Of the 540 patients in KEYNOTE-002, 61% were male, 43% were ≥ 65 years (median age was 62 years [range 15-89]) and 98% were white. Eighty-two percent of patients had M1c stage, 73% had at least two and 32% had three or more prior systemic therapies for advanced melanoma. Forty-five percent had an ECOG PS of 1, 40% had elevated LDH and 23% had a BRAF mutated tumour. Baseline characteristics were well-balanced across treatment arms.
The primary efficacy outcome measures were PFS (as assessed by IRO review using RECIST 1.1) and overall survival (OS). Secondary efficacy outcome measures were PFS as assessed by Investigator using RECIST 1.1, ORR and response duration. Table 37 summarises key efficacy measures in patients previously treated with ipilimumab. There was no statistically significant difference between Keytruda and chemotherapy in the final OS analysis that was not adjusted for the potentially confounding effects of crossover. Of the patients randomised to the chemotherapy arm, 55% crossed over and subsequently received treatment with Keytruda.
At the final analysis, a long-term PFS analysis was performed based on 466 PFS events (150 for Keytruda 2 mg/kg every 3 weeks; 144 for Keytruda 10 mg/kg every 3 weeks and 172 for chemotherapy). The PFS HRs vs. chemotherapy were 0.58 (95% CI: 0.46, 0.73) for patients treated with Keytruda 2 mg/kg every 3 weeks and 0.47 (95% CI: 0.37, 0.60 for patients treated with Keytruda 10 mg/kg every 3 weeks (Figure 3).

KEYNOTE-001: Open label study in melanoma patients.

The safety and efficacy of Keytruda were also investigated in an uncontrolled, open-label study for the treatment of unresectable or metastatic melanoma. Efficacy was evaluated for 276 patients from two defined cohorts of KEYNOTE-001, one which included patients previously treated with ipilimumab (and if BRAF V600 mutation-positive, a BRAF or MEK inhibitor) and another with included patients naïve to treatment with ipilimumab. Patients were randomised to receive Keytruda at a dose of 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks. The study excluded patients with autoimmune disease; medical conditions that required immunosuppression; a history of severe immune-mediated adverse reactions with ipilimumab, defined as any grade 4 toxicity requiring treatment with corticosteroids or grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of pneumonitis or interstitial lung disease; or any active infection requiring therapy, including HIV, HBV or HCV. Patients were treated with Keytruda until disease progression that was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status, at the discretion of the investigator, based on clinical judgment. Patients were also discontinued if disease progression was confirmed at 4 to 6 weeks with repeat imaging or unacceptable toxicity.
Of the 89 patients receiving 2 mg/kg of Keytruda who were previously treated with ipilimumab, 53% were male, 33% were ≥ 65 years of age and the median age was 59 years (range 18-88). All but two patients were white. Eighty-four percent of patients had M1c stage and 8% of patients had a history of brain metastases. Seventy-eight percent of patients had at least two and 35% of patients had three or more prior systemic therapies for advanced melanoma. BRAF mutations were reported in 13% of the study population.
Of the 51 patients receiving 2 mg/kg of Keytruda who were naïve to treatment with ipilimumab, 63% were male, 35% were ≥ 65 years of age and the median age was 60 years (range 35-80). All but one patient was white. Sixty-three percent of patients had M1c stage and 2% had a history of brain metastases. Forty-five percent had no prior therapies for advanced melanoma. BRAF mutations were reported in 39% of the study population.
The primary efficacy outcome measure was ORR as assessed by independent review using confirmed responses and RECIST 1.1. Secondary efficacy outcome measures were disease control rate (DCR; including complete response, partial response and stable disease), response duration, PFS, and OS. Tumour response was assessed at 12-week intervals. Table 38 summarises key efficacy measures in patients previously treated or naïve to treatment with ipilimumab, receiving Keytruda based on a minimum follow-up time of 30 months for all patients.
Results for patients previously treated with ipilimumab (n = 84) and naïve to treatment with ipilimumab (n = 52) who received 10 mg/kg of Keytruda every 3 weeks were similar to those seen in patients who received 2 mg/kg of Keytruda every 3 weeks.

KEYNOTE-716: Placebo-controlled trial for the adjuvant treatment of patients with completely resected stage IIB or IIC melanoma.

The efficacy of Keytruda was investigated in KEYNOTE-716, a multicentre, randomised, double-blind, placebo-controlled trial in patients with completely resected stage IIB or IIC melanoma. A total of 976 patients were randomised (1:1) to receive Keytruda 200 mg or the paediatric (≥ 12 years old) dose of Keytruda 2 mg/kg intravenously (up to a maximum of 200 mg) every three weeks (n = 487) or placebo (n = 489) for up to one year until disease recurrence or unacceptable toxicity. Randomisation was stratified by American Joint Committee on Cancer 8th edition (AJCC) T stage. Patients must not have been previously treated for melanoma beyond complete surgical resection for their melanoma prior to study entry. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Patients underwent imaging every 6 months for 1 year from randomisation, every 6 months from years 2 to 4, and then once in year 5 from randomisation or until recurrence, whichever came first.
Among the 976 patients, the baseline characteristics were: median age of 61 years (range: 16 to 87), 39% age 65 or older; 60% male; and 93% ECOG PS of 0 and 7% ECOG PS of 1. Sixty-four percent had stage IIB and 35% had stage IIC.
The primary efficacy outcome measure was investigator-assessed recurrence free survival (RFS) in the whole population, where RFS was defined as the time between the date of randomisation and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first. The secondary outcome measures were distant metastasis-free survival (DMFS) and OS in the whole population. OS was not formally assessed at the time of these analyses.
The trial initially demonstrated a statistically significant improvement in RFS and DMFS for patients randomised to the pembrolizumab arm compared with placebo. Results reported from the pre-specified interim analysis for RFS with a median follow-up of 14.3 months are summarised in Table 39. Results reported from the pre-specified interim analysis for DMFS with a median follow-up of 26.9 months are summarised in Table 39 and Figure 5.
A pre-specified sensitivity analysis of RFS that included new primary melanomas was consistent with the primary RFS analysis, with an HR of 0.64 (95% CI: 0.46, 0.88).
A pre-specified final analysis for RFS performed with a median follow-up of 20.5 months (range: 4.6 to 32.7 months). At the time of this analysis, the hazard ratio in patients randomised to pembrolizumab versus patients randomised to placebo was 0.61 (95% CI: 0.45, 0.82) with 72/487 (14.8%) events and 115/489 (23.5%), respectively. These efficacy results are summarised in Figure 4. Updated RFS results with a median follow-up of 26.9 months were consistent with the final analysis for RFS for patients randomised to the pembrolizumab arm compared with placebo (HR 0.64; 95% CI 0.50, 0.84).

KEYNOTE-054: Placebo-controlled trial for the adjuvant treatment of patients with completely resected stage III melanoma.

The efficacy of Keytruda was evaluated in KEYNOTE-054, a multicentre, randomised double-blind, placebo-controlled trial in patients with completely resected stage IIIA (> 1 mm lymph node metastasis), IIIB or IIIC melanoma. A total of 1019 patients were randomised (1:1) to receive Keytruda 200 mg every three weeks (n = 514) or placebo (n = 505), for up to one year until disease recurrence or unacceptable toxicity. Randomisation was stratified by AJCC stage (IIIA vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC ≥ 4 positive lymph nodes) and geographical region (North America, European countries, Australia and other countries as designated). Patients must have undergone lymph node dissection and if indicated, radiotherapy within 13 weeks prior to starting treatment. Patients with active autoimmune disease or a medical condition that required immunosuppression or mucosal or ocular melanoma were ineligible. Patients underwent imaging every 12 weeks after the first dose of Keytruda for the first two years, then every 6 months from year 3 to 5, and then annually.
Among the 1019 patients, the baseline characteristics were: median age of 54 years (25% age 65 or older); 62% male; ECOG PS of 0 (94%) and 1 (6%). Sixteen percent had stage IIIA; 46% had stage IIIB; 18% had stage IIIC (1-3 positive lymph nodes), and 20% had stage IIIC (≥ 4 positive lymph nodes); 50% were BRAF V600 mutation positive and 44% were BRAF wild-type; 84% had melanoma that was PD-L1 positive defined as a tumour proportion score (TPS) ≥ 1% according to an investigational use only assay.
The primary efficacy outcome was investigator-assessed RFS, measured in the intent-to-treat (ITT) population and in the subgroup with PD-L1 positive tumours. The secondary efficacy outcomes included distant metastasis-free survival (DMFS) and overall survival (OS) in the ITT population and in the subgroup with PD-L1 positive tumours. The OS data were not mature at the time of DMFS analysis. The trial demonstrated a statistically significant improvement in RFS and DMFS for patients randomised to the Keytruda arm compared with placebo. RFS efficacy results with a median follow-up time of 16.0 months are summarised in Table 40 and Figure 6. DMFS efficacy results with a median follow-up time of 45.5 months are summarised in Table 40 and Figure 7.
For patients in the ITT population, the RFS rate at 42 months was 60% in the Keytruda arm and 41% in the placebo arm (HR was 0.59 [95% CI: 0.49, 0.70]).
RFS and DMFS benefit was consistently demonstrated across subgroups, including tumour PD-L1 expression, BRAF mutation status, and stage of disease (using AJCC 7th edition). These results were consistent when reclassified in a post hoc analysis according to the current AJCC 8th edition staging system.
Non-small cell lung cancer (NSCLC).

KEYNOTE-189: Controlled trial of combination therapy in non-squamous NSCLC patients naïve to treatment.

The efficacy of Keytruda in combination with pemetrexed and platinum chemotherapy was investigated in a multicentre, randomised, active-controlled, double-blind trial, KEYNOTE-189. Key eligibility criteria were metastatic non-squamous NSCLC, no prior systemic treatment for metastatic NSCLC, and no EGFR or ALK genomic tumour aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Patients were randomised (2:1) to receive one of the following regimens:
Keytruda 200 mg with pemetrexed 500 mg/m2 and investigator's choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by Keytruda 200 mg and pemetrexed 500 mg/m2 intravenously every 3 weeks.
Placebo with pemetrexed 500 mg/m2 and investigator's choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously every 3 weeks for 4 cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks.
Treatment with Keytruda continued until RECIST 1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of Keytruda was permitted beyond RECIST-defined disease progression by BICR or beyond discontinuation of pemetrexed if the patient was clinically stable and deriving clinical benefit as determined by the investigator. For patients who completed 24 months of therapy or had a complete response, treatment with Keytruda could be reinitiated for disease progression and administered for up to 1 additional year. Assessment of tumour status was performed at week 6 and week 12, followed by every 9 weeks thereafter. Patients receiving placebo plus chemotherapy who experienced independently-verified progression of disease were offered Keytruda as monotherapy.
Among the 616 patients in KEYNOTE-189 (410 patients in the Keytruda combination arm and 206 in the placebo plus chemotherapy arm), baseline characteristics were: median age of 64 years (49% age 65 or older); 59% male; 94% White and 3% Asian; 43% and 56% ECOG performance status of 0 or 1, respectively; 31% with PD-L1 TPS < 1% (using the PD-L1 IHC 22C3 pharmDx Kit); and 18% with treated or untreated brain metastases at baseline. A total of 67 patients in the placebo plus chemotherapy arm crossed over to receive monotherapy Keytruda at the time of disease progression and 18 additional patients received a checkpoint inhibitor as subsequent therapy.
The primary efficacy outcome measures were OS and PFS (as assessed by BICR using RECIST 1.1). Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using RECIST 1.1. The median follow-up time was 10.5 months (range: 0.2 - 20.4 months). Table 41 summarises key efficacy measures.
The final OS analysis was performed at a median duration of follow-up of 18.8 months after 421 patient events (258 for Keytruda combination arm and 163 for the placebo plus chemotherapy arm). Median OS was 22.0 months (95% CI: 19.5, 24.5) for the Keytruda combination arm and 10.6 months (95% CI: 8.7, 13.6) for the placebo plus chemotherapy arm. The OS HR was 0.56 (95% CI: 0.46, 0.69; p < 0.00001). At final analysis, a PFS analysis was performed based on 534 patient events (337 for the Keytruda combination arm and 197 for the placebo plus chemotherapy arm). The median PFS was 9.0 months (95% CI: 8.1, 10.4) for the Keytruda combination arm and 4.9 months (95% CI: 4.7, 5.5) for the placebo plus chemotherapy arm. The PFS HR was 0.49 (95% CI: 0.41, 0.59, p < 0.00001). See Figures 8 and 9.
The ORR at the final analysis was 48% for the Keytruda combination arm and 20% for the placebo plus chemotherapy arm. The median duration of response was 12.5 months (range 1.1+, 34.9+) for the Keytruda combination arm and 7.1 months (range 2.4, 27.8+) for the placebo plus chemotherapy arm. The percentage of patients with ongoing responses based on Kaplan-Meier estimation was 53% at 12 months or longer, in patients who received Keytruda combination therapy, vs. 27% in patients who received placebo plus chemotherapy.
Patient-reported outcomes were assessed using the EORTC QLQ-C30 and EORTC QLQ-LC13. Exploratory analyses of patients receiving pembrolizumab combination therapy showed stable EORTC QLQ-C30 Global Health Status/QoL at week 12 and week 21 vs declines in patients receiving placebo plus chemotherapy. There was a trend toward a prolonged time to deterioration in the EORTC QLQ-LC13/QLQ-C30 endpoint of cough, dyspnoea or chest pain observed for patients receiving pembrolizumab combination therapy.

KEYNOTE-407: Controlled trial of combination therapy in squamous NSCLC patients naïve to treatment.

The efficacy of Keytruda in combination with carboplatin and either paclitaxel or nab-paclitaxel was investigated in study KEYNOTE-407, a randomised, double-blind, multicentre, placebo-controlled study. The key eligibility criteria for this study were metastatic squamous NSCLC, regardless of tumour PD-L1 expression status, and no prior systemic treatment for metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomisation was stratified by tumour PD-L1 expression (TPS < 1% [negative] vs. TPS ≥ 1%), investigator's choice of paclitaxel or nab-paclitaxel, and geographic region (East Asia vs. non-East Asia). Patients were randomised (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion.
Keytruda 200 mg and carboplatin AUC 6 mg/mL/min on day 1 of each 21 day cycle for 4 cycles, and paclitaxel 200 mg/m2 on day 1 of each 21 day cycle for 4 cycles or nab-paclitaxel 100 mg/m2 on days 1, 8 and 15 of each 21 day cycle for 4 cycles, followed by Keytruda 200 mg every 3 weeks. Keytruda was administered prior to chemotherapy on day 1.
Placebo and carboplatin AUC 6 mg/mL/min on day 1 of each 21 day cycle for 4 cycles and paclitaxel 200 mg/m2 on day 1 of each 21 day cycle for 4 cycles or nab-paclitaxel 100 mg/m2 on days 1, 8 and 15 of each 21 day cycle for 4 cycles, followed by placebo every 3 weeks.
Treatment with Keytruda or placebo continued until RECIST 1.1-defined progression of disease as determined by blinded independent central review (BICR), unacceptable toxicity, or a maximum of 24 months. Administration of Keytruda was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Treatment with Keytruda could be reinitiated for subsequent disease progression and administered for up to 1 additional year.
Patients in the placebo arm were offered Keytruda as a monotherapy at the time of disease progression.
Assessment of tumour status was performed every 6 weeks through week 18, every 9 weeks through week 45 and every 12 weeks thereafter. The major efficacy outcome measures were progression-free survival and objective response rate (ORR) as assessed by BICR using RECIST 1.1 and overall survival. An additional efficacy outcome measure was duration of response as assessed by BICR using RECIST 1.1.
A total of 559 patients were randomised: 278 patients to the Keytruda arm and 281 to the placebo arm. The study population characteristics were: median age of 65 years (range: 29 to 88); 55% age 65 or older; 81% male; 77% White; ECOG performance status of 0 (29%) and 1 (71%); and 8% with brain metastases at baseline. Thirty-five percent had tumour PD-L1 expression TPS < 1% [negative]; 19% were from the East Asian region; and 60% received paclitaxel.
In KEYNOTE-407, there was a statistically significant improvement in OS, PFS and ORR in patients randomised to Keytruda in combination with carboplatin and either paclitaxel or nab-paclitaxel compared with patients randomised to placebo with carboplatin and either paclitaxel or nab-paclitaxel (see Table 42).
The final OS analysis was performed at a median duration of follow-up of 14.3 months after 365 patient events (168 for Keytruda combination arm and 197 for placebo plus chemotherapy arm). Median OS was 17.1 months (95% CI: 14.4, 19.9) for the Keytruda combination arm and 11.6 months (95% CI: 10.1, 13.7) for the placebo plus chemotherapy arm. The OS HR was 0.71 (95% CI: 0.58, 0.88; p = 0.0006). At final analysis, a PFS analysis was performed based on 469 patient events (217 for the Keytruda combination arm and 252 for the placebo plus chemotherapy arm). The median PFS was 8.0 months (95% CI: 6.3, 8.4) for the Keytruda combination arm and 5.1 months (95% CI: 4.3, 6.0) for the placebo plus chemotherapy arm. The PFS HR was 0.57 (95% CI: 0.47, 0.69, p < 0.0001). See Figures 10 and 11.
The ORR at the final analysis was 63% for the Keytruda combination arm and 38% for the placebo plus chemotherapy arm. The median duration of response was 8.8 months (range 1.3+, 28.4+) for the Keytruda combination arm and 4.9 months (range 1.3+, 28.3+) for the placebo plus chemotherapy arm. The percentage of patients with ongoing responses based on Kaplan-Meier estimation were 64% and 38% at 6 and 12 months or longer, in patients who received Keytruda combination therapy, vs. 44% and 25% in patients who received placebo plus chemotherapy.

KEYNOTE-042: Controlled trial of NSCLC patients naïve to treatment.

The efficacy of Keytruda was investigated in KEYNOTE-042, a multicentre, randomised, controlled trial conducted in 1274 patients with stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or patients with metastatic NSCLC. Only patients whose tumours expressed PD-L1 (TPS ≥ 1%) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit and who had not received prior systemic treatment for metastatic NSCLC were eligible. Patients with EGFR or ALK genomic tumour aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Patients were randomised (1:1) to receive Keytruda 200 mg every 3 weeks (n = 637) or investigator's choice platinum-containing chemotherapy (n = 637; including pemetrexed + carboplatin or paclitaxel + carboplatin. Patients with non-squamous NSCLC could receive pemetrexed maintenance). Patients were treated with Keytruda until unacceptable toxicity or disease progression. Treatment could continue beyond disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients without disease progression could be treated for up to 24 months. Treatment with Keytruda could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumour status was performed every 9 weeks for the first 45 weeks, and every 12 weeks thereafter.
Among the 1274 patients in KEYNOTE-042, baseline characteristics were: median age 63 years (45% age 65 or older); 71% male; 64% White and 30% Asian: 19% Hispanic or Latino; and 31% and 69% with an ECOG performance status 0 and 1, respectively. Disease characteristics were squamous (39%) and non-squamous (61%); M0 (13%), M1 (87%); and treated brain metastases (6%). Forty-seven percent of patients had TPS ≥ 50%, and 53% had TPS 1 to 49%.
The primary efficacy outcome measure was OS. Secondary efficacy outcome measures were PFS and ORR as assessed by blinded independent central review (BICR) using RECIST 1.1. Table 43 summarises key efficacy measures for the subgroup of patients with TPS ≥ 50% and the entire ITT population (TPS ≥ 1%).
The results of all efficacy outcome measures in the subgroup of patients with PD-L1 TPS ≥ 20% NSCLC were intermediate between the results of those with PD-L1 TPS ≥ 1% and those with PD-L1 TPS ≥ 50%. In a pre-specified exploratory subgroup analysis for patients with TPS 1-49% NSCLC, the median OS was 13.4 months (95% CI: 10.7, 18.2) for the pembrolizumab group and 12.1 months (95% CI: 11.0, 14.0) in the chemotherapy group, with an HR of 0.92 (95% CI: 0.77, 1.11).
In KEYNOTE-042, a higher number of deaths within 4 months of treatment initiation followed by a long-term survival benefit was observed with pembrolizumab monotherapy compared to chemotherapy (see Figure 12).

KEYNOTE-024: Controlled trial of NSCLC patients naïve to treatment.

The efficacy of Keytruda in previously untreated patients with NSCLC was also investigated in KEYNOTE-024, a multicentre, randomised, controlled trial. The study design was similar to that of KEYNOTE-042, except that only patients with metastatic NSCLC whose tumours expressed PD-L1 with TPS of 50% or greater by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit were eligible. Patients with treated brain metastases were eligible if neurologically returned to baseline prior to enrolment and off corticosteroids. Patients were randomised (1:1) to receive Keytruda 200 mg every 3 weeks (n = 154) or investigator's choice platinum-containing chemotherapy (n = 151; including pemetrexed + carboplatin, pemetrexed + cisplatin, gemcitabine + cisplatin, gemcitabine + carboplatin, or paclitaxel + carboplatin. Patients with non-squamous NSCLC could receive pemetrexed maintenance). Patients on chemotherapy who experienced independently-verified progression of disease were able to crossover and receive Keytruda. Assessment of tumour status was performed every 9 weeks.
Among the 305 patients in KEYNOTE-024, baseline characteristics were: median age 65 years (54% age 65 or older); 61% male; 82% White and 15% Asian; and 35% and 65% with an ECOG performance status 0 and 1, respectively. Subjects with ECOG performance status > 1 and subjects with significant organ dysfunction were ineligible. Disease characteristics were squamous (18%) and non-squamous (82%); M1 (99%); and brain metastases (9%).
The primary efficacy outcome measure was PFS as assessed by blinded independent central review (BICR) using RECIST 1.1. Secondary efficacy outcome measures were OS and ORR (as assessed by BICR using RECIST 1.1). Table 44 summarises key efficacy measures for the entire ITT population. See Figure 13.
The final OS analysis was performed at a median follow-up of 25 months after 169 patient events (73 for Keytruda and 96 for chemotherapy). Median OS was 30.0 months (95% CI: 18.3, NA) for Keytruda and 14.2 months (95% CI: 9.8, 19.0) for chemotherapy. The OS HR was 0.63 (95% CI: 0.47, 0.86; p = 0.002). See Figure 14.
The improved benefit as assessed by PFS, OS, ORR, and response duration for Keytruda as compared to chemotherapy in the population studied was associated with improvements in health-related quality of life (HRQoL). The change from baseline to week 15 showed a meaningful improvement in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 global health status/QoL score for patients receiving Keytruda compared to chemotherapy (difference in LS means = 7.82; 95% CI: 2.85, 12.79; two-sided p = 0.002). The time to deterioration in the EORTC QLQ-LC13 composite endpoint of cough, dyspnoea, and chest pain was prolonged for patients receiving Keytruda compared to chemotherapy (HR = 0.66; 95% CI: 0.44, 0.97; two-sided p = 0.029), where deterioration is defined as a confirmed 10-point or greater score decrease from baseline in any one of these three symptoms.

KEYNOTE-010: Controlled trial of NSCLC patients previously treated with chemotherapy.

The efficacy of Keytruda was investigated in KEYNOTE-010, a multicentre, randomised, controlled trial. Key eligibility criteria were advanced NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for ALK or EGFR mutations, and PD-L1 expression TPS of 1% or greater by a clinical trial assay version of the PD-L1 IHC 22C3 pharmDx kit. Patients with autoimmune disease; a medical condition that required immunosuppression; who had received more than 30 Gy of thoracic radiation within the prior 26 weeks; or with untreated brain metastases were ineligible. Patients with treated brain metastases were eligible if neurologically returned to baseline prior to enrolment and off corticosteroids. Patients were randomised (1:1:1) to receive 2 mg/kg (n = 344) or 10 mg/kg (n = 346) of Keytruda every 3 weeks or 75 mg/m2 of docetaxel every 3 weeks (n = 343). Patients were treated with Keytruda until unacceptable toxicity or disease progression, up to a maximum of 35 treatments (24 months). Assessment of tumour status was performed every 9 weeks.
Among the 1033 patients in KEYNOTE-010, baseline characteristics were: median age 63 years (42% age 65 or older); 61% male; 72% White and 21% Asian; and 34% and 66% with an ECOG performance status 0 and 1, respectively. Disease characteristics were squamous (21%) and non-squamous (70%); M1 (91%); brain metastases (15%); and the incidence of genomic aberrations was EGFR (8%) or ALK (1%). Prior therapy included platinum-doublet regimen (100%); patients received one (69%), or two or more (29%) prior therapies.
The primary efficacy outcome measures were OS and PFS as assessed by an independent review committee using RECIST 1.1. Secondary efficacy outcome measures were ORR and response duration. Table 45 summarises key efficacy measures for the entire ITT population (TPS ≥ 1%) and for the subgroup of patients with TPS ≥ 50%. Kaplan-Meier curves for OS (TPS ≥ 1% and TPS ≥ 50%) are shown in Figures 15 and 16.
Efficacy results were similar for the 2 mg/kg and 10 mg/kg Keytruda arms. Efficacy results for OS were consistent regardless of the age of tumour specimen (new versus archival).

Sub-population analysis of patients with 1% ≤ TPS ≤ 49% in KEYNOTE-010.

A subgroup analysis of KEYNOTE-010 in patients with TPS 1-49% was performed. The OS HRs for Keytruda vs. docetaxel were 0.79 (95% CI: 0.61, 1.04) for patients treated with 2 mg/kg every three weeks and 0.71 (95% CI: 0.53, 0.94) for patients treated with 10 mg/kg every 3 weeks. The median OS was 9.4 months (95% CI: 8.7, 10.5), 10.8 months (95% CI: 8.9, 13.3) and 8.6 months (95% CI: 7.8, 9.9) for patients treated with Keytruda 2 mg/kg every three weeks (n = 205), 10 mg/kg every three weeks (n = 195) and docetaxel (n = 191) respectively. The PFS HRs (Keytruda vs. docetaxel) were 1.07 (95% CI: 0.85, 1.34) for patients treated with 2 mg/kg every three weeks and 0.99 (95% CI: 0.78, 1.25) for patients treated with 10 mg/kg every 3 weeks. The median PFS was 3.1 months (95% CI: 2.1, 3.8), 2.3 months (95% CI: 2.1, 4.0) and 3.9 months (95% CI: 2.5, 4.3) for Keytruda 2 mg/kg every three weeks, 10 mg/kg every three weeks and docetaxel, respectively. The ORR was 10% (95% CI: 6, 15), 10% (95% CI: 6, 15) and 10% (95% CI: 7, 16) for Keytruda 2 mg/kg every three weeks, 10 mg/kg every three weeks and docetaxel respectively. Furthermore, the median duration of response was 10.6 months (range: 2.1+, 20.1+), 10.4 months (range: 3.0+, 17.1+) and 6.0 months (range: 1.4+, 7.2) for Keytruda 2 mg/kg every three weeks, 10 mg/kg every three weeks and docetaxel, respectively.

KEYNOTE-671: Controlled trial for the neoadjuvant and adjuvant treatment of patients with resectable NSCLC.

The efficacy of Keytruda in combination with platinum containing chemotherapy given as neoadjuvant treatment and continued as monotherapy adjuvant treatment was investigated in KEYNOTE-671, a multicentre, randomised, double blind, placebo-controlled trial. Key eligibility criteria were previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition, regardless of tumour PD L1 expression. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomisation was stratified by stage (II vs. III), tumour PD L1 expression (TPS ≥ 50% or < 50%), histology (squamous vs. non squamous), and geographic region (East Asia vs. non East Asia).
Patients were randomised (1:1) to one of the following treatment arms:
Treatment arm A: neoadjuvant Keytruda 200 mg on Day 1 in combination with cisplatin 75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine 1000 mg/m2 on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Following surgery, Keytruda 200 mg was administered every 3 weeks for up to 13 cycles.
Treatment arm B: neoadjuvant placebo on Day 1 in combination with cisplatin 75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine 1000 mg/m2 on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Following surgery, placebo was administered every 3 weeks for up to 13 cycles.
All study medications were administered via intravenous infusion. Treatment with Keytruda or placebo continued until completion of the treatment (17 cycles), disease progression that precluded definitive surgery, disease recurrence in the adjuvant phase, disease progression for those who did not undergo surgery or had incomplete resection and entered the adjuvant phase, or unacceptable toxicity. Assessment of tumour status was performed at baseline, Week 7, and Week 13 in the neoadjuvant phase and within 4 weeks prior to the start of the adjuvant phase. Following the start of the adjuvant phase, assessment of tumour status was performed every 16 weeks through the end of Year 3, and then every 6 months thereafter.
The primary efficacy outcome measures were OS and investigator assessed event free survival (EFS). Secondary efficacy outcome measures were pathological complete response (pCR) rate and major pathological response (mPR) rate as assessed by blinded independent pathology review (BIPR).
A total of 797 patients in KEYNOTE-671 were randomised: 397 patients to the Keytruda arm and 400 to the placebo arm. Baseline characteristics were: median age of 64 years (range: 26 to 83), 45% age 65 or older; 71% male; 61% White, 31% Asian, and 2.0% Black. Sixty three percent and 37% had ECOG performance of 0 or 1, respectively; 30% had Stage II and 70% had Stage III disease; 33% had TPS ≥ 50% and 67% had TPS < 50%; 43% had tumours with squamous histology and 57% had tumours with non-squamous histology; 31% were from the East Asian region.
Eighty one percent of patients in the Keytruda in combination with platinum containing chemotherapy arm had definitive surgery compared to 76% of patients in the platinum containing chemotherapy arm.
The key results of KEYNOTE-671 are summarised in Table 46, Figure 17 and Figure 18.
A significant difference in EFS was demonstrated at interim analysis 1 (IA1). EFS analysis was repeated at IA2; after 422 patient events (174 for the Keytruda arm and 248 for the placebo arm). Median EFS at IA2 was 47.2 months (95% CI: 32.9, NR) for the Keytruda arm and 18.3 months (95% CI: 14.8, 22.1) for the placebo arm. The EFS HR at IA2 was 0.59 (95% CI: 0.48, 0.72). The EFS Kaplan-Meier curve for IA2 is presented in Figure 18 rather than the primary EFS analysis.

KEYNOTE-091: Controlled trial for the adjuvant treatment of patients with resected NSCLC.

The efficacy of Keytruda was investigated in KEYNOTE-091, a multicentre, randomised, triple-blind, placebo-controlled trial in patients with completely resected stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC by AJCC 7th edition, regardless of tumour PD-L1 expression status. Patients had not received neoadjuvant radiotherapy or chemotherapy, and no prior or planned adjuvant radiotherapy for the current malignancy. Adjuvant chemotherapy of up to 4 cycles was optional.
Patients were ineligible if they had autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or had a history of interstitial lung disease or pneumonitis.
Randomisation was stratified by stage (IB vs. II vs. IIIA), receipt of adjuvant chemotherapy (yes vs no), PD-L1 status (TPS < 1% [negative] vs. TPS 1-49% vs. TPS ≥ 50%), and geographic region (Western Europe vs. Eastern Europe vs. Asia vs. Rest of World). Patients were randomised (1:1) to receive Keytruda 200 mg or placebo intravenously every 3 weeks.
Treatment continued until RECIST 1.1-defined disease recurrence as determined by the investigator, unacceptable toxicity, or approximately one year (18 doses). Tumours were assessed by imaging every 12 weeks after the first dose of Keytruda for the first year, then every 6 months for years 2 to 3, and then annually up to the end of year 5. After year 5, imaging is performed as per local standard of care. The major efficacy outcome measure was investigator-assessed disease free survival (DFS). An additional efficacy outcome measure was OS.
Of 1177 patients randomised, 1010 (86%) received adjuvant platinum-based chemotherapy following complete resection. Among these 1010 patients, the median age was 64 years (range: 35 to 84), 49% age 65 or older; 68% male; 77% White, 18% Asian; 86% current or former smokers; and 39% with ECOG PS of 1. Eleven percent had Stage IB, 57% had Stage II, and 31% had Stage IIIA disease. Thirty-nine percent had PD-L1 TPS < 1% [negative], 33% had TPS 1 49%, and 28% had TPS ≥ 50%. Fifty-two percent were from Western Europe, 20% from Eastern Europe, 17% from Asia, and 11% from Rest of World.
The trial met its primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population for patients randomised to the Keytruda arm compared to patients randomised to the placebo arm. In an exploratory subgroup analysis of the 167 patients (14%) who did not receive adjuvant chemotherapy, the DFS HR was 1.25 (95% CI: 0.76, 2.05). OS results were not mature with only 42% of pre-specified OS events in the overall population.
Table 47 and Figure 19 summarise the efficacy results for KEYNOTE-091 in patients who received adjuvant chemotherapy.
Head and neck cancer.

KEYNOTE-048: Controlled trial of first-line monotherapy or combination therapy in HNSCC.

The efficacy of Keytruda was investigated in study KEYNOTE-048, a multicentre, randomised, open-label, active-controlled study in patients with metastatic or recurrent HNSCC who had not previously received systemic therapy for recurrent or metastatic disease and who were considered incurable by local therapies. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible for the study. Patients with nasopharyngeal tumours were excluded. Randomisation was stratified by tumour PD-L1 expression (TPS ≥ 50% or < 50%) based on the PD-L1 IHC 22C3 pharmDx kit, HPV status (positive or negative), and ECOG PS (0 vs. 1). A prospective classification of patients' tumour PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx kit was conducted using the tumour specimens used for randomisation. Patients were randomised 1:1:1 to one of the following treatment arms:
Keytruda 200 mg every 3 weeks.
Keytruda 200 mg every 3 weeks, carboplatin AUC 5 mg/mL/min every 3 weeks or cisplatin 100 mg/m2 every 3 weeks, and 5-FU 1000 mg/m2/d 4 days continuous every 3 weeks (maximum of 6 cycles of platinum and 5-FU).
Cetuximab 400 mg/m2 load then 250 mg/m2 once weekly, carboplatin AUC 5 mg/mL/min every 3 weeks or cisplatin 100 mg/m2 every 3 weeks, and 5-FU 1000 mg/m2/d 4 days continuous every 3 weeks (maximum of 6 cycles of platinum and 5-FU).
Treatment with Keytruda continued until RECIST 1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of Keytruda was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumour status was performed at week 9 and then every 6 weeks for the first year, followed by every 9 weeks through 24 months.
A total of 882 patients were randomised; 301 patients to the Keytruda monotherapy arm, 281 patients to the Keytruda plus chemotherapy arm, and 300 patients to the standard treatment arm. The study population characteristics were: median age of 61 years (range: 20 to 94); 36% age 65 or older; 83% male; 73% White and 20% Asian; 61% ECOG PS of 1; and 79% were former/current smokers. Disease characteristics were: 22% HPV positive, 15%, 85%, 43%, and 23% had PD-L1 expression defined as CPS < 1, CPS ≥ 1, CPS ≥ 20, and TPS ≥ 50%, respectively, and 95% had stage IV disease (stage IVa 19%, stage IVb 6%, and stage IVc 70%).
The primary efficacy outcome measures were OS and PFS (assessed by BICR according to RECIST 1.1). ORR, as assessed by BICR according to RECIST 1.1, was a secondary outcome measure. The trial demonstrated a statistically significant improvement in OS for patients randomised to Keytruda in combination with chemotherapy compared to standard treatment. A statistically significant improvement in OS was also demonstrated for patients with PD-L1 CPS ≥ 1 randomised to Keytruda as monotherapy compared with cetuximab in combination with chemotherapy. Tables 48 and 49 and Figures 20 and 21 describe key efficacy results for Keytruda in KEYNOTE-048.
In KEYNOTE-048, OS HRs for patients randomised to Keytruda in combination with chemotherapy, compared with cetuximab in combination with chemotherapy, were similar for all populations regardless of PD-L1 expression in a pre-specified interim analysis: ITT (HR 0.77, 95% CI: 0.63, 0.93), CPS ≥ 1 (HR 0.71, 95% CI: 0.57, 0.88), CPS ≥ 20 (HR 0.69, 95% CI: 0.51, 0.94). A positive association was observed between increasing PD-L1 expression and treatment benefit. The trial also demonstrated a statistically significant improvement in OS for the patients expressing PD-L1 CPS ≥ 1 and CPS ≥ 20. The OS HRs at final analysis were CPS ≥ 1 (0.65, 95% CI: 0.53, 0.80), CPS ≥ 20 (0.60, 95% CI: 0.45, 0.82).
Additional OS analyses based on PD-L1 expression (CPS ≥ 1 and CPS ≥ 20) were performed in KEYNOTE-048. The trial demonstrated a statistically significant improvement in OS at the protocol-specified interim analysis for patients randomised to Keytruda monotherapy compared to standard treatment for PD-L1 expression CPS ≥ 1 and CPS ≥ 20. OS for patients who had PD-L1 CPS ≥ 1 or CPS ≥ 20 for Keytruda monotherapy compared to standard treatment is summarised in Table 50.

KEYNOTE-040: Controlled trial in HNSCC patients previously treated with platinum-containing chemotherapy.

The efficacy of Keytruda was investigated in KEYNOTE-040, a multicentre, open-label, randomised, active-controlled study for the treatment of recurrent or metastatic HNSCC in patients with disease progression who received prior platinum-containing chemotherapy. The study excluded patients with active autoimmune disease that required systemic therapy within 2 years of treatment, a medical condition that required immunosuppression, or who were previously treated with 3 or more systemic regimens for recurrent and/or metastatic HNSCC.
Patients were stratified by PD-L1 expression, HPV status and ECOG performance status and then randomised (1:1) to receive either Keytruda 200 mg every 3 weeks (n = 247) or one of three standard treatments (n = 248): methotrexate 40 mg/m2 once weekly (n = 64), docetaxel 75 mg/m2 once every 3 weeks (n = 99), or cetuximab 400 mg/m2 loading dose and then 250 mg/m2 once weekly (n = 71). Patients were treated with Keytruda for up to 24 months or until unacceptable toxicity or disease progression. Treatment could continue beyond progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Assessment of tumour status was performed at 9 weeks, then every 6 weeks through week 52, followed by every 9 weeks through 24 months.
Among the 495 randomised patients in KEYNOTE-040, the baseline characteristics included: median age 60 years (33% age 65 or older); 83% male; 84% White, 6% Asian, and 2% Black; and 28% and 72% with an ECOG performance status 0 or 1, respectively. Disease characteristics were: HPV positive (24%) and PD-L1 expression defined as CPS < 1 (20%), CPS ≥ 1 (79%) and TPS ≥ 50% (26%). Seventy-one percent (71%) of patients had M1 disease and the majority had stage IV disease (stage IV 33%, stage IVa 11%, stage IVb 5%, and stage IVc 45%). Fifteen percent (15%) had disease progression following platinum-containing neoadjuvant or adjuvant chemotherapy, and 84% had received 1-2 prior systemic regimens for metastatic disease.
The primary efficacy outcome was OS. There was no statistically significant difference between Keytruda and standard treatment. Secondary efficacy outcome measures were PFS, ORR, and duration of response (as assessed by BICR using RECIST 1.1). Efficacy measures for KEYNOTE-040 for the CPS ≥ 1 population are summarised in Table 51, and the Kaplan-Meier curve for OS is shown in Figure 22.
Classical Hodgkin lymphoma.

KEYNOTE-204: Controlled study in patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYNOTE-204 was a randomised, open-label, active controlled trial conducted in 304 patients with relapsed or refractory cHL. Patients with active, non-infectious pneumonitis, an allogeneic HSCT within the past 5 years (or > 5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Randomisation was stratified by prior auto-SCT (yes vs. no) and disease status after frontline therapy (primary refractory vs. relapse less than 12 months after completion vs. relapse 12 months or more after completion). Patients were randomised (1:1) to one of the following treatment arms:
Keytruda 200 mg intravenously every 3 weeks;
brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks.
Patients received Keytruda 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Disease assessment was performed every 12 weeks. The major efficacy outcome measures were PFS and ORR as assessed by BICR according to the 2007 revised International Working Group (IWG) criteria.
Among KEYNOTE-204 patients, the baseline characteristics were median age 35 years (16% age 65 or older); 57% male; 77% White; and 61% and 38% had an ECOG performance status 0 and 1, respectively. The median number of prior lines of therapy administered for the treatment of cHL was 2 (range 1 to 11). Forty-two percent were refractory to the last prior therapy and 29% had primary refractory disease. Thirty-seven percent had undergone prior auto-HSCT, 5% had received prior BV, and 39% had prior radiation therapy.
In the ITT population, the median follow-up time for 151 patients treated with pembrolizumab was 24.9 months (range: 1.8 to 42.0 months). The initial analysis resulted in a HR for PFS of 0.65 (95% CI: 0.48, 0.88) with a one-sided p value of 0.0027. The ORR was 66% for pembrolizumab compared to 54% for standard treatment with a p-value of 0.0225. Table 52 summarises the efficacy results in a subpopulation consisting of 112 patients who failed a transplant before enrolling and 137 who failed 2 or more prior therapies and were ineligible for ASCT at the time of enrolment; 124 patients received pembrolizumab and 125 patients received BV. Efficacy results in this subpopulation were consistent with the ITT population. The Kaplan-Meier curve for PFS for this subpopulation is shown in Figure 23.
Patient-reported outcomes (PROs) were assessed using EORTC QLQ-C30. A prolonged time to deterioration in EORTC QLQ C30 global health status/QoL was observed for patients treated with pembrolizumab compared to BV (HR 0.40; 95% CI: 0.22-0.74). Over 24 weeks of follow-up, patients treated with pembrolizumab had an improvement in global health status/QoL compared to BV which showed a decline (difference in Least Square (LS) means = 8.60; 95% CI: 3.89, 13.31; nominal two-sided p = 0.0004). These results should be interpreted in the context of the open-label study design and therefore taken cautiously.

KEYNOTE-013 and KEYNOTE-087: Open-label studies in patients with refractory classical Hodgkin lymphoma, or those who have relapsed after 3 or more prior lines of therapy.

The efficacy of Keytruda was investigated in 241 patients with refractory classical Hodgkin Lymphoma, or who have relapsed after 3 or more prior lines of therapy, enrolled in two multicentre, nonrandomised, open-label studies (KEYNOTE-013 and KEYNOTE-087). Both studies included patients regardless of PD-L1 expression. Patients with active, non-infectious pneumonitis, an allogeneic haematopoietic stem cell transplant within the past 5 years (or greater than 5 years but with GVHD), active autoimmune disease or a medical condition that required immunosuppression were ineligible for either trial. Patients received Keytruda 10 mg/kg every 2 weeks (n = 31) or 200 mg every 3 weeks (n = 210) until unacceptable toxicity or documented disease progression. Response was assessed using the revised lymphoma criteria by PET CT scans, with the first planned post-baseline assessment at week 12. The major efficacy outcome measures (ORR, CRR, and duration of response) were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria. Secondary efficacy outcome measures were PFS and OS.
Among KEYNOTE-013 patients, the baseline characteristics were median age 32 years (6% age 65 or older), 58% male, 94% White; and 45% and 55% had an ECOG performance status 0 and 1, respectively. The median number of prior lines of therapy administered for the treatment of cHL was 5 (range 2 to 15). Eighty-seven percent were refractory to at least one prior therapy, including 39% who were refractory to first line therapy. Seventy-four percent of patients had received Auto-SCT, 26% were transplant ineligible; and 42% of patients had prior radiation therapy.
Among KEYNOTE-087 patients, the baseline characteristics were median age 35 years (9% age 65 or older); 54% male; 88% White; and 49% and 51% had an ECOG performance status 0 and 1, respectively. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range 1 to 12). Eighty-one percent were refractory to at least one prior therapy, including 34% who were refractory to first line therapy. Sixty-one percent of patients had received Auto-SCT, 38% were transplant ineligible; 17% had no prior brentuximab vedotin use; and 37% of patients had prior radiation therapy.
Efficacy results are summarised in Table 53.
The improved benefit as assessed by ORR, CRR, and response duration in the KEYNOTE-087 population was accompanied by overall improvements in health-related quality of life (HRQoL) as assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the European Quality of Life Five Dimensions Questionnaire (EQ-5D). Relative to subjects with stable disease or progressive disease, subjects with a complete or partial response had the largest improvement and the highest proportion with a 10 point or greater increase in their EORTC QLQ-C30 global health status/QoL score, as well as, had the largest improvement in their EQ-5D utility and VAS scores from baseline to week 12.
Primary mediastinal B-cell lymphoma.

KEYNOTE-170: Open-label study in patients with relapsed or refractory PMBCL.

The efficacy of Keytruda was investigated in KEYNOTE-170, a multicentre, open-label, single-arm trial in 53 patients with relapsed or refractory PMBCL. Patients with active, non-infectious pneumonitis, an allogeneic HSCT within the past 5 years (or greater than 5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Patients received Keytruda 200 mg every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients that did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, CRR, PFS, and duration of response) were assessed by blinded independent central review according to the 2007 revised IWG criteria.
Among the 53 patients, the baseline characteristics were: median age 33 years (range: 20 to 61 years), 43% male; 92% White; 43% had an ECOG performance status (PS) of 0 and 57% had an ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of PMBCL was 3 (range 2 to 8). Seventy-seven percent were refractory to the last prior therapy, 40% had primary refractory disease, and 89% had disease that was chemo-refractory to any prior regimen. Twenty-six percent of patients had undergone prior auto-HSCT, 74% did not receive prior transplant; and 32% of patients had prior radiation therapy.
Efficacy results for KEYNOTE-170 are summarised in Table 54.
Urothelial carcinoma.

KEYNOTE-A39: Controlled trial of combination therapy with enfortumab vedotin in urothelial carcinoma patients.

The efficacy of Keytruda in combination with enfortumab vedotin was investigated in KEYNOTE A39, an open-label, multicenter, randomised, active-controlled trial that enrolled 886 platinum eligible patients with locally advanced or metastatic urothelial carcinoma. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression, active CNS metastases, ongoing sensory or motor neuropathy Grade ≥ 2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥ 8% or HbA1c ≥ 7% with associated diabetes symptoms. Patients were considered cisplatin-ineligible if they had at least one of the following criteria: glomerular filtration rate 30-59 mL/min, ECOG PS ≥ 2, Grade ≥ 2 hearing loss, or NYHA Class III heart failure. Patients randomised to the gemcitabine and platinum-based chemotherapy arm were permitted to receive maintenance immunotherapy. Randomisation was stratified by cisplatin eligibility (eligible or ineligible), PD-L1 expression [high (CPS ≥ 10) or low (CPS < 10)], and liver metastases (present or absent). Patients were randomised (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion.
Keytruda 200 mg over 30 minutes on Day 1 and enfortumab vedotin 1.25 mg/kg on Days 1 and 8 of each 21-day cycle.
Gemcitabine 1000 mg/m2 on Days 1 and 8 and investigator's choice of cisplatin 70 mg/m2 or carboplatin (AUC 4.5 or 5 mg/mL/min according to local guidelines) on Day 1 of each 21-day cycle.
Treatment with Keytruda and enfortumab vedotin continued until RECIST v1.1-defined progression of disease, unacceptable toxicity or, for Keytruda, a maximum of 35 cycles (up to approximately 2 years). Treatment was permitted beyond RECIST v1.1 defined disease progression if the treating investigator considered the patient to be deriving clinical benefit and the treatment was tolerated. Assessment of tumour status was performed every 9 weeks for 18 months and then every 12 weeks thereafter. The major efficacy outcome measures were PFS as assessed by BICR according to RECIST v1.1 and OS. Additional outcome measures included ORR and DoR as assessed by BICR according to RECIST v1.1.
The median age was 69 years (range 22 to 91); 77% were male; and 67% were White. Ninety five percent had M1 disease, and 5% had M0 disease. Seventy three percent had a primary tumour in the lower tract, and 27% of patients had a primary tumour in the upper tract. Fifty four percent were cisplatin-eligible, 58% were PD L1 high, and 72% of patients had visceral metastases, including 22% with liver metastases. Twenty percent had normal renal function, and 37%, 41% and 2% were characterised with mild, moderate, or severe renal impairment, respectively. Ninety seven percent had ECOG PS of 0 1 and 3% had ECOG PS of 2. Eighty five percent of patients had transitional cell carcinoma (TCC) histology, 2% had TCC with other histology, and 6% had TCC with squamous differentiation.
Thirty-two percent of patients receiving Keytruda in combination with enfortumab vedotin went on to receive subsequent cancer-related therapies, compared to 70% in the gemcitabine and platinum-based chemotherapy arm. Thirty-two percent of patients in the gemcitabine and platinum-based chemotherapy arm received maintenance immunotherapy, and 26% received immunotherapy as first subsequent therapy after disease progression.
The trial demonstrated a statistically significant improvement in OS, PFS, and ORR in patients randomised to Keytruda in combination with enfortumab vedotin compared with patients randomised to gemcitabine and platinum based chemotherapy. Efficacy results were consistent across all pre-specified patient subgroups.
The median follow-up time for 442 patients treated with Keytruda and enfortumab vedotin was 17.3 months (range: 0.3 to 37.2 months). Efficacy results are summarised in Table 55 and Figure 24 and Figure 25.

KEYNOTE-052: Open label trial in urothelial carcinoma patients ineligible for cisplatin-containing chemotherapy.

The efficacy of Keytruda was investigated in KEYNOTE-052, a multicentre, open-label single-arm trial of patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients with creatinine clearance ≥ 30 mL/min were eligible for treatment. Patients with an ECOG higher than 2, autoimmune disease or a medical condition that required immunosuppression were ineligible for treatment.
Patients received Keytruda 200 mg every 3 weeks until unacceptable toxicity or disease progression. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumour status was performed at 9 weeks after the first dose, then every 6 weeks through the first year, followed by every 12 weeks thereafter. The primary efficacy outcome measure was ORR according to RECIST 1.1 and a secondary efficacy outcome measure was duration of response. Efficacy is reported for patients who had the opportunity for at least 2 post-baseline scans representing at least 4 months of follow-up.
Among 370 patients with urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy, baseline characteristics were: median age 74 years (82% age 65 or older); 77% male; and 89% White and 7% Asian. Eighty-eight percent had M1 disease, 12% had M0 disease. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Reasons for cisplatin ineligibility included: baseline creatinine clearance of < 60 mL/min (50%), ECOG performance status of 2 (32%), ECOG performance status of 2 and baseline creatinine clearance of < 60 mL/min (9%), and other (class III heart failure, grade 2 or greater peripheral neuropathy, and grade 2 or greater hearing loss; 9%). Ninety percent of patients were treatment naïve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy. Eighty-one percent had a primary tumour in the lower tract, and 19% of patients had a primary tumour in the upper tract.
At a pre-specified interim analysis, the median follow-up time for 370 patients treated with Keytruda was 11.5 months. Efficacy results are summarised in Table 56.
The final ORR analysis was performed 9.9 months after the interim analysis with 106 ORR events for all patients [median follow-up of 11.4 months (range: 0.1, 41.2 months)]. ORR was 29% (95% CI: 24, 34) and 47% (95% CI: 38, 57), respectively, for all subjects and subjects with CPS ≥ 10. The complete and partial response rates were 9% and 20%, respectively, in all subjects and 20% and 27%, respectively, in subjects with CPS ≥ 10. At the final analysis among the responding patients, the median response duration was 30.1 months (range 1.4+ to 35.9+ months) in all subjects (n = 106) and not reached (range 1.4+ to 35.4+ months) in subjects with CPS ≥ 10 (n = 52). Responses of 6 months or longer (based on Kaplan-Meier estimation) were 81% and 82%, respectively for all subjects and subjects with CPS ≥ 10.

KEYNOTE-361: Controlled trial in previously untreated urothelial carcinoma patients.

The efficacy of Keytruda for the first-line treatment of platinum-eligible patients with locally advanced or metastatic urothelial carcinoma was investigated in KEYNOTE-361, a multicentre, randomised, open-label, active-controlled study in 1,010 previously untreated patients. The safety and efficacy of Keytruda in combination with platinum-based chemotherapy for previously untreated patients with locally advanced or metastatic urothelial carcinoma has not been established.
The study compared Keytruda with or without platinum-based chemotherapy (i.e. cisplatin or carboplatin with gemcitabine) to platinum-based chemotherapy alone. Among the patients receiving Keytruda plus platinum-based chemotherapy, 44% received cisplatin and 56% received carboplatin.
The study did not meet its primary efficacy outcome measures of improved PFS or OS in the Keytruda plus chemotherapy arm compared to the chemotherapy-alone arm. Additional efficacy endpoints, including improvement of OS in the Keytruda monotherapy arm, could not be formally tested.

KEYNOTE-045: Controlled trial in urothelial carcinoma patients previously treated with platinum-containing chemotherapy.

The efficacy of Keytruda was evaluated in KEYNOTE-045, a multicentre, randomised (1:1), active-controlled trial in patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. Patients with creatinine clearance ≥ 30 mL/min, were eligible for treatment. Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for treatment.
Patients were randomised to receive either Keytruda 200 mg every 3 weeks (n = 270) or investigator's choice of any of the following chemotherapy regimens all given intravenously every 3 weeks (n = 272): paclitaxel 175 mg/m2 (n = 84), docetaxel 75 mg/m2 (n = 84), or vinflunine 320 mg/m2 (n = 87). Patients received Keytruda until unacceptable toxicity or disease progression. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Patients without disease progression were treated for up to 24 months. While this trial permitted re-initiation of treatment with pembrolizumab for subsequent disease progression and administration for up to 1 additional year, due to limited data at the time of data cutoff any benefit remains unknown. Assessment of tumour status was performed at 9 weeks after randomisation, then every 6 weeks through the first year, followed by every 12 weeks thereafter. The primary efficacy outcomes were OS and PFS as assessed by BICR per RECIST v1.1. Secondary efficacy outcome measures were ORR as assessed by BICR per RECIST v1.1 and duration of response.
Among the 542 randomised patients, the study population characteristics were: median age 66 years (range: 26 to 88), 58% age 65 or older; 74% male; 72% White and 23% Asian; 42% ECOG PS of 0, 56% ECOG PS of 1, < 2% of patients were ECOG PS of 2 with no patients ECOG PS > 2; and 96% M1 disease and 4% M0 disease. Eighty-seven percent of patients had visceral metastases, including 34% with liver metastases. Eighty-six percent had a primary tumour in the lower tract and 14% had a primary tumour in the upper tract. Fifteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy as the most recent line of therapy. Twenty-one percent had received 2 or more prior systemic regimens in the metastatic setting. Seventy-six percent of patients received prior cisplatin, 23% had prior carboplatin, and 1% were treated with other platinum-based regimens.
At a pre-specified interim analysis, the median follow-up time for 270 patients treated with Keytruda was 10.3 months. The study demonstrated statistically significant improvements in OS and ORR for patients randomised to Keytruda as compared to chemotherapy where the ORR for patients on Keytruda was approximately two-fold greater than those on chemotherapy alone (21% versus 11%, p = 0.001) (Table 57). There was no statistically significant difference between Keytruda and chemotherapy with respect to PFS. Efficacy results are summarised in Table 57.
At the interim analysis, median duration of response was not reached in the Keytruda arm (range 1.6+ to 15.6+ months) and was 4.3 months (range: 1.4+ to 15.4+ months) in the chemotherapy arm. At the time of the analysis, responses were ongoing in 41 and 14 patients at 6 and 12 months, respectively, in the Keytruda arm, and 7 and 3 patients at 6 and 12 months, respectively, in the chemotherapy arm.
The final OS analysis was performed 13.6 months after the interim analysis with 419 patient events (200 for Keytruda and 219 for chemotherapy). Median OS was 10.1 months (95% CI: 8.0, 12.3) for Keytruda and 7.3 months (95% CI: 6.1, 8.1) for chemotherapy. The OS HR was 0.70 (95% CI: 0.57, 0.85; p < 0.001). See Figure 26. In the final analysis there was no statistically significant difference between Keytruda and chemotherapy with respect to PFS.
At the final analysis, among the 57 responding patients who received Keytruda vs. 30 responding patients who received chemotherapy, the median response duration was not reached (range 1.6+ to 30.0+ months) in patients who received Keytruda, vs. 4.4 months (range 1.4+ to 29.9+ months) in patients who received chemotherapy. In patients who received Keytruda, 84% had responses of 6 months or longer and 68% had responses of 12 months or longer (based on Kaplan-Meier estimation) vs. 47% who had responses of 6 months or longer and 35% who had responses of 12 months or longer (based on Kaplan-Meier estimation) in patients who received chemotherapy. The complete and partial response rates were 9% and 12%, respectively in patients who received Keytruda vs. 3% and 8%, respectively in patients who received chemotherapy.
Patient-reported outcomes (PROs) were assessed using EORTC QLQ-C30. A prolonged time to deterioration in EORTC QLQ-C30 global health status/QoL was observed for patients treated with pembrolizumab compared to investigator's choice chemotherapy (HR 0.70; 95% CI 0.55-0.90). Over 15 weeks of follow-up, patients treated with pembrolizumab had stable global health status/QoL, while those treated with investigator's choice chemotherapy had a decline in global health status/QoL. These results should be interpreted in the context of the open-label study design and therefore taken cautiously.
In KEYNOTE-045, a higher number of deaths within 2 months was observed in pembrolizumab compared to chemotherapy, followed by a long-term survival benefit (see Figure 26). Factors associated with early deaths were fast progressive disease on prior platinum therapy and liver metastases.

KEYNOTE-057: BCG-unresponsive high-risk non-muscle invasive bladder cancer.

The efficacy of Keytruda was investigated in KEYNOTE-057, a multicentre, open-label, single-arm trial in 96 patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in-situ (CIS) with or without papillary tumours who are ineligible for or have elected not to undergo cystectomy. BCG-unresponsive high-risk NMIBC is defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumour-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Prior to treatment, all patients had received adequate BCG therapy, had undergone recent cystoscopic procedure(s) and transurethral resection of bladder tumour (TURBT) to remove all resectable disease (Ta and T1 components) and assure the absence of muscle invasive disease. Residual CIS (Tis components) not amenable to complete resection was acceptable. The trial excluded patients with muscle invasive (i.e. T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma, concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium, autoimmune disease or a medical condition that required immunosuppression.
Patients received Keytruda 200 mg every 3 weeks until progressive disease, unacceptable toxicity, persistent high-risk NMIBC at 12 week cystoscopy, recurrent high-risk NMIBC (low grade Ta recurrence could be treated by repeat TURBT instead of ceasing Keytruda). Assessment of tumour status was performed every 12 weeks, and patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography [CTU] imaging) and duration of response. Patients who have completed a minimum of 18 months of treatment with Keytruda and who have remained without evidence of disease at 2 or more consecutive 3-monthly evaluation visits were permitted to electively discontinue treatment.
The study population characteristics were: median age 73 years (69% age 65 or older); 84% male; 67% White; and 73% and 27% with an ECOG performance status of 0 or 1, respectively. Tumour pattern at study entry was CIS with T1 (13%), CIS with high grade TA (25%), and CIS (63%). Baseline high-risk NMIBC disease status was 27% persistent and 73% recurrent. The median number of prior instillations of BCG was 12.
The median follow-up time was 28.0 months (range: 4.6 to 40.5 months). Efficacy results are summarised in Table 58.
At the time of analysis, among the 96 patients there were no occurrences of progression to muscle-invasive disease (T2) or metastatic bladder cancer while on Keytruda.
Microsatellite instability-high (MSI-H) cancer.

KEYNOTE-164, KEYNOTE-158, and KEYNOTE-051: open-label studies in patients with MSI-H, or dMMR cancer.

The efficacy of Keytruda was investigated in 504 patients with MSI-H or dMMR cancer enrolled in three multicentre, non-randomised, open-label, multi-cohort studies (KEYNOTE-164, KEYNOTE-158, and KEYNOTE-051). All studies excluded patients with autoimmune disease or a medical condition that required immunosuppression. Regardless of histology, MSI or MMR tumour status was determined using polymerase chain reaction (PCR) or immunohistochemistry (IHC), respectively.
KEYNOTE-164 enrolled 124 patients with advanced MSI-H or dMMR colorectal cancer (CRC) that progressed following treatment with a fluoropyrimidine and either oxaliplatin or irinotecan +/- anti-VEGF/EGFR mAb-based therapy.
KEYNOTE-158 enrolled 373 patients with advanced MSI-H or dMMR non-colorectal cancer (non-CRC) who had disease progression following prior therapy.
KEYNOTE-051 enrolled 7 paediatric patients with MSI-H or dMMR cancers.
Adult patients received Keytruda 200 mg every 3 weeks (paediatric patients received 2 mg/kg every 3 weeks) until unacceptable toxicity or disease progression. Clinically stable patients with initial evidence of disease progression were permitted to remain on treatment until disease progression was confirmed. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. In KEYNOTE-164 and KEYNOTE-158, assessment of tumour status was performed every 9 weeks through the first year, then every 12 weeks thereafter. In KEYNOTE-051, assessment of tumour status was performed every 8 weeks for 24 weeks, and then every 12 weeks thereafter. The major efficacy outcome measures were ORR and duration of response as assessed by BICR according to RECIST 1.1 and as assessed by the investigator according to RECIST 1.1 in KEYNOTE-051.
In KEYNOTE-164 and KEYNOTE-158, the baseline characteristics were: median age of 60 years (36% age 65 or older); 44% male; 78% White, 14% Asian; and ECOG PS 0 (45%) and 1 (55%). Ninety-two percent of patients had M1 disease and 4% had M0 disease. Thirty-seven percent of patients received one prior line of therapy and 61% received two or more prior lines of therapy.
In KEYNOTE-051, the baseline characteristics were: median age of 11 years (range: 3 to 16); 71% female; 86% White and 14% Asian; and 57% had a Lansky/Karnofsky Score of 100. Seventy-one percent of patients had Stage IV and 14% had Stage III disease. Fifty-seven percent of patients received one prior line of therapy and 29% received two prior lines of therapy.
The median follow-up time for 497 adult and 7 paediatric patients treated with Keytruda was 20.5 months and 5.2 months, respectively. Efficacy results are summarised in Table 59 and Table 60.
Among the 7 paediatric patients from KEYNOTE-051 (6 with brain cancer, 1 with abdominal adenocarcinoma), 1 patient with brain cancer had a response per irRECIST.

KEYNOTE-177: Controlled trial for first-line treatment of patients with MSI-H or dMMR CRC.

The efficacy of Keytruda was investigated in KEYNOTE-177, a multicentre, randomised, open-label, active-controlled trial that enrolled 307 patients with previously untreated metastatic MSI-H or dMMR CRC. MSI or MMR tumour status was determined locally using polymerase chain reaction (PCR) or immunohistochemistry (IHC), respectively. Patients with autoimmune disease, or a medical condition that required immunosuppression were ineligible.
Patients were randomised (1:1) to receive Keytruda 200 mg intravenously every 3 weeks or investigator's choice of the following chemotherapy regimens given intravenously every 2 weeks:
mFOLFOX6 (oxaliplatin, leucovorin, and 5-FU) or mFOLFOX6 in combination with either bevacizumab or cetuximab: oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and 5-FU 400 mg/m2 bolus on day 1, then 5-FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.
FOLFIRI (irinotecan, leucovorin, and 5-FU) or FOLFIRI in combination with either bevacizumab or cetuximab: irinotecan 180 mg/m2, leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2), and 5-FU 400 mg/m2 bolus on day 1, then 5-FU 2400 mg/m2 over 46-48 hours. Bevacizumab 5 mg/kg on day 1 or cetuximab 400 mg/m2 on first infusion, then 250 mg/m2 weekly.
Treatment with Keytruda or chemotherapy continued until RECIST v1.1-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients treated with Keytruda without disease progression could be treated for up to 24 months. Assessment of tumour status was performed every 9 weeks. Patients randomised to chemotherapy were offered Keytruda at the time of disease progression. The primary efficacy outcome measures were PFS (assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) and OS. Secondary outcome measures were ORR and DoR.
A total of 307 patients were enrolled and randomised to Keytruda (n = 153) or chemotherapy (n = 154). The baseline characteristics of these 307 patients were: median age of 63 years (range: 24 to 93), 47% age 65 or older; 50% male; 75% White and 16% Asian; 52% had an ECOG PS of 0 and 48% had an ECOG PS of 1; 25% had a BRAF V600E mutation and 24% had a KRAS/NRAS mutation; and 27% had received prior adjuvant or neoadjuvant chemotherapy. Of the 154 patients randomised to receive chemotherapy, 143 were treated: 56% of them received mFOLFOX6 and 44% received FOLFIRI; with bevacizumab added for 70% of regimens and cetuximab for 11%.
The trial demonstrated a statistically significant improvement in PFS for patients randomised to Keytruda compared with chemotherapy at an interim analysis. There was no statistically significant difference between Keytruda and chemotherapy in the final OS analysis, with an additional 12 months of follow-up, in which 60% of the patients who had been randomised to receive chemotherapy had crossed over to receive subsequent anti PD 1/PD L1 therapies including Keytruda. The median follow-up time was 38.1 months (range: 0.2 to 58.7 months). Table 61, Figure 27 and Figure 28 summarise the key efficacy measures for KEYNOTE-177.
It is not known how Keytruda compares with platinum-based chemotherapy as the first-line treatment for patients with unresectable non-metastatic MSI-H/dMMR CRC to induce tumour regression sufficient to allow for resection with curative intent.
At the final analysis, the PFS and ORR results were consistent with the primary analysis.
Biliary tract carcinoma (BTC).

KEYNOTE-966: Controlled trial of combination therapy in patients with locally advanced unresectable or metastatic biliary tract carcinoma.

The efficacy of Keytruda in combination with gemcitabine and cisplatin was investigated in KEYNOTE-966, a multicentre, randomised, double-blind, placebo-controlled trial that enrolled 1069 patients with locally advanced unresectable or metastatic BTC, who had not received prior systemic therapy in the advanced disease setting. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomisation was stratified by region (Asia vs. non-Asia), locally advanced versus metastatic, and site of origin (gallbladder, intrahepatic or extrahepatic cholangiocarcinoma).
Patients were randomised (1:1) to one of the two treatment groups:
Keytruda 200 mg on Day 1 plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Day 1 and Day 8 every 3 weeks.
Placebo on Day 1 plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Day 1 and Day 8 every 3 weeks.
All study medications were administered via intravenous infusion. Treatment continued until unacceptable toxicity or disease progression. For pembrolizumab, treatment continued for a maximum of 35 cycles, or approximately 24 months. For cisplatin, treatment could be administered for a maximum of 8 cycles and for gemcitabine, treatment could be continued beyond 8 cycles.
Administration of Keytruda with chemotherapy was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Assessment of tumour status was performed at baseline and then every 6 weeks through 54 weeks, followed by every 12 weeks thereafter.
The study population characteristics were median age of 64 years (range: 23 to 85), 47% age 65 or older; 52% male; 49% White, 46% Asian; 46% ECOG PS of 0 and 54% ECOG PS of 1; 31% of patients had a history of hepatitis B infection, and 3% had a history of hepatitis C infection.
The primary efficacy outcome measure was OS and the secondary efficacy measures were PFS, ORR and DOR as assessed by BICR according to RECIST v1.1.
Table 62 and Figure 29 summarise the efficacy results for KEYNOTE-966.
There was no statistically significant improvement in progression-free survival, objective response rate or duration of response in patients receiving pembrolizumab plus gemcitabine and cisplatin or placebo plus gemcitabine and cisplatin.
Endometrial carcinoma.

KEYNOTE-868/NRG-GY018: Controlled trial of combination therapy for treatment of patients with primary advanced or recurrent endometrial carcinoma.

The efficacy of Keytruda in combination with paclitaxel and carboplatin was investigated in KEYNOTE-868, a multicentre, randomised, double blind, placebo controlled trial in 810 patients with advanced or recurrent endometrial carcinoma including those with dMMR and pMMR tumours. Patients had not received prior systemic therapy or had received prior chemotherapy in the adjuvant setting. Patients who had received prior adjuvant chemotherapy were eligible if their chemotherapy free interval was at least 12 months. Patients with endometrial sarcoma, including carcinosarcoma, or patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomisation was stratified according to MMR status, ECOG PS (0 or 1 vs. 2), and prior adjuvant chemotherapy. Patients were randomised (1:1) to one of the following treatment arms:
Keytruda 200 mg every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by Keytruda 400 mg every 6 weeks for up to 14 cycles.
Placebo every 3 weeks, paclitaxel 175 mg/m2 and carboplatin AUC 5 mg/mL/min for 6 cycles, followed by placebo every 6 weeks for up to 14 cycles.
All study medications were administered as an intravenous infusion on Day 1 of each treatment cycle. Treatment continued until disease progression, unacceptable toxicity, or a maximum of 20 cycles (up to approximately 24 months). Patients with measurable disease who had RECIST defined stable disease or partial response at the completion of cycle 6 were permitted to continue receiving paclitaxel and carboplatin with Keytruda or placebo for up to 10 cycles as determined by the investigator. Assessment of tumour status was performed every 9 weeks for the first 9 months and then every 12 weeks thereafter.
Among the 810 randomised patients, 222 (27%) had dMMR tumour status and 588 (73%) had pMMR tumour status.
The dMMR population characteristics were: median age of 66 years (range: 37 to 86), 55% age 65 or older; 79% White, 9% Black, and 3% Asian; 5% Hispanic or Latino; 64% ECOG PS of 0, 33% ECOG PS of 1, and 3% ECOG PS of 2; 61% had recurrent disease and 39% had primary or persistent disease; 5% received prior adjuvant chemotherapy and 43% received prior radiotherapy. The histologic subtypes were endometrioid carcinoma (24% grade 1, 43% grade 2, 14% grade 3), adenocarcinoma NOS (11%), and other (8% including dedifferentiated/undifferentiated, serous, and mixed epithelial).
The pMMR population characteristics were: median age of 66 years (range: 29 to 94), 54% age 65 or older; 72% White, 16% Black, and 5% Asian; 6% Hispanic or Latino; 67% ECOG PS of 0, 30% ECOG PS of 1, and 3% ECOG PS of 2; 56% had recurrent disease and 44% had primary or persistent disease; 26% received prior adjuvant chemotherapy and 41% received prior radiotherapy. The histologic subtypes were endometrioid carcinoma (17% grade 1, 19% grade 2, 16% grade 3), serous (26%), adenocarcinoma NOS (10%), clear cell carcinoma (7%), and other (5% including mixed epithelial and dedifferentiated/undifferentiated).
The primary efficacy outcome measure was PFS as assessed by the investigator according to RECIST 1.1 in the dMMR and pMMR populations. Secondary efficacy outcome measures included OS, ORR, and response duration in the dMMR and pMMR populations. The study demonstrated statistically significant improvements in PFS for patients randomised to pembrolizumab in combination with chemotherapy compared to placebo in combination with chemotherapy in both the dMMR and pMMR populations. The median follow-up time was 13.6 months (range: 0.6 to 39.4 months) and 8.7 months (range: 0.1 to 37.2 months) in the dMMR and pMMR populations, respectively. OS endpoint was not formally assessed within multiplicity control. OS results were not mature. Efficacy results by MMR status are summarised in Table 63. The Kaplan-Meier curves for PFS by MMR status are shown in Figures 30 and 31, respectively.

KEYNOTE-775: Controlled trial of combination therapy in advanced endometrial carcinoma patients previously treated with systemic therapy.

The efficacy of Keytruda in combination with lenvatinib was investigated in KEYNOTE-775 (NCT03517449), a multicentre, open-label, randomised, active-controlled trial that enrolled 827 patients with advanced endometrial carcinoma who had been previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with endometrial sarcoma, including carcinosarcoma, or patients who had active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients with endometrial carcinoma that were not MSI-H or dMMR were stratified by ECOG performance status, geographic region, and history of pelvic radiation. Patients were randomised (1:1) to one of the following treatment arms:
Keytruda 200 mg intravenously every 3 weeks in combination with lenvatinib 20 mg orally once daily.
Investigator's choice, consisting of either doxorubicin 60 mg/m2 every 3 weeks or paclitaxel 80 mg/m2 given weekly, 3 weeks on/1 week off.
Treatment with Keytruda and lenvatinib continued until RECIST v1.1-defined progression of disease as verified by BICR, unacceptable toxicity, or for Keytruda, a maximum of 24 months. Treatment was permitted beyond RECIST v1.1-defined disease progression if the treating investigator considered the patient to be deriving clinical benefit, and the treatment was tolerated. Assessment of tumour status was performed every 8 weeks. The major efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR and DoR, as assessed by BICR.
Among the 697 not dMMR patients, 346 patients were randomised to Keytruda in combination with lenvatinib, and 351 patients were randomised to investigator's choice of doxorubicin (n = 254) or paclitaxel (n = 97). The not dMMR population characteristics were: median age of 65 years (range: 30 to 86), 52% age 65 or older; 62% White, 22% Asian, and 3% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1. The histologic subtypes were endometrioid carcinoma (55%), serous (30%), clear cell carcinoma (7%), mixed (4%), and other (3%). All 697 of these patients received prior systemic therapy for endometrial carcinoma: 67% had one, 30% had two, and 3% had three or more prior systemic therapies. Thirty-seven percent of patients received only prior neoadjuvant or adjuvant therapy.
Efficacy results from the first interim analysis, in the not MSI-H or dMMR population, are summarised in Table 64. Kaplan-Meier curves for final OS and updated PFS analyses are shown in Figures 32 and 33, respectively.
The protocol-specified final OS analysis with approximately 16 months of additional follow-up duration from the interim analysis (overall median follow-up time of 14.7 months [range: 0.3 to 43.0 months]) was performed without statistical inferential testing, which was not required after the success criteria for study hypotheses was met at the pre-specified interim analysis for OS. The median OS for Keytruda in combination with lenvatinib was 18.0 months (95% CI: 14.9, 20.5) compared to 12.2 months (95% CI: 11.0, 14.1) for doxorubicin or paclitaxel, with an HR of 0.70 (95% CI: 0.58, 0.83). At the time of the protocol-specified final OS analysis, the median PFS for Keytruda in combination with lenvatinib was 6.7 months (95% CI: 5.6, 7.4) compared to 3.8 months (95% CI: 3.6, 5.0) for doxorubicin or paclitaxel, with an HR of 0.60 (95% CI: 0.50, 0.72).
Cervical cancer.

KEYNOTE-A18: Controlled trial of combination therapy with chemoradiotherapy in patients with high-risk, locally advanced cervical cancer.

The efficacy of Keytruda in combination with cisplatin and external beam radiation therapy (EBRT) followed by brachytherapy (BT) was investigated in KEYNOTE-A18, a multicentre, randomised, double-blind, placebo-controlled trial that enrolled 1060 patients with high-risk, locally advanced cervical cancer (LACC) who had not previously received any definitive surgery, radiation, or systemic therapy for cervical cancer. To be eligible, patients required either:
FIGO 2014 Stage III-IVA disease (tumour involvement of the lower vagina with or without extension onto pelvic sidewall or hydronephrosis/nonfunctioning kidney or has spread to adjacent pelvic organs), regardless of node status, or
Node-positive, FIGO 2014 Stage IB2-IIB disease (tumour lesions > 4 cm or clinically visible lesions that have spread beyond the uterus but have not extended onto the pelvic wall or to the lower third of vagina) [consistent with FIGO 2018 Stage IIIC].
Eligible patients enrolled are consistent with FIGO 2018 Stage III or IV (Stage IIIC patients must have at least two or more positive pelvic lymph nodes or 1 positive para-aortic lymph node and clinical lesions greater than 4 cm in size when confined to the cervix). Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomisation was stratified by planned type of EBRT (Intensity-modulated radiation therapy [IMRT] or volumetric modulated arc therapy [VMAT] vs. non-IMRT and non-VMAT), planned total radiotherapy dose ([EBRT + BT dose] of < 70 Gy vs. ≥ 70 Gy as per equivalent dose [EQD2]), and FIGO 2014 stage of cervical cancer at screening (IB2-IIB vs. III-IVA). Patients were randomised (1:1) to one of two treatment arms:
Keytruda 200 mg IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2 IV weekly (5 cycles, an optional sixth infusion could be administered per local practice) and radiotherapy (EBRT followed by BT), followed by Keytruda 400 mg IV every 6 weeks (15 cycles).
Placebo IV every 3 weeks (5 cycles) concurrent with cisplatin 40 mg/m2 IV weekly (5 cycles, an optional sixth infusion could be administered per local practice), and radiotherapy (EBRT followed by BT), followed by placebo IV every 6 weeks (15 cycles).
Treatment continued until RECIST v1.1-defined progression of disease as determined by investigator or unacceptable toxicity. Assessment of tumour status was performed every 12 weeks for the first two years, every 24 weeks in year 3, and then annually. The primary efficacy outcomes were PFS as assessed by investigator according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, or histopathologic confirmation), or histopathologic confirmation, and OS.
Among the 1060 patients enrolled in KEYNOTE-A18, the baseline characteristics were: median age of 50 years (range: 22 to 87); 13% age 65 or older, 49% White, 2% Black, 29% Asian; 32% Hispanic or Latino; 73% ECOG PS 0 and 27% ECOG PS 1; 94% with CPS ≥ 1; 43% were FIGO 2014 Stage IB2 to IIB, 57% were FIGO 2014 Stage III to IVA, 83% had positive pelvic and/or positive para-aortic lymph node(s), 17% had neither positive pelvic nor para-aortic lymph node. Eighty-three percent had squamous cell carcinoma and 17% had non squamous histology. Regarding radiation, 89% of patients received IMRT or VMAT EBRT, and the median EQD2 dose was 87 Gy (range: 3 to 207).
The trial demonstrated statistically significant improvements in PFS at the first prespecified interim analysis (IA1) and OS at the second pre-specified interim analysis (IA2) for patients randomised to Keytruda with CRT compared to placebo with CRT. At the first pre-specified interim analysis (IA1), the HR for PFS was 0.70 (95% CI: 0.55, 0.89; p-Value 0.0020) and median follow-up time was 17 months (range: 0.9 to 31 months). Results reported from the pre-specified interim analysis for OS (IA2) with a median follow up of 28 months (range 0.9 to 43 months) are summarised in Table 65, Figure 34 and Figure 35.
At IA2, PFS and OS hazard ratios (HR; with 95% CI) by stage stratum were as follows:
FIGO 2014 Stage III-IVA: PFS HR: 0.57 (0.43, 0.76); OS HR: 0.57 (0.39, 0.83).
Node-positive FIGO 2014 Stage IB2-IIB (FIGO 2018 Stage IIIC): PFS HR: 0.85 (0.62, 1.16); OS HR: 0.89 (0.55, 1.44).
Subgroup analyses were uninformative regarding a predictive effect of PD-L1 at a cut-off of CPS 1 (PD-L1 positive), as only 4.7% of the study population had a CPS < 1.

KEYNOTE-826: Controlled trial of combination therapy in patients with persistent, recurrent, or metastatic cervical cancer.

The efficacy of Keytruda in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was investigated in KEYNOTE-826, a multicentre, randomised, double-blind, placebo-controlled trial that enrolled 617 patients with persistent, recurrent, or first-line metastatic cervical cancer who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent. Patients were enrolled regardless of tumour PD-L1 expression status. Patients with autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomisation was stratified by metastatic status at initial diagnosis, investigator decision to use bevacizumab, and PD-L1 status (CPS < 1 vs. CPS 1 to < 10 vs. CPS ≥ 10). Patients were randomised (1:1) to one of the two treatment groups:
Treatment group 1: Keytruda 200 mg plus chemotherapy.
Treatment group 2: placebo plus chemotherapy.
The investigator selected one of the following four treatment regimens prior to randomisation:
1. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2.
2. Paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 + bevacizumab 15 mg/kg.
3. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min.
4. Paclitaxel 175 mg/m2 + carboplatin AUC 5 mg/mL/min + bevacizumab 15 mg/kg.
All study medications were administered as an intravenous infusion. All study treatments were administered on Day 1 of each 3-week treatment cycle. Cisplatin could be administered on Day 2 of each 3-week treatment cycle. The option to use bevacizumab was by investigator choice prior to randomisation. Treatment with Keytruda continued until RECIST v1.1-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of Keytruda was permitted beyond RECIST defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumour status was performed at Week 9 and then every 9 weeks for the first year, followed by every 12 weeks thereafter. The primary efficacy outcome measures were OS and PFS as assessed by investigator according to RECIST v1.1. Secondary efficacy outcome measures were ORR and DoR, according to RECIST v1.1, as assessed by investigator.
Of the 617 enrolled patients, 548 patients (89%) had tumours expressing PD-L1 with a CPS ≥ 1. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx Kit. Among these 548 enrolled patients with tumours expressing PD-L1, 273 patients were randomised to Keytruda in combination with chemotherapy with or without bevacizumab, and 275 patients were randomised to placebo in combination with chemotherapy with or without bevacizumab. The baseline characteristics of these 548 patients were: median age of 51 years (range: 22 to 82), 16% age 65 or older; 59% White, 18% Asian, and 1% Black; 37% Hispanic or Latino; 56% and 43% ECOG performance status of 0 or 1, respectively; 63% received bevacizumab as study treatment; 21% with adenocarcinoma and 5% with adenosquamous histology; for patients with persistent or recurrent disease with or without distant metastases, 39% had received prior chemoradiation only and 17% had received prior chemoradiation plus surgery. The median follow-up time was 17.2 months (range: 0.3 to 29.4 months).
A statistically significant improvement in OS and PFS was demonstrated in patients randomised to receive Keytruda compared with patients randomised to receive placebo. An updated OS analysis was conducted at the time of final analysis when 354 deaths in the CPS ≥ 1 population were observed. Efficacy results for patients with tumours expressing PD-L1 (CPS ≥ 1) in KEYNOTE-826 are summarised in Table 66 and Figure 36.
Renal cell carcinoma.

KEYNOTE-426: Controlled trial of combination therapy with axitinib for first-line treatment of patients with advanced RCC.

The efficacy of Keytruda in combination with axitinib was investigated in a randomised, multicentre, open-label, active-controlled trial KEYNOTE-426, conducted in patients with advanced RCC, regardless of PD-L1 tumour status and International Metastatic RCC Database Consortium (IMDC) risk group categories. The trial excluded patients with a history of severe autoimmune disease, patient with a medical condition that required immunosuppression within 2 years of pembrolizumab-axitinib therapy, or those who had experienced a significant cardiac, cardiovascular, or cerebrovascular event within 12 months of pembrolizumab-axitinib therapy. Randomisation was stratified by risk categories (favourable versus intermediate versus poor) and geographic region (North America versus Western Europe versus "Rest of the World"). Patients were randomised (1:1) to one of the following treatment arms:
Keytruda 200 mg intravenously every 3 weeks in combination with axitinib 5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive treatment cycles (i.e. 6 weeks) with no > grade 2 treatment related adverse events to axitinib and with blood pressure well controlled to ≤ 150/90 mmHg were permitted dose escalation of axitinib to 7 mg twice daily. Dose escalation of axitinib to 10 mg twice daily was permitted using the same criteria. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.
Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks.
Treatment with Keytruda and axitinib continued until RECIST 1.1-defined progression of disease as verified by BICR or confirmed by the investigator, unacceptable toxicity, or for Keytruda, a maximum of 24 months. Administration of Keytruda and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumour status was performed at baseline, after randomisation at week 12, then every 6 weeks thereafter until week 54, and then every 12 weeks thereafter. Chemistry and haematology laboratory tests were performed at each cycle.
Among the 861 patients in KEYNOTE-426 (432 patients in the Keytruda combination arm and 429 in the sunitinib arm), baseline characteristics were: median age of 62 years (range: 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 99.9% had a Karnofsky Performance Score (KPS) of ≥ 70%; patient distribution by IMDC risk categories was 31% favourable, 56% intermediate and 13% poor.
The primary efficacy outcome measures were OS and PFS (as assessed by BICR according to RECIST 1.1). Secondary efficacy outcome measures were ORR and response duration, as assessed by BICR using RECIST 1.1. The median follow-up time for 432 patients treated with Keytruda and axitinib was 13.2 months (range: 0.1 - 21.5 months). Table 67 summarises key efficacy measures. Improvements in OS, PFS and ORR were shown consistently across all tested subgroups, including subgroups by IMDC risk category and PD-L1 tumour expression status.
The protocol-specified final OS analysis was performed at a median duration of follow-up of 37.7 months after 418 patient events (193 in the Keytruda and axitinib arm and 225 in the sunitinib arm). Median OS was 45.7 months (95% CI: 43.6, NA) in the Keytruda and axitinib arm and 40.1 months (95% CI: 34.3, 44.2) in the sunitinib arm. The OS HR was 0.73 (95% CI: 0.60, 0.88). The 12-month OS rates were 90% (95% CI: 86, 92) in the Keytruda and axitinib arm and 79% (95% CI: 75, 83) in the sunitinib arm. The 24-month OS rates were 74% (95% CI: 70, 78) in the Keytruda and axitinib arm and 66% (95% CI: 61, 70) in the sunitinib arm. The 36-month OS rates were 63% (95% CI: 58, 67) in the Keytruda and axitinib arm and 54% (95% CI: 49, 58) in the sunitinib arm. The 42-month OS rates were 58% (95% CI: 53, 62) in the Keytruda and axitinib arm and 49% (95% CI: 44, 53) in the sunitinib arm. At final analysis, a PFS analysis was performed based on 587 patient events (286 in the Keytruda and axitinib arm and 301 in the sunitinib arm). The median PFS was 15.7 months (95% CI: 13.6, 20.2) in the Keytruda and axitinib arm and 11.1 months (95% CI: 8.9, 12.5) in the sunitinib arm. The PFS HR was 0.68 (95% CI: 0.58, 0.80).
The ORR at the final analysis was 60% in the Keytruda and axitinib arm and 40% in the sunitinib arm. The median duration of response was 23.6 months (range: 1.4+ to 43.4+) in the Keytruda and axitinib arm and 15.3 months (range: 2.3 to 42.8+) in the sunitinib arm. The percentage of patients with ongoing responses based on Kaplan-Meier estimation were 71%, 59%, 49%, and 45% at 12, 18, 24, and 30 months, respectively, in patients with confirmed response in the Keytruda and axitinib arm, vs. 62%, 46%, 37%, and 32% in patients with confirmed response in the sunitinib arm. See Figures 37 and 38.

KEYNOTE-581: Controlled trial of combination therapy with lenvatinib for first-line treatment of patients with advanced RCC.

The efficacy of Keytruda in combination with lenvatinib was investigated in KEYNOTE-581 (CLEAR), a multicentre, open-label, randomised trial conducted in 1069 patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumour expression status. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomisation was stratified by geographic region (North America versus Western Europe versus "Rest of the World") and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favourable versus intermediate versus poor risk).
Patients were randomised (1:1:1) to one of the following treatment arms:
Keytruda 200 mg intravenously every 3 weeks up to 24 months in combination with lenvatinib 20 mg orally once daily.
Lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily.
Sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks.
Treatment continued until unacceptable toxicity or disease progression as determined by the investigator and confirmed by BICR using RECIST 1.1. Administration of Keytruda with lenvatinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Keytruda was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Assessment of tumour status was performed at baseline and then every 8 weeks.
Among the 1069 patients in KEYNOTE-581 (355 patients in the Keytruda with lenvatinib arm, 357 patients in the lenvatinib with everolimus arm, and 357 patients in the sunitinib arm), the study population characteristics were: median age of 62 years (range: 29 to 88 years); 42% age 65 or older; 75% male; 74% White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by IMDC risk categories was 33% favourable, 56% intermediate and 10% poor, and by MSKCC risk categories was 27% favourable, 64% intermediate and 9% poor. Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%).
The primary efficacy outcome measure was PFS based on BICR using RECIST 1.1. Key secondary efficacy outcome measures included OS and ORR. The trial demonstrated statistically significant longer PFS and OS, and a higher ORR, amongst patients randomised to receive Keytruda in combination with lenvatinib compared with those randomised to receive sunitinib. The main efficacy results for KEYNOTE-581 (with a median OS follow-up time of 26.6 months) are summarised in Table 68 and Figure 39. Consistent results were observed across pre-specified subgroups, MSKCC prognostic groups and PD-L1 tumour expression status. OS analyses were not adjusted to account for subsequent therapies.
The final OS analysis was conducted at an updated data cut-off date of 31 July 2022 (median OS follow-up 49.4 months). The median duration of treatment was 22.6 months (range: 2 days - 62.1 months) in the Keytruda in combination with lenvatinib arm and 7.8 months (range: 3 days - 57.5 months) in the sunitinib arm. Median OS for Keytruda in combination with lenvatinib was 53.7 months (95% CI: 48.7, NE) compared to 54.3 months (95% CI: 40.9, NE) for sunitinib, with a HR 0.79 (95% CI: 0.63, 0.99). See Figure 40. Subsequent to their participation in KEYNOTE-581, 55% of patients in the sunitinib arm and 16% of patients in the Keytruda plus lenvatinib arm received subsequent systemic anti-PD-1/PD-L1 therapy. OS analyses were not adjusted to account for subsequent therapies.

KEYNOTE-B61.

The efficacy of Keytruda in combination with lenvatinib was investigated in KEYNOTE-B61 (NCT04704219), a multicentre, single-arm trial that enrolled 160 patients with advanced/metastatic non-clear cell RCC in the first-line setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.
Patients received Keytruda 400 mg every 6 weeks in combination with lenvatinib 20 mg orally once daily. Keytruda was continued for a maximum of 24 months; however, lenvatinib could be continued beyond 24 months. Treatment continued until unacceptable toxicity or disease progression. Administration of Keytruda with lenvatinib was permitted beyond RECIST-defined disease progression if the patient was considered by the investigator to be deriving clinical benefit.
Among the 158 treated patients, the baseline characteristics were: median age of 60 years (range: 24 to 87 years); 71% male; 86% White, 8% Asian, and 3% Black; < 1% Hispanic or Latino; 22% and 78% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; histologic subtypes were 59% papillary, 18% chromophobe, 4% translocation, < 1% medullary, 13% unclassified, and 6% other; patient distribution by IMDC risk categories was 35% favourable, 54% intermediate, and 10% poor. Common sites of metastases in patients were lymph node (65%), lung (35%), bone (30%), and liver (21%).
The major efficacy outcome measure was ORR as assessed by BICR using RECIST 1.1. Additional efficacy outcome measures included DOR as assessed by BICR using RECIST 1.1. Efficacy results are summarised in Table 69.

KEYNOTE-564: Placebo-controlled study for the adjuvant treatment of patients with resected RCC.

The efficacy of Keytruda was investigated as adjuvant therapy for RCC in KEYNOTE 564, a multicentre randomised, double-blind, placebo-controlled study in 994 patients with intermediate-high or high risk of recurrence of RCC, or M1 no evidence of disease (NED). The intermediate high-risk category included: pT2 with grade 4 or sarcomatoid features; pT3, any grade without nodal involvement (N0) or distant metastases (M0). The high-risk category included: pT4, any grade N0 and M0; any pT, any grade with nodal involvement and M0. The M1 NED category included patients with metastatic disease who had undergone complete resection of primary and metastatic lesions. Patients must have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants) with negative surgical margins ≥ 4 weeks prior to the time of screening. A clear cell component to the RCC histology was required for trial inclusion. Patients with active autoimmune disease, with a medical condition that required immunosuppression, or who had received prior systemic therapy for advanced RCC were ineligible. Patients were randomised (1:1) to receive Keytruda 200 mg every 3 weeks (n=496) or placebo (n=498) for up to 1 year until disease recurrence or unacceptable toxicity. Randomisation was stratified by metastasis status (M0, M1 NED), within M0 group, further stratified by ECOG PS (0,1), and geographic region (US, non-US). Patients underwent imaging every 12 weeks for the first 2 years from randomisation, then every 16 weeks from year 3 to 5, and then every 24 weeks annually.
Among the 994 patients, the baseline characteristics were: median age of 60 years (range: 25 to 84), 33% age 65 or older; 71% male; and 85% ECOG PS of 0 and 15% ECOG PS of 1. Ninety-four percent were N0; 84% had no sarcomatoid features; 86% were pT2 with grade 4 or sarcomatoid features or pT3; 8% were pT4 or with nodal involvement; and 6% were M1 NED. Baseline characteristics and demographics were generally comparable between the Keytruda and placebo arms.
The primary efficacy outcome measure was investigator-assessed disease free survival (DFS). The key secondary outcome measure was OS. The study demonstrated statistically significant improvements in DFS and OS for patients randomised to the Keytruda arm compared with placebo. Generally consistent results were observed across pre-specified subgroups. Efficacy results are summarised in Table 70 and Figure 41 and Figure 42.
Cutaneous squamous cell carcinoma (cSCC).

KEYNOTE-629: Open-label trial of monotherapy in cSCC.

The efficacy of Keytruda was investigated in KEYNOTE-629, a multicentre, multi-cohort, non-randomised, open-label, single-arm trial that enrolled 159 patients with recurrent or metastatic cSCC or locally advanced cSCC. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression.
Patients received Keytruda 200 mg intravenously every 3 weeks until documented disease progression, unacceptable toxicity, or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of Keytruda during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status.
Assessment of tumour status was performed every 6 weeks during the first year, and every 9 weeks during the second year. The major efficacy outcome measures were ORR and DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Among the 105 patients with recurrent or metastatic cSCC treated, the study population characteristics were: median age of 72 years (range: 29 to 95); 71% age 65 or older; 76% male; 71% White; 25% race unknown; 34% ECOG PS of 0 and 66% ECOG PS of 1. Forty-five percent of patients had locally recurrent only cSCC, 24% had metastatic only cSCC, and 31% had both locally recurrent and metastatic cSCC. Eighty-seven percent received one or more prior lines of therapy; 74% received prior radiation therapy.
Among the 54 patients with locally advanced cSCC treated, the study population characteristics were: median age of 76 years (range: 35 to 95), 80% age 65 or older; 72% male; 83% White, 13% race unknown; 41% ECOG PS of 0 and 59% ECOG PS of 1. Twenty-two percent received one or more prior lines of therapy; 63% received prior radiation therapy.
Efficacy results are summarised in Table 71.
Gastric or GOJ adenocarcinoma.

KEYNOTE-859: In combination with chemotherapy as first-line treatment for advanced HER2-negative gastric or gastroesophageal junction (GOJ) adenocarcinoma.

The efficacy of Keytruda in combination with fluoropyrimidine and platinum chemotherapy was investigated in KEYNOTE-859, a multicentre, randomised, double-blind, placebo-controlled trial that enrolled 1579 patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GOJ) adenocarcinoma that was HER2-negative (not HER2-positive per local standards), regardless of PD-L1 expression status, who had not previously received systemic therapy for metastatic disease. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomisation was stratified by PD-L1 expression (CPS ≥ 1 or < 1), chemotherapy regimen (5-FU plus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]), and geographic region (Europe/ Israel/ North America/ Australia, Asia or Rest of the World). See Figure 43.
All study medications, except oral capecitabine, were administered as an intravenous infusion, in 3 week cycles. All patients received investigators choice of combination chemotherapy: either cisplatin 80 mg/m2 and 5-FU 800 mg/m2/day for 5 days (FP), or oxaliplatin 130 mg/m2 and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). Patients were randomised (1:1) to receive either Keytruda 200 mg or a matching placebo prior to chemotherapy on Day 1 of each cycle. Treatment continued until radiographic progression of disease, unacceptable toxicity, or for a maximum of 24 months. Tumour status was assessed by BICR using RECIST v1.1 (modified to allow up to 10 target lesions total/5 per organ), with imaging taken at 6 week intervals. The primary efficacy outcome measure was OS. Additional secondary efficacy outcome measures included BICR-assessed PFS, ORR, and DOR.
The population characteristics were: median age of 62 years (range: 21 to 86), 39% age 65 or older; 68% male; 55% White and 34% Asian; 37% ECOG PS of 0 and 63% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (stage IV) and 3% had locally advanced unresectable disease. Seventy-eight percent had tumours that expressed PD-L1 with a CPS ≥ 1 and 5% (n=74) of patients had tumours that were MSI-H. Eighty-six percent of patients received CAPOX.
A statistically significant improvement in OS, PFS and ORR was demonstrated in patients randomised to Keytruda in combination with chemotherapy compared with placebo in combination with chemotherapy. Efficacy results are summarised in Table 72.
In an exploratory subgroup analysis in patients with PD-L1 CPS < 1 (n=344): The median OS was 12.7 months (95% CI: 11.4, 15.0) for the Keytruda arm and 12.2 months (95% CI: 9.5, 14.0) for the placebo arm, with a HR of 0.92 (95% CI: 0.73, 1.17); The median PFS was 7.2 months (95% CI: 6.0, 8.5) for the Keytruda arm and 5.8 months (95% CI: 5.4, 6.9) for the placebo arm, with a HR of 0.90 (95% CI: 0.70, 1.15). See Figure 44.

KEYNOTE-811: In combination with trastuzumab and chemotherapy as first-line treatment for advanced HER2-positive gastric or gastroesophageal junction (GOJ) adenocarcinoma.

The efficacy of Keytruda in combination with trastuzumab plus fluoropyrimidine and platinum chemotherapy was investigated in KEYNOTE-811, a multicentre, randomised, double-blind, placebo-controlled trial that enrolled 698 patients with HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction (GOJ) adenocarcinoma regardless of PD-L1 expression status, who had not previously received systemic therapy for metastatic disease. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomisation was stratified by PD-L1 expression (CPS ≥ 1 or < 1), chemotherapy regimen (5-FU plus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]), and geographic region (Europe/ Israel/ North America/ Australia, Asia or Rest of the World).
All study medications, except oral capecitabine, were administered as an intravenous infusion in 3 week cycles. All patients received trastuzumab (8 mg/kg on first infusion and 6 mg/kg in subsequent cycles), followed by investigator's choice of combination chemotherapy: either cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2/day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). Patients were randomised (1:1) to additionally receive either Keytruda 200 mg or a matching placebo, given on Day 1 of each cycle prior to trastuzumab and chemotherapy. Treatment continued until radiographic progression of disease, unacceptable toxicity, or for a maximum of 24 months. Tumour status was assessed by BICR using RECIST v1.1 (modified to allow up to 10 target lesions total/5 per organ), with imaging taken at 6 week intervals. The primary efficacy outcome measure was OS. Additional secondary efficacy outcome measures included BICR-assessed PFS, ORR, and DOR.
Among the 698 patients randomised in KEYNOTE-811, 594 (85%) had tumours that expressed PD-L1 with a CPS ≥ 1. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. The population characteristics of these 594 patients were: median age of 63 years (range: 19 to 85), 43% age 65 or older; 80% male; 63% White, 33% Asian, and 0.7% Black; 42% ECOG PS of 0 and 58% ECOG PS of 1. Ninety-eight percent of patients had metastatic disease (stage IV) and 2% had locally advanced unresectable disease. Ninety-five percent (n=562) had tumours that were not MSI-H, 1% (n=8) had tumours that were MSI-H, and in 4% (n=24) the MSI status was not known. Eighty-five percent of patients received CAPOX.
The primary efficacy outcome measures were PFS, based on BICR using RECIST 1.1, and OS. Secondary efficacy outcome measures included ORR and DoR, based on BICR using RECIST 1.1.
At the first interim analysis conducted on the first 264 patients randomised in the overall population (133 patients in the Keytruda arm and 131 in the placebo arm), a statistically significant improvement was observed in the objective response rate (74.4% vs 51.9%, representing a 22.7% difference; 95% CI (11.2, 33.7); p-Value 0.00006).
At the second interim analysis in the overall population (n=698), a statistically significant improvement in PFS (HR 0.72; 95% CI 0.60, 0.87; p-Value 0.0002) was demonstrated in patients randomised to Keytruda in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy. In a pre-specified subgroup analysis based on PD-L1 status, the HR for PFS in patients with PD-L1 CPS < 1 (N=104) was 1.17 (95% CI: 0.73, 1.89) and for OS in the same subgroup was 1.61 (95% CI: 0.98, 2.64). At the time of this analysis, there was no statistically significant difference with respect to OS in the overall population.
Efficacy results at the second interim analysis for the pre-specified subgroup of patients whose tumours expressed PD-L1 with a CPS ≥ 1 are summarised in Table 73 and Figures 45 and 46.
Oesophageal cancer.

KEYNOTE-590: First-line treatment of locally advanced unresectable or metastatic oesophageal/gastroesophageal junction cancer.

The efficacy of Keytruda was investigated in KEYNOTE-590, a multicentre, randomised, placebo-controlled trial that enrolled 749 patients as a first-line treatment in patients with locally advanced unresectable or metastatic carcinoma of the oesophagus or gastroesophageal junction (GOJ). All patients were required to have tumour specimens for PD-L1 testing at a central laboratory; PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. Patients with active autoimmune disease, a medical condition that required immunosuppression, or known HER-2 positive GOJ adenocarcinoma patients were ineligible. Randomisation was stratified by tumour histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia), and ECOG performance status (0 vs. 1).
Patients were randomised (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:
Keytruda 200 mg on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months.
Placebo on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle for up to six cycles and FU 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months.
Treatment with Keytruda or chemotherapy continued until unacceptable toxicity or disease progression. Patients randomised to Keytruda were permitted to continue beyond the first RECIST v1.1-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging. Patients treated with Keytruda without disease progression could be treated for up to 24 months. Assessment of tumour status was performed every 9 weeks. The major efficacy outcome measures were OS and PFS as assessed by the investigator according to RECIST v1.1. Secondary efficacy outcome measures were ORR and DoR, according to RECIST v1.1, as assessed by the investigator.
The baseline characteristics were: median age of 63 years (range: 27 to 94), 43% age 65 or older; 83% male; 37% White and 53% Asian; 40% had an ECOG PS of 0 and 60% had an ECOG PS of 1. Ninety-one percent had M1 disease and 9% had M0 disease. Seventy-three percent had a tumour histology of squamous cell carcinoma, and 27% had adenocarcinoma.
Keytruda, in combination with chemotherapy, demonstrated a statistically significant and clinically meaningful improvement in OS and PFS when compared to chemotherapy (cisplatin and FU) in previously untreated participants with locally advanced unresectable or metastatic carcinoma of the oesophagus or gastroesophageal junction. The investigator-assessed results were consistent with BICR.
Table 74 summarises the key efficacy measures for KEYNOTE-590. The Kaplan-Meier curves for OS and PFS are shown in Figures 47-52.
In a pre-specified formal test of OS in patients with PD-L1 CPS ≥ 10 (n = 383), the median was 13.5 months (95% CI: 11.1, 15.6) for the Keytruda arm and 9.4 months (95% CI: 8.0, 10.7) for the placebo arm, with a HR of 0.62 (95% CI: 0.49, 0.78; p-Value < 0.0001). In an exploratory analysis, in patients with PD-L1 CPS < 10 (n = 347), the median OS was 10.5 months (95% CI: 9.7, 13.5) for the Keytruda arm and 10.6 months (95% CI: 8.8, 12.0) for the placebo arm, with a HR of 0.86 (95% CI: 0.68, 1.10).
Tumour mutational burden high (TMB-H) cancer. The efficacy of Keytruda was investigated in a prospectively-planned retrospective analysis of 102 adult patients with certain previously treated, unresectable or metastatic solid tumours with high tumour mutational burden (TMB-H), who were enrolled in Cohorts A through J of KEYNOTE-158, a multicentre, non-randomised, open-label, multi-cohort trial. Tumour types eligible for enrolment in Cohorts A through J were anal squamous cell carcinoma, cholangiocarcinoma, neuroendocrine carcinoma, endometrial carcinoma, cervical squamous cell carcinoma, vulvar squamous cell carcinoma, small cell lung carcinoma, mesothelioma, thyroid carcinoma and salivary gland carcinoma. The trial excluded patients who had previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease or a medical condition that required immunosuppression. Patients received Keytruda 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. Assessment of tumour status was performed every 9 weeks for the first 12 months, and every 12 weeks thereafter.
The statistical analysis plan pre-specified ≥ 10 and ≥ 13 mutations per megabase (mut/Mb) using the FoundationOne CDx assay as cutpoints to assess TMB. Testing of TMB was blinded with respect to clinical outcomes. The primary efficacy outcome measures were ORR and DoR in patients who received at least one dose of Keytruda as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
In KEYNOTE-158, 1050 patients were included in the efficacy analysis population. TMB was analysed in the subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumours identified as TMB-H, defined as TMB ≥ 10 mut/Mb. Among the 102 patients with TMB-H advanced solid tumours, the study population characteristics were: median age of 61 years (range: 27 to 80), 34% age 65 or older; 34% male; 81% White; and 41% ECOG PS of 0 and 58% ECOG PS of 1. Fifty-six percent of patients had at least two prior lines of therapy.
Efficacy results are summarised in Tables 75 and 76.
In an exploratory analysis in 32 patients enrolled in KEYNOTE-158 whose cancer had TMB ≥ 10 mut/Mb and < 13 mut/Mb, the ORR was 13% (95% CI: 4%, 29%), including two complete responses and two partial responses.
Triple-negative breast cancer (TNBC).

KEYNOTE-522: Controlled study of neoadjuvant and adjuvant treatment of patients with high risk early stage TNBC.

The efficacy of Keytruda in combination with carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide, given as a neoadjuvant treatment and continued as monotherapy adjuvant treatment was investigated in Study KEYNOTE-522, a randomised, double blind, multicentre, placebo controlled study. The key eligibility criteria for this study were newly diagnosed previously untreated high risk early stage TNBC (tumour size > 1 cm but ≤ 2 cm in diameter with nodal involvement or tumour size > 2 cm in diameter regardless of nodal involvement), regardless of tumour PD-L1 expression. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible for the study. Randomisation was stratified by nodal status (positive vs. negative), tumour size (T1/T2 vs. T3/T4), and choice of carboplatin (dosed every 3 weeks vs. weekly).
Patients were randomised (2:1) to one of the following treatment arms; all study medications were administered via intravenous infusion.
Arm 1: Four cycles of preoperative Keytruda 200 mg every 3 weeks on Day 1 of cycles 1-4 of treatment regimen in combination with:
Carboplatin. AUC 5 mg/mL/min every 3 weeks on Day 1 of cycles 1-4 of treatment regimen or AUC 1.5 mg/mL/min every week on Day 1, 8, and 15 of cycles 1-4 of treatment regimen; and
Paclitaxel 80 mg/m2 every week on Day 1, 8, and 15 of cycles 1-4 of treatment regimen.
Followed by four additional cycles of preoperative Keytruda 200 mg every 3 weeks on Day 1 of cycles 5-8 of treatment regimen in combination with:
Doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen; and
Cyclophosphamide 600 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen.
Following surgery, 9 cycles of Keytruda 200 mg every 3 weeks were administered.
Arm 2: Four cycles of preoperative placebo every 3 weeks on Day 1 of cycles 1-4 of treatment regimen in combination with:
Carboplatin. AUC 5 mg/mL/min every 3 weeks on Day 1 of cycles 1-4 of treatment regimen or AUC 1.5 mg/mL/min every week on Day 1, 8, and 15 of cycles 1-4 of treatment regimen; and
Paclitaxel 80 mg/m2 every week on Day 1, 8, and 15 of cycles 1-4 of treatment regimen.
Followed by four additional cycles of preoperative placebo every 3 weeks on Day 1 of cycles 5-8 of treatment regimen in combination with:
Doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen; and
Cyclophosphamide 600 mg/m2 every 3 weeks on Day 1 of cycles 5-8 of treatment regimen.
Following surgery, 9 cycles of placebo every 3 weeks were administered.
Treatment with Keytruda or placebo continued until completion of the treatment (17 cycles), disease progression that precludes definitive surgery, disease recurrence in the adjuvant phase, or unacceptable toxicity.
The major efficacy outcome measures were pathological complete response (pCR) rate and event free survival (EFS). pCR was defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0) and was assessed by the blinded local pathologist at the time of definitive surgery. EFS was defined as the time from randomisation to the first occurrence of any of the following events: progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause. An additional efficacy outcome measure was OS.
A total of 1174 patients were randomised: 784 patients to the Keytruda arm and 390 patients to the placebo arm. The study population characteristics were: median age of 49 years (range: 22 to 80), 11% age 65 or older; 99.9% female; 64% White, 20% Asian, 5% Black, and 2% American Indian or Alaska Native; 87% ECOG PS of 0 and 13% ECOG PS of 1; 56% were pre menopausal status and 44% were post-menopausal status; 7% were primary Tumour 1 (T1), 68% T2, 19% T3, and 7% T4; 49% were nodal involvement 0 (N0), 40% N1, 11% N2, and 0.2% N3; 75% of patients were overall stage II and 25% were stage III.
The trial demonstrated a statistically significant improvement in pCR and EFS at a pre-specified analysis for patients randomised to Keytruda in combination with chemotherapy followed by Keytruda monotherapy compared with patients randomised to placebo in combination with chemotherapy followed by placebo alone. At the time of EFS analysis, OS results were not yet mature (45% of the required events for final analysis). At a pre specified interim analysis, the median follow-up time for 784 patients treated with Keytruda was 37.8 months (range: 2.7-48 months). Efficacy results are summarised in Table 77 and Figure 53.

KEYNOTE-355: Controlled study of combination therapy in patients with locally recurrent unresectable or metastatic TNBC.

The efficacy of Keytruda in combination with paclitaxel, nab paclitaxel, or gemcitabine and carboplatin was investigated in Study KEYNOTE-355, a randomised, double blind, multicentre, placebo controlled study. The key eligibility criteria for this study were locally recurrent unresectable or metastatic TNBC, regardless of tumour PD-L1 expression, and which had not been previously treated with chemotherapy in the metastatic setting. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible for the study. Randomisation was stratified by chemotherapy treatment (paclitaxel or nab paclitaxel vs. gemcitabine and carboplatin), tumour PD-L1 expression (CPS ≥ 1 vs. CPS < 1) based on the PD-L1 IHC 22C3 pharmDxTM kit, and prior treatment with the same class of chemotherapy in the neoadjuvant setting (yes vs. no).
Patients were randomised (2:1) to one of the following treatment arms; all study medications were administered via intravenous infusion.
Keytruda 200 mg on Day 1 every 3 weeks in combination with nab paclitaxel 100 mg/m2 on Days 1, 8 and 15 every 28 days, or paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days.
Placebo on Day 1 every 3 weeks in combination with nab paclitaxel 100 mg/m2 on Days 1, 8 and 15 every 28 days, or paclitaxel 90 mg/m2 on Days 1, 8, and 15 every 28 days, or gemcitabine 1000 mg/m2 and carboplatin AUC 2 mg/mL/min on Days 1 and 8 every 21 days.
Treatment with Keytruda or placebo continued until RECIST 1.1 defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of Keytruda was permitted beyond RECIST defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumour status was performed at Weeks 8, 16, and 24, then every 9 weeks for the first year, and every 12 weeks thereafter.
The major efficacy outcome measures were OS and PFS as assessed by BICR using RECIST 1.1, in patients with tumour PD-L1 expression CPS ≥ 10. Additional efficacy outcome measures were ORR, DOR, and DCR (stable disease for at least 24 weeks, or complete response, or partial response) in patients with tumour PD-L1 expression CPS ≥ 10 as assessed by BICR using RECIST 1.1.
A total of 847 patients were randomised: 566 patients to the Keytruda arm and 281 patients to the placebo arm. The study population characteristics were: median age of 53 years (range: 22 to 85), 21% age 65 or older; 100% female; 68% White, 21% Asian, and 4% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1; and 68% were post menopausal status. Seventy five percent of the patients had tumour PD-L1 expression defined as CPS ≥ 1 and 38% had tumour PD-L1 expression CPS ≥ 10.
In KEYNOTE-355, there was a statistically significant improvement in OS and PFS in patients with tumour PD-L1 expression CPS ≥ 10 randomised to Keytruda in combination with paclitaxel, nab paclitaxel, or gemcitabine and carboplatin compared with patients randomised to placebo in combination with paclitaxel, nab paclitaxel, or gemcitabine and carboplatin.
Efficacy results are summarised in Table 78 and Figures 54 and 55.

Paediatric population.

KEYNOTE-051, a study of pembrolizumab in the paediatric population, 22 patients aged 11 years to 17 years with Hodgkin Lymphoma. The baseline characteristics were median age 15 years; 64% male; 68% White; 77% had a Lansky/Karnofsky scale 90-100 and 23% had scale 70-80. Eighty-six percent had two or more prior lines of therapy and 91% had Stage 3 or higher. In these paediatric patients with cHL, the ORR assessed by BICR according to the IWG 2007 criteria was 54.5%, 1 patient (4.5%) had a complete response and 11 patients (50.0%) had a partial response, and the ORR assessed by the Lugano 2014 criteria was 63.6%, 4 patients (18.2%) had a complete response and 10 patients (45.5%) had a partial response. Efficacy in this population was supported by extrapolation from adult data in Hodgkin lymphoma.

Immunogenicity.

In clinical studies in patients treated with pembrolizumab at a dose of 2 mg/kg every 3 weeks, 200 mg every 3 weeks or 10 mg/kg every 2 or 3 weeks, 36 (1.8%) of 2034 evaluable patients tested positive for treatment-emergent antibodies against pembrolizumab of which 9 (0.4%) patients had neutralizing antibodies against pembrolizumab. There was no evidence of an altered pharmacokinetic or safety profile with anti-pembrolizumab binding antibody development.

5.2 Pharmacokinetic Properties

The pharmacokinetics of pembrolizumab was studied in 2993 patients with various cancers who received doses in the range of 1 to 10 mg/kg every 2 weeks, 2 to 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. There are no clinically meaningful differences in pharmacokinetics of pembrolizumab across indications.

Absorption.

Keytruda is dosed via the IV route and therefore is immediately and completely bioavailable.

Distribution.

Consistent with a limited extravascular distribution, the volume of distribution of pembrolizumab at steady state is small (6.0 L; coefficient of variation [CV]: 20%). As expected for an antibody, pembrolizumab does not bind to plasma proteins in a specific manner.

Metabolism.

Pembrolizumab is catabolised through non-specific pathways; metabolism does not contribute to its clearance.

Excretion.

Pembrolizumab clearance (CV%) is approximately 23% lower [geometric mean, 195 mL/day (40%)] after achieving maximal change at steady state compared with the first dose (252 mL/day [CV%: 37%]); this decrease in clearance with time is not considered clinically important. The geometric mean value (CV%) for the terminal half-life (t½) is 22 days (32%).
Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3 week regimen and the systemic accumulation was 2.1 fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks.
Following administration of pembrolizumab 200 mg every 3 weeks in patients with cHL, the observed median Cmin at steady-state was up to 40% higher than that in other tumour types treated with the same dosage; however, the range of trough concentrations is similar. There are no notable differences in the median Cmax between cHL and other tumour types. Based on available safety data in cHL and other tumour types, these differences are not considered clinically meaningful.

Special populations.

The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in population pharmacokinetic analyses. The following factors had no clinically important effect on the clearance of pembrolizumab: age (range 15-94 years), gender, race, mild or moderate renal impairment, mild hepatic impairment, and tumour burden. The relationship between body weight and clearance supports the use of either fixed dose or body weight-based dosing to provide adequate and similar control of exposure. Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 3 weeks in paediatric patients (6 to 17 years) are comparable to those of adults at the same dose. For patients aged < 2 years, systemic exposure is predicted to be approximately 120% greater than in adults; this should be interpreted with caution as it is based on PK extrapolation.

Renal impairment.

The effect of renal impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analysis in patients with mild (GFR < 90 and ≥ 60 mL/min/1.73 m2) or moderate (GFR < 60 and ≥ 30 mL/min/1.73 m2) renal impairment compared to patients with normal (GFR ≥ 90 mL/min/1.73 m2) renal function. No clinically important differences in the clearance of pembrolizumab were found between patients with mild or moderate renal impairment and patients with normal renal function. Keytruda has not been studied in patients with severe (GFR < 30 and ≥ 15 mL/min/1.73 m2) renal impairment [see Section 4.2 Dose and Method of Administration].

Hepatic impairment.

The effect of hepatic impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analysis in patients with mild hepatic impairment (total bilirubin (TB) 1.0 to 1.5 x ULN or AST > ULN as defined using the National Cancer Institute criteria of hepatic dysfunction) compared to patients with normal hepatic function (TB and AST ≤ ULN). No clinically important differences in the clearance of pembrolizumab were found between patients with mild hepatic impairment and normal hepatic function. Keytruda has not been studied in patients with moderate (TB > 1.5 to 3 x ULN and any AST) or severe (TB > 3 x ULN and any AST) hepatic impairment [see Section 4.2 Dose and Method of Administration].

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of pembrolizumab has not been evaluated. As a large protein molecule, pembrolizumab is not expected to interact directly with DNA or other chromosomal material.

Carcinogenicity.

The carcinogenic potential of pembrolizumab has not been evaluated in long-term animal studies.

6 Pharmaceutical Particulars

6.1 List of Excipients

Histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 80, water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C to 8°C).
Protect from light. Do not freeze. Do not shake.
For storage conditions after dilution of the medicinal product, see Section 4.2 Dose and Method of Administration.

6.5 Nature and Contents of Container

Carton of one 100 mg/4 mL concentrated injection single-use vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Keytruda (pembrolizumab) is a selective humanised monoclonal antibody designed to block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in Chinese hamster ovary cells by recombinant DNA technology.

CAS number.

1374853-91-4.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes