Approved indication: metastatic melanoma
Keytruda (MSD)
vials containing 50 mg powder
Australian Medicines Handbook section 14.2.1

Along with vemurafenib1, dabrafenib2 and trametinib3, pembrolizumab is approved for metastatic melanoma. Like ipilimumab4, it is an immune checkpoint inhibitor that works by modulating the patient’s own immune response to tumour cells.5

Pembrolizumab was formerly known as MK3475 and lambrolizumab. It is a humanised monoclonal antibody that blocks the interaction between programmed death 1 (PD-1) on T cells with its ligands PD-L1 and PD-L2 on immune and tumour cells. Blocking this interaction boosts the immune response and potentially leads to tumour regression.

This antibody is indicated as monotherapy for inoperable or metastatic melanoma. It is given intravenously (over 30 minutes) every three weeks. The drug’s terminal half-life is approximately 26 days. The drug is catabolised and its clearance is not affected by mild−moderate renal impairment or mild hepatic impairment. Pembrolizumab has not been studied in patients with more severe renal or hepatic impairment.

Pembrolizumab has been assessed in a number of clinical trials. A phase I non-randomised trial enrolled 135 patients with advanced disease. The majority of participants (69%) had received previous systemic treatment, including chemotherapy, immunotherapy, or a BRAF inhibitor. Patients were given pembrolizumab 10 mg/kg every two or three weeks, or 2 mg/kg every three weeks. Across all doses, 38% of patients who could be evaluated had a confirmed response to treatment (see Table). The estimated median progression-free survival was over seven months and median overall survival was not reached.6

Table Efficacy of pembrolizumab in metastatic melanoma

Phase I trial 6


10 mg/kg every 2 weeks

(52 patients)


10 mg/kg every 3 weeks

(45 patients)


2 mg/kg every 3 weeks

(20 patients)

Response rate‡




Phase I trial – expanded cohort 7


10 mg/kg every 3 weeks

(76 patients)


2 mg/kg every 3 weeks

(81 patients)

Response rate‡

26% (1 complete and 19 partial responses)

26% (1 complete and 20 partial responses)

Median progression-free survival

14 weeks

22 weeks

Overall survival at 12 months



Phase III trial 8


10 mg/kg every 2 weeks

(279 patients)


10 mg/kg every 3 weeks

(277 patients)


3 mg/kg every 3 weeks

(278 patients)

Response rate‡

33.7% (14 complete, 80 partial responses)

32.9% (17 complete, 74 partial responses)

11.9% (4 complete, 29 partial responses)

Median progression-free survival

5.5 months

4.1 months

2.8 months

Overall survival at 12 months




‡ Complete and partial responses were based on assessment of target and non-target lesions according to the RECIST 1.1 criteria.6

This phase I trial was expanded to include another cohort of patients who were refractory to ipilimumab and, if they had the BRAF mutation, had previously been treated with a BRAF or MEK inhibitor, or both. They were randomly assigned to pembrolizumab 2 mg/kg or 10 mg/kg every three weeks. Just over a quarter of patients responded to treatment and 58−63% were still alive after a year (see Table).7 The efficacy of pembrolizumab in the phase I trial seemed to be independent of the dose.6,7

An analysis of 146 patients who received pembrolizumab 2 mg/kg found that response rates were better in those who had not previously been treated with ipilimumab compared with those who had (37% vs 26%). The median duration of progression-free survival was also longer (36 vs 22 weeks). At six months, overall survival was similar in ipilimumab-naïve and pre-treated patients (79% vs 83%). This analysis has not yet been published in full.

A randomised phase III trial compared pembrolizumab to ipilimumab. All enrolled patients had advanced melanoma but only 34% had been previously treated with systemic therapy. Pembrolizumab 10 mg/kg every two or three weeks improved progression-free and overall survival compared to ipilimumab. Response rates were also better with pembrolizumab (see Table).8

In the safety cohort of 411 patients, the most common treatment-related adverse events included arthralgia (14.8%), diarrhoea (14.8%), fatigue (30.2%), nausea (10%), pruritus (22.8%), cough (11.1%) and rash (19.8%). Albumin (36.7%), haemoglobin (51.6%) and lymphocytes (28.2%) went down with pembrolizumab. Decreased calcium (28.5%) and sodium (32.6%) concentrations were also observed. Liver function should be monitored as increases in alanine aminotransferase (23.6% of patients), alkaline phosphatase (22.6%) and aspartate aminotransferase (27.7%) were common.

Because of pembrolizumab’s mechanism of action, immune-mediated adverse reactions are a concern. In the safety cohort, these included pneumonitis (12 patients), colitis (4 patients), hepatitis (2 patients) and nephritis (3 patients). Immune-mediated endocrinopathies have also been reported including hypophysitis (2 patients), type 1 diabetes, hyperthyroidism (5 patients) and hypothyroidism (34 patients). Monitoring blood glucose and thyroid function at the start and during pembrolizumab therapy is recommended. Depending on severity of these events, pembrolizumab should be interrupted or stopped and patients should be treated with corticosteroids. Severe infusion-related reactions have occasionally been reported with pembrolizumab and this is a contraindication to further treatment.

More patients discontinued the 10 mg/kg dose than the 2 mg/kg dose because of an adverse event.7 The most common reasons for stopping pembrolizumab were pneumonitis, renal failure and pain.

Pembrolizumab is a category D drug in pregnancy. Although there are no data in pregnant women, blocking PD-1 in animals increases fetal loss. Contraception should be used during and for four months after treatment has finished.

The recommended dose of pembrolizumab is 2 mg/kg every three weeks. Around a quarter of patients with pre-treated metastatic melanoma responded to this dose. Response rates were better in those who had not previously been treated with ipilimumab. Autoimmune adverse reactions are a problem with this drug and regular patient monitoring is vital. Patients do not need to carry the BRAF mutation to be eligible for pembrolizumab.


🅃 🅃 manufacturer provided additional useful information

The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available the websites of the Food and Drug Administration in the USA and the European Medicines Agency.


Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.