Table 1 lists current oral small-molecule inhibitors for specific cancers that are reimbursed by the Pharmaceutical Benefits Scheme (PBS). A large number are also under investigation in clinical trials so it is expected that more will be approved over the next few years.
Mode of action
Small-molecule inhibitors are able to cross the cell plasma membrane and interfere with intracellular targets. They often act on multiple pathways in the cell.
Protein kinases play an important role in regulating cellular activity and are often found to be mutated in cancer. A number of therapies have been developed that block kinase activity and hence block cell growth. These drugs carry the suffix -nib.
BCR-ABL inhibitors
Imatinib was one of the first targeted therapies to be developed for the treatment of chronic myeloid leukaemia. It blocks the BCR-ABL protein kinase which results from a chromosomal translocation (the Philadelphia chromosome) in chronic myeloid leukaemia. Imatinib inhibits the proliferation of leukaemia cells and results in durable responses in over 80% of patients.1 Imatinib is also active against gastrointestinal stromal tumours and certain types of acute leukaemia.
Epidermal growth factor receptor inhibitors
The epidermal growth factor receptor (EGFR) exists on the outside of cells and is activated by growth factor ligands. Once activated, intracellular tyrosine kinase activity occurs and several signal transduction cascades are initiated which lead to cell proliferation. In many cancers the EGFR activity is increased due to mutations in the receptor or tyrosine kinase protein domains. EGFR tyrosine kinase inhibitors, such as erlotinib and gefitinib, act on the EGFR tyrosine kinase domain. They are used to treat advanced non-small cell lung cancers that have the EGFR mutation.2,3
Lapatinib inhibits the tyrosine kinase activity associated with EGFR and human epidermal growth factor receptor 2 (HER2).4 The HER2 receptor is overexpressed in about 25–30% of breast cancers.
BRAF and MEK inhibitors
Other targeted drugs inhibit pathways that occur downstream of the EGFR receptor. Dabrafenib inhibits the activity of BRAF, an intracellular protein kinase of the RAF kinase family that drives cell proliferation and can be mutated in melanoma cells (Aust Prescr 2014;37:28-35 ). Dabrafenib significantly improves progression-free survival (by approximately two months) in melanoma compared to standard chemotherapy.5
Trametinib inhibits the MEK pathway and has been combined with dabrafenib in an effort to reduce resistance to dabrafenib, and to reduce some of the adverse effects associated with BRAF inhibition.6
Multi-targeted drugs including vascular endothelial growth factor inhibitors
Sunitinib, sorafenib and pazopanib are kinase inhibitors that affect multiple pathways involved in cancer cell growth. In addition to blocking tyrosine kinase pathways they block the vascular endothelial growth factor (VEGF) protein which promotes angiogenesis. These drugs are active in a variety of cancers due to their diverse activity (Table 1).7-11
Table 1 Oral targeted therapies subsidised by the Pharmaceutical Benefits Scheme 7-11
Target
|
Medicine (brand name)
|
Indication
|
BRAF
|
dabrafenib (Tafinlar)
|
melanoma
|
BCR-ABL
|
imatinib (Glivec)
|
chronic myeloid leukaemia, gastrointestinal stromal tumour
|
dasatinib (Sprycel)
|
chronic myeloid leukaemia
|
nilotinib (Tasigna)
|
chronic myeloid leukaemia
|
EGFR
|
erlotinib (Tarceva)
|
non-small cell lung cancer
|
gefitinib (Iressa)
|
non-small cell lung cancer
|
lapatinib (Tykerb)
|
metastatic breast cancer
|
MEK
|
trametinib (Mekinist)
|
melanoma
|
mTOR
|
everolimus (Afinitor)
|
metastatic breast cancer, renal cell carcinoma
|
Multi-targeted, including VEGF
|
pazopanib (Votrient)
|
renal cell carcinoma, soft tissue sarcoma
|
sunitinib (Sutent)
|
renal cell carcinoma, pancreatic neuroendocrine tumour
|
sorafenib (Nexavar)
|
hepatocellular carcinoma
|
Immune system (immunomodulators)
|
thalidomide (Thalomid)
|
myeloma
|
lenalidomide (Revlimid)
|
myeloma, myelodysplastic syndrome
|
pomalidomide (Pomalyst)
|
myeloma
|
BRAF Intracellular protein kinase that forms part of the mitogen-activated protein (MAP) kinase pathway and drives cell proliferation
|
BCR-ABLBCR = breakpoint cluster region, ABL = abelson murine leukemia oncogene-1 (BCR-ABL is a fusion gene created by the ABL1 gene on chromosome 9 to the BCR gene on chromosome 22)
|
EGFR Epidermal growth factor receptor (member of the ErbB family of receptors that promotes cell proliferation)
|
MEK MAPK/ERK kinase (MAPK = mitogen activated protein kinase, ERK = extracellular-signal-regulated kinase)
|
mTOR Mammalian target of rapamycin (protein kinase that regulates cell growth)
|
VEGF Vascular endothelial growth factor (protein produced by cancer cells that stimulates angiogenesis)
|
|
Adverse effects
Despite their selectivity, targeted therapies still have adverse effects, ranging from mild skin reactions to fatal gastrointestinal perforation (see Table 2). Toxicity depends largely on the target of the drug and the drug’s individual properties. Most targeted therapies, with the exception of immunomodulatory drugs, are known to cause nausea, diarrhoea and skin problems. Adverse effects of individual drugs and the management of these can be found in the eviQ Cancer Treatments Online website (www.eviq.org.au ).12
Patients require constant monitoring while on therapy. All healthcare professionals who see the patient should be aware of the toxicity profile of the therapy and the appropriate management. Many targeted therapies can adversely affect liver and renal function so laboratory results should be monitored regularly. It is usual for the treating haematologist or oncologist to review blood tests monthly. Some targeted therapies are used in combination with cytotoxic chemotherapy. For example, the combination of lapatinib and capecitabine is used in breast cancer and these patients require a regular check of their blood counts before each cycle of chemotherapy.
Table 2 Common adverse affects associated with oral cancer therapies
Adverse effect
|
Drug (affects >1% of patients)
|
Diarrhoea
|
dabrafenib, dasatinib, erlotinib, gefitinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib
|
Hypertension
|
pazopanib, sorafenib, sunitinib
|
Prolongation of QT interval
|
dabrafenib, dasatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib
|
Bleeding
|
dasatinib, erlotinib, gefitinib, pazopanib, sorafenib, sunitinib
|
Constipation
|
lenalidomide, thalidomide
|
Fever
|
dabrafenib
|
Hypothyroidism
|
imatinib, pazopanib, sunitinib
|
Oedema
|
dasatinib, everolimus, imatinib, nilotinib
|
Pulmonary complications
|
dasatinib, imatinib, erlotinib, gefitinib, lapatinib
|
Venous thromboembolic events
|
lenalidomide, pazopanib, sorafenib, sunitinib, thalidomide
|
Reduction in left ventricular ejection fraction
|
dasatinib, lapatinib, pazopanib, sorafenib, sunitinib, trametinib
|
Dermatological effects
Skin reactions are common with targeted therapies that affect the EGFR pathways since the EGFR is found in the skin. These effects tend to develop a few weeks after starting therapy and include rash, itching, and changes in hair and nails.13 Table 3 details common dermatological effects of targeted therapies.
Patients taking EGFR inhibitors should use a mild soap that is free from alcohol and perfume, and apply a bland moisturiser as a preventive measure at least twice a day. Skin can be extra sensitive to the sun and patients should be advised to use a broad spectrum sunscreen (SPF 30+). Hydrocortisone cream and oral antibiotics such as doxycycline which have an anti-inflammatory action are alternatives for skin rashes not responsive to moisturising creams.
The BRAF inhibitors have a potential to cause skin malignancies. These patients should be regularly checked for signs of malignant skin changes such as the development of a squamous cell carcinoma.
The Multinational Association of Supportive Care in Cancer (www.mascc.org) provides useful clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatological toxicities.14 Therapy may need to be interrupted or reduced for severe reactions. This decision will be made by the treating haematologist or oncologist in consultation with the patient.
Table 3 Common skin problems with oral cancer therapies
Skin problems
|
Presentation
|
Papulopustular (acneiform) rash
|
Erythematous pustules with or without pruritus Occurs on scalp, face, upper chest and back Onset occurs 1–6 weeks after treatment commences
|
Xerosis (dry skin) and fissures
|
Dry, scaly, itchy skin Often follows the acneiform rash Painful fissures on tips of fingers and toes Onset 1–2 months after treatment commences
|
Pruritus
|
Often accompanies acneiform rash and dry skin
|
Paronychia
|
Tender and oedematous inflammation of the nail folds of fingers and toes Lesions can become infected Onset about 6 weeks after treatment commences
|
Hand–foot syndrome
|
Redness in the palms of the hands and soles of feet Blisters and cracked peeling skin can develop May be accompanied by painful paraesthesia Onset 1–2 months after treatment commences
|
Hair changes
|
Trichomegaly (elongation and curling of the eyelashes) Hypertrichosis (usually as facial hair) Hyperpigmentation Scalp hair changes including brittle hair, slowed growth and alopecia Onset 2–5 months after treatment commences
|
Gastrointestinal effects
Gastrointestinal-related toxicity is prominent with many targeted therapies. Complications include diarrhoea, constipation and nausea.
Diarrhoea affects up to 80% of patients. In many cases the diarrhoea can be managed with antidiarrhoeal medication, such as loperamide. If not controlled, it can quickly develop into serious dehydration and electrolyte imbalance. Patients must be educated about self-monitoring and self-treatment of diarrhoea when they start therapy. It is usual to provide the patient with a supply of loperamide to use should diarrhoea develop. Patients must be advised to seek advice from their specialist if diarrhoea lasts for longer than 24 hours or does not respond to medication.15 Patients who develop severe diarrhoea may require a dose adjustment, treatment interruption or even discontinuation of the therapy.
Bleeding risk and implications for surgery
Because angiogenesis inhibitors (e.g. pazopanib, sorafenib, sunitinib) affect blood vessels, patients can have problems with bleeding and wound healing.
These drugs should be stopped before any planned surgery or invasive procedures including dental surgery. It is generally recommended that therapy is stopped a week before major surgery and at least 3–4 days before minor surgery. Treatment is generally restarted four weeks after surgery to reduce complications with wound healing, but this may vary according to the therapy, surgery and the patient. Advice should always be sought from the treating oncologist or haematologist with regard to stopping and starting of therapy and for surgical or dental procedures.