Melanoma is a malignancy of the melanocytes caused by UV exposure, resulting in gene mutations due to DNA thymine dimerisation leading to tumours, predominantly in the skin. Melanoma is one of the less common forms of cancer with an annual incidence of approximately 160,000 and is prominent in Caucasians living in sunny climates.
However, the incidence has increased substantially in the last few decades, particularly in women, and the disease is responsible for 75 per cent of all skin cancer mortality (48,000 melanoma-related deaths annually). The average overall survival of advanced melanoma is approximately nine months. Many forms of the disease have a strong hereditary link.
Initial melanoma diagnosis and staging is made visually and confirmed by biopsy; a lactate dehydrogenase (LDH) test is used to screen for metastases. Successful treatment of melanoma – complete surgical excision of the tumour – is possible only if diagnosed and treated early when the tumour is small and thin (during the radial growth phase).
Skin tumours thicken with longer disease duration (invasive vertical growth phase) and eventually reach the blood and lymph vessels in the dermis – at this stage they are more likely to metastasise, occurring in <20 per cent of cases. BRAF gene mutations (seen in 50 per cent of malignant melanoma cases) are associated with increased growth and proliferation of cancer cells.
Chemotherapy (eg, dacarbazine) and immunotherapy (interleukin [IL]-2 or interferon [IFN]) are used after surgery depending on the staging of the tumour, but response rates are low. Radiotherapy is also used but mainly palliatively.
The costs of treating melanoma have increased dramatically in recent years due to increasing incidence and a rise in cancer healthcare costs. The most expensive parts of medical care are drug and administration costs of chemotherapy, immunotherapy and palliative care. Even taking into account the cost of long-term surveillance, total medical costs are much lower in patients diagnosed and treated early.
Recent pharmacotherapy advances for advanced melanoma include BRAF inhibitors vemurafenib (Zelboraf; Plexxicon), which was approved in 2011 in the US, and dabrafenib (GSK) that is awaiting registration in Europe and the US.
Two types of BRAF inhibitors have been developed for advanced melanoma. Type 1 selective BRAF inhibitors, such as dabrafenib and vemurafenib, bind and inhibit the active conformation of the proto oncogene protein b raf (BRAF kinase) selectively, whereas Type 2 non-selective BRAF inhibitors bind to the inactive conformation of the protein.
Dabrafenib is a selective reversible inhibitor of the BRAF protein, a product of the B-Raf gene, which is one of the genes involved in the mitogen-activated protein (MAP) kinase pathway. The B-Raf gene contains a mutation in approximately 50 per cent of melanoma cases, resulting in expression of an oncogenic protein – mutant BRAF kinase, which elevates activity of the MAP kinase pathway.
BRAF inhibition reduces MAP kinase activity, resulting in suppression of progression or regression in the majority of patients with the mutation.
Dabrafenib clinical profile
The phase II trial (BREAK-2) involving patients with metastatic melanoma with B-Raf gene mutation BRAFV600E showed that dabrafenib 150mg twice daily was characterised by a rapid onset of action, high response rates (53 per cent partial response and 7 per cent complete response) and prolonged progression-free survival (PFS) over standard chemotherapy, such as dacarbazine 1000 mg/m3 every three weeks (27 weeks longer).
In patients with the BRAFV600K mutation, the response rates were lower (13 per cent partial response and 0 per cent complete response) and PFS was a little less prolonged (20 weeks longer than standard chemotherapy).
The phase II brain metastases trial (BREAK-MB) was conducted in patients with BRAF mutant melanoma with or without prior local treatment for brain metastases (surgery, stereotactic radiosurgery, and/or whole brain radiotherapy). Dabrafenib was well tolerated and effective in terms of investigator-assessed overall intracranial response rate [OIRR], overall response rate, PFS and OS. Furthermore, the findings were impressive compared with data from studies of standard chemotherapy.
Data from the phase III trial (BREAK-3) in 250 BRAFV600E patients with stage IV or unresectable stage IIIC melanoma (including those with brain metastases) confirmed phase II data.
Interim data showed that the median PFS was significantly longer with dabrafenib, compared with dacarbazine (5.1 months versus 2.1 months; hazard ratio for progression 0.30; 95 per cent CI 0.18–0.51; P < 0.0001). Response rates were substantially higher with dabrafenib (47 per cent partial and 3 per cent complete) versus dacarbazine (4 per cent partial and 2 per cent complete), and toxicities were similar to earlier phase studies with only 3 per cent of patients discontinuing because of toxicity issues. Indirect comparison of study data suggests that dabrafenib has similar efficacy in terms of response and PFS and lower toxicity than vemurafenib.
Dabrafenib has been well tolerated with a mild and manageable toxicity profile. In phase II clinical trials, adverse events were common – the most frequent toxicities of any grade being arthralgia, hyperkeratosis, pyrexia, fatigue, headache, nausea, and skin papilloma (15–33%) – but rarely led to dose reduction (14 per cent) or discontinuation (1 per cent). Serious adverse events included cutaneous squamous cell carcinoma (9 per cent), basal cell carcinomas (4 per cent) and pyrexia (3 per cent).
Cutaneous disorders are known adverse effects of RAF inhibitors. In addition to cutaneous squamous cell carcinoma, other rare cutaneous disorders observed on treatment include hyperkeratotic lesions, Grover's disease, keratosis pilaris-like reactions and photosensitivity.
Interim data showed that the median PFS was significantly longer with dabrafenib
To avoid a marked negative impact on patients' quality of life, regular dermatological assessment and timely management is required for patients receiving BRAF inhibitors.
Ongoing dabrafenib research
Combination therapy with dabrafenib plus trametinib is being investigated in phase III trials, COMBI-d and COMBI-v. Trametinib (GSK) is a MAP kinase kinase inhibitor (MEK inhibitor) awaiting registration in the US as monotherapy in patients with late-stage, metastatic BRAFV600-positive melanoma.
COMBI-d is comparing the combination with dabrafenib monotherapy and COMBI-v with vemurafenib monotherapy. Patients have stage IIIC or IV metastatic melanoma and are BRAF V600E/K-mutation positive. Efficacy (PFS and overall survival) by LDH level (> upper limit of normal [ULN] vs ≤ULN) and BRAF mutation type (V600E vs V600K) are also being evaluated.
This trial will enrol approximately 340 patients from the US, Australia, Argentina, Canada, Europe, Russia and Ukraine. Another phase II trial (COMBI-AD) is planned to compare dabrafenib plus trametinib versus placebo for adjuvant treatment of melanoma after surgical resection, and another will investigate the combination in metastatic melanoma refractory to a BRAF inhibitor.
An open-label, dose escalation study is currently recruiting and is investigating the safety, pharmacokinetics, pharmacodynamics and clinical activity of the combination in patients with stage III/IV melanoma failing prior treatment with dabrafenib or vemurafenib.
The phase II BREAK-MB trial involving patients with BRAF mutant melanoma that has metastasised to the brain started in February 2011 and approximately 172 patients have been enrolled. Patients with or without prior local therapy for brain metastases will receive dabrafenib (150 mg twice daily) until disease progression, death or unacceptable adverse event. The primary efficacy measure is the overall intracranial response rate. Another phase II study is planned to compare dabrafenib monotherapy with dabrafenib adjuvant therapy plus stereotactic radiosurgery in BRAFV600E melanoma brain metastases.
Future pipeline for melanoma
Other BRAF inhibitors
Vemurafenib is an oral agent already approved for the first-line treatment of malignant melanoma in the UK and US, and is registered in many other countries. It is being used as an adjuvant therapy and is in phase III development in the US and Europe, and as combination therapy in the US. Phase III development of a type 2 BRAF inhibitor sorafenib (Nexavar; Onyx Pharmaceuticals) was suspended as the phase III clinical trials showed that the drug did not improve PFS or overall survival.
In addition, several other BRAF inhibitors – LGX 818 (Novartis), RAF 265 (Novartis) and XL 281 (Exelixis) – are in phase I development in metastatic/late-stage melanoma.
Early-stage development is ongoing into the use of a range of MAP kinase pathway inhibitors in the treatment of melanoma.
Other targeted therapies being investigated in clinical trials in advanced (metastatic) melanoma include adoptive cell therapy. This involves isolating tumour infiltrating lymphocytes from the patient's tumour, growing them in vitro and returning them to the patient after lymphodepletion therapy to knock out the patient's normal T cells.
A form of gene therapy – adoptive immunotherapy – is also being investigated in this indication. This involves genetic alteration of the patients' lymphocytes so that they encode specific T cell receptors (TCRs). This allows the lymphocytes to recognise and bind to certain molecules found on the surface of melanoma cells and kill them.
Clinical data has shown that dabrafenib monotherapy is effective and well tolerated in patients with unresectable or metastatic melanoma who also have the BRAF V600 mutation; registration for use in this patient population is expected in 2013.
To aid identification of BRAFV600-positive patients who are suitable candidates for dabrafenib therapy, GSK is collaborating with bioMérieux to develop a molecular theranostic test to identify BRAFV600 (V600E and V600K) mutations.
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