The incidence of melanoma has increased over recent years and one in 10 patients with melanoma will present with metastatic disease at diagnosis. Metastatic melanoma is associated with a poor prognosis so it is timely that a number of targeted drug therapies have been developed to treat the condition. This article reviews the most recent cancer drugs that have been designed to treat metastatic melanoma and outlines the evidence for their use.
Combination therapies, drug therapies, metastatic melanoma, skin cancer, targeted treatment
Melanoma is a malignant tumour originating from melanocytes associated with excessive exposure to UV radiation, with fair-skinned individuals at greatest risk.1,2
The incidence of melanoma has increased in recent years; the most recent statistics available for the UK estimate age-standardised incidence and mortality rates of 17.1 and 2.6 per 100,000 population, respectively, with 12,818 cases diagnosed in 2010 and 2,209 deaths in 2011.3
One important feature of melanoma is a tendency to metastasise and 10% of patients present with metastatic disease at diagnosis.1 Metastatic melanoma is associated with a poor prognosis; the 10-year survival rate in patients with regional metastases is 20-40%, while median survival in untreated patients with distant metastases is only six to nine months.1
A number of drug therapies have recently been developed for the treatment of metastatic melanoma, with an increasing trend towards the use of targeted therapies.
Many of these therapies target the mitogen-activated protein kinase (MAPK) signalling protein pathway, where mutations have been identified.
BRAF mutations are the most common mutations in cutaneous melanomas, detected in approximately 40-60% of tumours.4-6 The most common BRAF mutation in melanoma is BRAF V600E, which accounts for approximately 75% of BRAF mutations detected.4
Mutations such as BRAF V600E lead to activation of the MAPK signalling pathway, stimulating cell proliferation.4-6 Vemurafenib and dabrafenib, both BRAF inhibitors, are licensed for use in patients with metastatic or unresectable BRAF V600E mutation-positive melanoma.7,8
Early studies showed significant improvement in survival in patients with metastatic or unresectable BRAF V600E mutation-positive melanoma who were treated with vemurafenib versus dacarbazine, the previous standard chemotherapy for metastatic melanoma.9
Although generally well tolerated by patients, it is now recognised that vemurafenib is associated with a number of adverse events, particularly skin toxicity.9-11 In the largest study to date, of 3,222 patients with metastatic melanoma, assessing the safety profile of vemurafenib,12 the most frequently observed adverse events were rash, photosensitivity, alopecia, hyperkeratosis, dry skin and cutaneous squamous cell carcinoma. Basal cell carcinomas and new primary melanomas were both observed in 1% of patients in the study.12
Dabrafenib has similar skin toxicity to vemurafenib, but unlike vemurafenib, dabrafenib is not associated with increased occurrence of photosensitivity.13,14
Cutaneous adverse events were also assessed in a prospective study of 43 patients treated with dabrafenib.15 Of these, 93% developed skin toxicity, including 49% verrucal keratosis, 20% squamous cell carcinoma, 27% Grover's disease, 34% seborrhoeic keratosis and 22% plantar hyperkeratosis.
The MEK inhibitors, whose actions are downstream of BRAF signalling, have also demonstrated improved progression-free and overall survival when compared with conventional cytotoxic chemotherapy.16
Recently, the combination of BRAF and MEK inhibitors has shown increased progression-free survival compared with BRAF inhibition alone.16,17 They are also associated with significant skin toxicity, including acneiform eruptions, peripheral oedema and alopecia.18 However, combination therapy of BRAF and MEK inhibitors leads to a reduction in overall skin toxicity, in particular, less frequent development of squamous cell carcinomas.18
Pan-RAF inhibitors have recently been developed to treat patients with BRAF wild-type metastatic melanoma or NRAS mutant metastatic melanoma, and those patients who have developed resistance to BRAF inhibitors.19
BRAF inhibitor resistance is well recognised and is mainly a result of RAF paradoxical activation via RAF dimerisation in BRAF wild-type cells.
A recent study has demonstrated that the selective pan-RAF inhibitor TAK-632 suppresses RAF activity in BRAF wild-type cells with minimal RAF paradoxical activation.19
In preclinical models, TAK-632 demonstrated potent antiproliferative effects on NRAS- and BRAF-mutated melanoma cells with acquired resistance to BRAF inhibitors through NRAS mutation or BRAF truncation. The combination of pan-RAF and MEK inhibitors exhibits synergistic antiproliferative effects.19,20
Immunomodulatory treatments including ipilimumab, anti-PD1 and anti-PDL-1 are now being widely used in the treatment of BRAF-mutated and wild-type metastatic melanoma.
Ipilimumab is a fully human monoclonal antibody (IgG1) that blocks CTLA-4 to promote antitumour immunity. Original studies showed improved survival with ipilimumab in patients with metastatic melanoma.21,22
This treatment is also associated with significant adverse events, including skin toxicity (rash), hepatitis, colitis and endocrine abnormalities.
Pembrolizumab (MK-3475) is a monoclonal antibody that binds to the PD-1 receptor on T cells and prevents binding to its ligands PD-L1 and PD-L2. Blocking this receptor frees T cells from the inhibitory effects of PD-L1 and allows them to mediate antitumour effects against cancer cells.
In a large phase I study of 411 patients with melanoma, high durable response rates over a range of doses and schedules have been shown, with very little toxicity.23 Another study showed that pembrolizumab can be effective in patients who do not respond to ipilimumab.24
Targeted treatment of metastatic melanoma is a rapidly advancing field and huge advances have been made in the past five years. These recently approved therapies for metastatic melanoma have made a significant impact on patient survival, although development of drug resistance is challenging.
Combination therapies provide a rational strategy to potentiate efficacy and overcome resistance. These agents are associated with significant toxicities, especially skin toxicity, so dermatologists need to be involved in managing these patients, to enable them to remain on this life-saving treatment.
- Dr Louise Fearfield is a consultant dermatologist at The Royal Marsden and Chelsea and Westminster Hospitals, London
Competing interests: Dr Fearfield has received honoraria for lectures from Roche
1. Garbe C, Peris K, Hauschild A et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline: Update 2012. Eur J Cancer 2012; 48: 2375-90.
2. Garbe C, Leiter U. Melanoma epidemiology and trends. Clin Dermatol 2009; 27: 3-9.
3. Cancer Research UK. Skin cancer incidence statistics 2014.
4. Greaves WO, Verma S, Patel KP et al. Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma. J Mol Diagn 2013; 15: 220-6.
5. Curtin JA, Fridlyand J, Kageshita T et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353: 2135-47.
6. Davies H, Bignell GR, Cox C et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949-54.
7. Roche. Zelboraf summary of product characteristics 2014.
8. GSK. Dabrafenib summary of product characteristics 2014.
9. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507-16.
10. Sinha R, Edmonds K, Newton-Bishop JA et al. Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br J Dermatol 2012; 167: 987-94.
11. Boussemart L, Routier E, Mateus C et al. Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol 2013; 24: 1691-7.
12. Larkin J, Del Vecchio M, Ascierto PA et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol 2014; 15: 436-44.
13. Ascierto PA, Minor D, Ribas A et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol 2013; 31: 3205-11.
14. Hauschild A, Grob JJ, Demidov LV et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380: 358-65.
15. Anforth RM, Blumetti TC, Kefford RF et al. Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br J Dermatol 2012; 167: 1153-60.
16. Larkin J, Ascierto PA, Dreno B et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014; 371: 1867-76.
17. Robert C, Karaszewska B, Schachter J et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2014; 372: 30-9.
18. Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367: 1694-703.
19. Nakamura A, Arita T, Tsuchiya S et al. Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Cancer Res 2013; 73: 7043-55.
20. Atefi M, Titz B, Avramis E et al. Combination of Pan-RAF and MEK inhibitors in NRAS mutant melanoma. Mol Cancer 2015; 14(1): 27. (Epub ahead of print).
21. Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711-23.
22. Robert C, Thomas L, Bondarenko I et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364: 2517-26.
23. Hersey P, Gowrishankar K. Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Future Oncol 2015; 11(1): 133-40.
24. Robert C, Ribas A, Wolchok JD et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014; 384: 1109-17.