Cutaneous malignant melanoma, the most aggressive form of skin cancer, primarily affects young adults.1 Treatment is usually with surgical excision, which provides disease clearance for most patients.2
But if the disease metastasises, survival is poor. Stage I disease has a five-year survival of more than 90%, but stage IV disease is only 20%.3 Collaborative efforts in basic and clinical research have investigated novel therapeutic approaches for the management of patients with metastatic melanoma.
Oncogenic BRAF signalling
Perhaps the most important determinant of treatment modality for patients with metastatic melanoma is the presence or absence of BRAF mutations. BRAF is a deregulated cellular signalling mechanism linked to the development of melanoma.
Mutations in BRAF lead to activation of the mitogen-activated protein kinase (MAPK) signalling pathway (figure 1), which promotes cell growth, proliferation, differentiation and migration, and regulates apoptosis.4 About 60% of cutaneous melanomas have a mutation in BRAF.
The presence or absence of a BRAF mutation determines whether targeted BRAF/MEK inhibition, immunotherapy or standard treatment with chemotherapy are used.
Metastatic disease has traditionally been treated with chemotherapy, including dacarbazine5 and temozolomide,6 alone or in combination with other agents. These approaches had a response rate of about 15% (with dacarbazine)5 and a modest improvement in overall survival of 7.4 months. Combinations failed to demonstrate a significant clinical advantage.
It is now known that activation of a number of survival mechanisms and resistance to apoptosis renders this type of tumour unresponsive to conventional chemotherapy. Research has focused on the development of more specific and efficacious targeted therapies and immunomodulatory treatments. Despite this, there is still a role for chemotherapy in patients who have developed resistance to targeted agents and immunotherapy.
One of the most significant advances in malignant melanoma treatment over the past decade is the development of inhibitors to MAPK signalling (either BRAF-specific inhibitors, or ?MEK-specific inhibitors).
Vemurafenib was the first BRAF inhibitor to be licensed in the UK for patients with metastatic or unresectable stage III malignant melanoma. It has demonstrated enhanced overall and progression-free survival for patients with BRAF-mutant melanomas (5.3 months with vemurafenib versus 1.6 months with dacarbazine).7 Vemurafenib has a number of potential ?side-effects, including photosensitivity, hepatitis, skin rash, uveitis and secondary skin cancers.8
Another BRAF inhibitor, dabrafenib , was developed and is extensively used in clinical practice because of its favourable safety profile. Dabrafenib is effective in prolonging overall and progression-free survival compared with dacarbazine.9 Both vemurafenib and dabrafenib have revolutionised melanoma therapy, but their efficacy is limited by acquired resistance.10
To overcome this, downstream MEK inhibitors have been developed, including the MEK1/2-specific inhibitors trametinib and cobimetinib , which have been used in combination with BRAF inhibitors (figure 2).
A dabrafenib and trametinib combination is approved by NICE for use as first-line therapy in BRAF-mutant metastatic melanoma.11 The combination has shown improved progression-free survival for patients with BRAF-mutant melanoma over a BRAF inhibitor alone (11.4 months in combination group versus 7.3 months in vemurafenib group).12-14
Both BRAF and MEK inhibitors have a wide range of potential side-effects, including pyrexia, rigors, nausea, vomiting, rash, acral hyperkeratosis, arthralgia and, rarely, decrease in cardiac function – but the combination is well tolerated.
Immunotherapy relies on activation and augmentation of immune responses that target cancer cells.15 Ipilimumab , a cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor inhibitor that enhances T-cell activity,16 was the first immunotherapy to be approved by the US Food and Drug Administration for metastatic melanoma.17 Ipilimumab has demonstrated superior outcomes over the melanoma vaccine gp100 and has an improved effect on patient overall survival.18
However, its use is limited by a number of side-effects – the most common and serious is autoimmune colitis. Diarrhoea occurs in about 20% of patients. Other side-effects include skin rash, autoimmune thyroiditis and endocrinopathies, and inflammation of the nerves and eyes.
Recent studies have highlighted novel and more effective immunomodulatory approaches. PD-1 (programmed death-1) is an important immune checkpoint receptor in activated T-cells. When PD-1 binds to PD-1 ligand (PD-L1), which is expressed on the surface of cancer cells,19 T-cell function is inhibited (figure 3).20,21
There is growing evidence to support the use of PD-1 and PD-L1 inhibitors in patients with advanced melanoma, although response rates remain at about 30% in PD-1 monotherapy.22-25
The combination of PD-1 and CTLA-4 blockade with ipilimumab and nivolumab has also acquired approval from NICE and is the first-line treatment for patients with BRAFWT (wild type) metastatic melanoma.
This combination demonstrates a significantly enhanced effect on progression-free survival (11.5 months with nivolumab plus ipilimumab, compared with 2.9 months with ipilimumab and 6.9 months with nivolumab alone).26 Although this has been a major breakthrough, combination immunotherapy presents a higher risk of serious side-effects compared with monotherapy (55% combination versus 16% nivolumab versus 27% ipilimumab).26
Side-effects in patients receiving combination immunotherapy include diarrhoea and autoimmune colitis, thyroiditis and autoimmune endocrinopathies, pruritus and skin rashes, inflammation of the eyes and peripheral nerves, hepatitis, nausea, vomiting and fatigue. Healthcare professionals need to recognise these side-effects and initiate appropriate treatment promptly.
The introduction of targeted therapies and immunotherapy has revolutionised the management of patients with metastatic melanoma. Targeted therapy with dabrafenib and trametinib has significantly improved survival in patients with BRAF mutant metastatic melanoma.
The introduction of immunotherapy with nivolumab, pembrolizumab or ipilimumab alone or in combination has significantly changed clinical practice, introducing more treatment options for patients with both BRAF mutant and WT disease. These recent developments have ushered in a new era in the management of patients with melanoma, but also bring new challenges for clinicians.
There is no clear evidence on the best sequence of these treatments or management of side-effects. Several prospective clinical studies combining immunotherapy and targeted therapies or other novel targets for melanoma are under way.
- Dr Stamatina Verykiou is a dermatology SpR and clinical fellow in dermato-oncology at the Royal Victoria Infirmary, Newcastle upon Tyne
- Cancer Research UK. Cancer statistics.
- Balch CM, Gershenwald JE, Soong SJ et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27: 6199-206
- Cancer Research UK. Melanoma skin cancer.
- Dhillon AS, Hagan S, Rath O et al. MAP kinase signalling pathways in cancer. Oncogene 2007; 26: 3279-90
- Lens MB, Eisen TG. Systemic chemotherapy in the treatment of malignant melanoma. Expert Opin Pharmacother 2003; 4: 2205-11
- Middleton MR, Grob JJ, Aaronson N et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000; 18: 158
- 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
- Hagen B, Trinh VA. Managing side effects of vemurafenib therapy for advanced melanoma. J Adv Pract Oncol 2014; 5: 400-10
- Hauschild A, Grob J-J, Demidov LV et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet; 380: 358-65
- Sosman JA, Kim KB, Schuchter L et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012; 366: 707-14
- NICE. Trametinib in combination with dabrafenib for treating unresectable or metastatic melanoma. NICE 2016.
- Larkin J, Ascierto PA, Dréno B et al. Combined vemurafenib and cobimetinib in BRAF-mutated aelanoma. N Engl J Med 2014; 371: 1867-76
- Long GV, Stroyakovskiy D, Gogas H et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014; 371: 1877-88
- Flaherty KT, Robert C, Hersey P et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367: 107-14
- Tjin EPM, Konijnenberg D, Krebbers G et al. T-cell immune function in tumor, skin, and peripheral blood of advanced stage melanoma patients: implications for immunotherapy. Clin Cancer Res 2011; 17: 5736-47
- Walunas TL, Lenschow DJ, Bakker CY et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994; 1: 405-13
- Mansh M. Ipilimumab and cancer immunotherapy: a new hope for advanced stage melanoma. Yale J Biol Med 2011; 84: 381-9
- 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
- Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012; 24: 207-12
- Melero I, Grimaldi AM, Perez-Gracia JL et al. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res 2013; 19: 997-1008
- Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252-64
- Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti–PD-1 antibody in Cancer. N Engl J Med 2012; 366: 2443-54
- Robert C, Schachter J, Long GV et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015; 372: 2521-32
- Postow MA, Chesney J, Pavlick AC et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372: 2006-17
- Hamid O, Robert C, Daud A et al. Safety and tumor responses with lambrolizumab (Anti–PD-1) in melanoma. N Engl J Med 2013; 369: 134-44
- Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373: 23-34