Metastatic Melanoma: Recent Therapeutic Progress and Future Perspectives
The prognosis of patients with metastatic melanoma has dramatically improved in recent years with the introduction of two new therapeutic strategies. BRAF and MEK inhibitors are small molecules that are able to block the mitogen-activated protein kinase (MAPK) pathway, which is constitutively activated by recurrent BRAF V600 mutations in 45% of melanoma patients. These agents were shown to provide a rapid and strong response but are often limited by a high rate of secondary resistance. Monoclonal antibodies against the immune checkpoints cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) can restore an efficient and durable anti-tumor immunity, even following treatment discontinuation. Anti-PD-1 antibodies were shown to prolong survival of metastatic melanoma patients and a real cure seems to be obtainable in some patients. Many more therapies are currently under investigation, given that 50% of patients still do not have long-term benefits from approved treatments. The main goal is to avoid or circumvent primary or secondary immune resistance to anti-PD-1 therapy not only by targeting other players in the tumor microenvironment but also by optimizing treatment sequencing and combining anti-PD-1 with other treatments, especially with BRAF and MEK inhibitors. The unexpected major successes of immunotherapies in melanoma have opened the way for the development of these treatments in other cancers. In this review, we describe the different available treatments, their toxicities, and the key components of our decisional algorithms, and give an overview of what we expect to be the near future of melanoma treatment.
Compliance with Ethical Standards
No external funding was used in the preparation of this review.
Conflict of interest
Jean-Jacques Grob has received consulting fees or honorarium for Bristol-Myers Squibb, Roche, Novartis, Amgen, and Pierre-Fabre. Nausicaa Malissen has received consulting fees from Bristol-Myers Squibb and payment for lectures from Bristol-Myers Squibb, Amgen, and MSD.
- 5.Korn EL, Liu P-Y, Lee SJ, Chapman J-AW, Niedzwiecki D, Suman VJ, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol. 2008;26(4):527–34.CrossRefPubMedGoogle Scholar
- 11.Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28(7):1631–9.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248–60.CrossRefPubMedGoogle Scholar
- 23.Weber JS, Dummer R, de Pril V, Lebbé C, Hodi FS. MDX010-20 Investigators. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119(9):1675–82.CrossRefPubMedGoogle Scholar
- 32.Ugurel S, Röhmel J, Ascierto PA, Flaherty KT, Grob JJ, Hauschild A, et al. Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017. Eur J Cancer. 1990;2017(83):247–57.Google Scholar
- 34.Long GV, Grob J-J, Nathan P, Ribas A, Robert C, Schadendorf D, et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016;17(12):1743–54.CrossRefPubMedGoogle Scholar
- 37.Lond GV, Atkinson V, Menzies AM, Lo S, Guminski AD, Brown MP, et al. A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): the Anti-PD1 Brain Collaboration (ABC) [abstract]. J Clin Oncol. 2017;35(15_suppl):9508.Google Scholar
- 38.Gaudy-Marqueste C, Dussouil AS, Carron R, Troin L, Malissen N, Loundou A, et al. Survival of melanoma patients treated with targeted therapy and immunotherapy after systematic upfront control of brain metastases by radiosurgery. Eur J Cancer. 1990;2017(84):44–54.Google Scholar
- 44.Sanmamed MF, Perez-Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez-Ruiz ME, et al. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients. Ann Oncol. 2017;28(8):1988–95.CrossRefPubMedPubMedCentralGoogle Scholar
- 60.Amgen. Pembrolizumab with or without talimogene laherparepvec or talimogene laherparepvec placebo in unresected melanoma (KEYNOTE-034) [ClinicalTrials.gov identifier NCT02263508]. US National Institutes of Health, ClinicalTrials.gov. https://www.clinicaltrials.gov. Accessed 27 Jun 2018.
- 61.University of Utah. Neoadjuvant trial of nivolumab in combination with HF10 oncolytic viral therapy in resectable stage IIIB, IIIC, IVM1a melanoma [ClinicalTrials.gov identifier NCT03259425]. US National Institutes of Health, ClinicalTrials.gov. https://www.clinicaltrials.gov. Accessed 27 Jun 2018.
- 62.Viralytics. Intratumoral CAVATAK (CVA21) and pembrolizumab in patients with advanced melanoma (VLA-011 CAPRA) (CAPRA) [ClinicalTrials.gov identifier NCT02565992]. US National Institutes of Health, ClinicalTrials.gov. https://www.clinicaltrials.gov. Accessed 27 Jun 2018.
- 67.Incyte Corporation. A phase 3 study of pembrolizumab + epacadostat or placebo in subjects with unresectable or metastatic melanoma (Keynote-252/ECHO-301) [ClinicalTrials.gov identifier NCT02752074]. US National Institutes of Health, ClinicalTrials.gov. https://www.clinicaltrials.gov. Accessed 27 Jun 2018.
- 68.Long GV, Dummer R, Hamid O, Gajewski T, Caglevic C, Dalle S, et al. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study [abstract no. 108]. 2018 ASCO Annual Meeting; 1–5 Jun 2018; Chicago.Google Scholar
- 70.Corvus Pharmaceuticals, Inc. Phase 1/1b study to evaluate the safety and tolerability of CPI-444 alone and in combination with atezolizumab in advanced cancers [ClinicalTrials.gov identifier NCT02655822]. US National Institutes of Health, ClinicalTrials.gov. https://www.clinicaltrials.gov. Accessed 27 Jun 2018.Google Scholar
- 73.Hoffmann-La Roche. Cobimetinib (targeted therapy) plus atezolizumab (immunotherapy) in participants with advanced melanoma whose cancer has worsened during or after treatment with previous immunotherapy and atezolizumab monotherapy in participants with previously untreated advanced melanoma [ClinicalTrials.gov identifier NCT03178851]. US National Institutes of Health, ClinicalTrials.gov. https://www.clinicaltrials.gov. Accessed 27 Jun 2018.
- 81.Novartis Pharmaceuticals. Phase I/Ib study of NIS793 in combination with PDR001 in patients with advanced malignancies [ClinicalTrials.gov identifier NCT02947165]. US National Institutes of Health, ClinicalTrials.gov. https://www.clinicaltrials.gov. Accessed 27 Jun 2018.
- 82.EMD Serono Research & Development Institute, Inc. MSB0011359C (M7824) in metastatic or locally advanced solid tumors [ClinicalTrials.gov identifier NCT02517398]. US National Institutes of Health, ClinicalTrials.gov. https://www.clinicaltrials.gov. Accessed 27 Jun 2018.
- 85.Luke JJ, Callahan MK, Postow MA, Romano E, Ramaiya N, Bluth M, et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer. 2013;119(20):3687–95.CrossRefPubMedPubMedCentralGoogle Scholar