David Bulir, MD, PhD1; Steven Liang, BHSc, PhD (Candidate)2; Maureen O’Malley, MD, FRCPC3; Elaine McWhirter, MD, MSc4
1Division of Dermatology, Department of Medicine, McMaster University, Hamilton, ON, Canada
2Medical Sciences Program, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
3Division of Dermatology, Department of Medicine, McMaster University, Hamilton, ON, Canada
4Department of Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, ON, Canada
Conflict of interest:
David Bulir, Steven Liang and Maureen O’Malley have no conflicts to report for this work.
Elaine McWhirter has served on advisory boards for Bristol-Myers Squibb, EMD Serono, Merck, Novartis and Roche
Today, a number of treatment options are now available for metastatic melanoma. Within the last decade, the development of novel immunotherapies for cancer has significantly altered the course of the disease in patients with melanoma. With more patients receiving these potentially life-saving treatments, not only have we learned more about the interplay between the immune system and melanoma, but more importantly, which treatment options are most appropriate given the clinical picture.
immunotherapy, melanoma, update, checkpoint inhibitors, BRAF
Today, malignant melanoma represents a significant disease affecting Canadians. In Canada alone, there were an estimated 7200 new cases of melanoma in 2017; of that, approximately 17% (1250 patients) will die from the disease.1,2 Melanoma represents the 7th leading cause of all cancer-related deaths in Canada. In 2014, approximately 1050 Canadians died from melanoma (from 6500 cases), and 440 from non-melanoma skin cancers (from 76,100 cases). Although melanoma accounts for less than 1% of all skin cancers, the vast majority of deaths are caused by melanoma.1,2 According to the Canadian Cancer Society, there has been increasing incidence of 2.1% per year for males and 2.0% per year for females over the last 25 years in Canada.1,2 Despite this increase in incidence, limited therapies have existed for the treatment of metastatic melanoma until recently.3
Dual inhibition of MEK and BRAF
Approximately 50% of all melanomas are positive for BRAF mutations. BRAF encodes the B-Raf proto-oncogene; when mutated, it leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and unregulated cell growth.4,5 Specific inhibitors of BRAFV600 mutations were first approved for use by Health Canada in 2012.4,5 Confirmation of BRAF mutational status from testing either primary tumor samples or metastatic lesions is required before initiating therapy.4 Monotherapy with the BRAF inhibitors dabrafenib and vemurafenib have shown significant clinical benefit compared to standard chemotherapy.6-8 Acquired resistance and paradoxical activation of the MAPK pathway in response to BRAF inhibition has been addressed through combination therapy of BRAF and MEK inhibitors.4 Combination MEK/ BRAF inhibition has been shown to provide a greater overall survival, response rate, and progression-free survival compared to monotherapy with BRAF inhibitors alone.9-11 Recently, a phase II trial comparing dabrafenib to dabrafenib plus trametinib, a MEK inhibitor, demonstrated durable long-term overall survival. Patients receiving dabrafenib were allowed to cross over to the combination therapy group if disease progression occurred. In patients who received combination therapy from the start, or crossed over from monotherapy, the 4 year and 5 year overall survival rates were 30% and 28%, respectively. Overall survival rates were noted to be higher at 45% and 51% in patients with normal baseline serum lactate dehydrogenase (LDH) levels or with normal LDH with fewer than three metastases, respectively, in patients receiving both dabrafenib and trametinib.12
Inhibition of CTLA-4 and PD-1
Presently, two main classes of immunotherapeutics, also known as immunotherapy or checkpoint inhibitors, exist for metastatic melanoma: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) receptor antagonists.13-16 CTLA-4, also known as CD152, is a receptor found on the surface of both regulatory T cells, and activated T cells.13-16 Activation or inhibition of the T cell depends on a sequence of events involving antigen-presenting cells (APCs). The T cell receptor (TCR) interacts with the APC via an epitope in the major histocompatibility complex (MHC).13-16 In addition to the MHC, co-receptors CD80 or CD86 interact with the T cell through CTLA-4 or CD28, providing an inhibitory or activating signal, respectively. CTLA-4 binds CD80 and CD86 with higher affinity and avidity compared to CD28, leading to inhibition of T cell activation, thereby reducing the chance of T cells spontaneously reacting to self-antigens.13-16 The fine balance between activating and inhibitory signals provided by CD28 and CTLA-4, respectively, is exploited in melanoma immunotherapy to non-specifically activate the immune system in attempts to destroy cancerous cells.
Programmed cell death protein 1 (PD-1), known as CD279, like CTLA-4, is a surface receptor on immune cells that also plays an important role in down-regulating the adaptive immune system at the effector phase and promoting tolerance in tissues.13-16 Endogenous ligands for PD-1 are programmed cell death protein ligand 1 and 2 (PD-L1 and PD-L2).13-16 In the absence of PDL1 or PD-L2 binding to PD-1, the immune system remains activated, leading to CD4+ and CD8+ T cell proliferation, and subsequent effector function through cytokine production and direct cytotoxic effect, respectively.13-16 Although tumor cells can present antigens on MHC, which can signal to the immune system to respond and clear the cancerous cell, these aberrant cells are capable of immune evasion through a number of mechanisms, including upregulation of PD-L1 and subsequent downregulation of T cell effector function.13-16 Like CTLA-4 receptor antagonists, the development of immunotherapeutics blocking the inhibitory nature of PD-1 following activation has also revolutionized the treatment of metastatic melanoma by harnessing the natural ability of the immune system to clear these cancerous cells. See Figures 1 and 2 for a brief overview of CTLA-4 and PD-1 in T cell regulation.
The first immunotherapeutic for metastatic melanoma approved by Health Canada was ipilimumab in 2012, a monoclonal antibody targeting the CTLA-4 receptor.17 Approval for ipilimumab followed a trial demonstrating a significant overall survival of 10.1 months in the ipilimumab group compared to 6.4 months in the control arm of glycoprotein 100 (gp100) vaccine alone in patients who had previously treated, unresectable advanced melanoma.17-19 Furthermore, 24-month overall survival rates were significantly higher in the ipilimumab group at 23.5%, compared to 13.7% in the gp100 vaccine group.17-19 However, the unregulated proliferation and activity of immune cells induced by ipilimumab led to significant adverse reactions, including immune-mediated enterocolitis, dermatitis, hepatitis, endocrinopathies, and neuropathy among a significant number of patients.17-19 It has been over a decade since the first clinical trial was conducted involving ipilimumab. In follow-up studies, patients who received ipilimumab and dacarbazine (DTIC) as part of a phase III trial have had an overall survival rate of 18.2%, compared to 8.8% among patients who received DTIC alone. The survival curve for patients receiving ipilimumab began to plateau 3 years after starting therapy, with minimal change thereafter.20
The first antibody targeting the PD-1 receptor was pembrolizumab, approved by Health Canada in June 2015 based on data from the KEYNOTE-001 trial.21 Patients with metastatic melanoma and disease progression after receiving at least two doses of ipilimumab were randomized to different doses of pembrolizumab. Patients receiving either 2 mg/kg or 10 mg/kg pembrolizumab every 3 weeks had a similar overall response rate at 26% and median follow-up of approximately 8 months.21 Follow-up of the phase Ib KEYNOTE-001 trial has demonstrated a 3-year overall survival rate of 40% in patients who received pembrolizumab, regardless of previous treatment.22 The randomized, phase III KEYNOTE-006 trial compared two doses of pembrolizumab to ipilimumab in patients with unresectable or metastatic melanoma. Interim analysis during the study shows significant improvements in progression-free survival (47.3% and 46.4% pembrolizumab vs. 26.5% ipilimumab), 1-year overall survival (74.1% and 68.4% pembrolizumab vs. 58.2% ipilimumab), and overall response rate (33.7% and 32.9% pembrolizumab vs. 11.9% ipilimumab).23 Recent updated results demonstrate a median overall survival of 16 months on the ipilimumab arm, which was not reached in either of the pembrolizumab groups. The 24-month overall survival rate was identical on the pembrolizumab arms at 55%, compared to 43% for ipilimumab.24
Shortly after approval of pembrolizumab, nivolumab, also an anti-PD-1 antibody, was approved for the treatment of melanoma. Interim analysis of 120 patients who received nivolumab in the CheckMate-037 trial provided the basis for nivolumab’s approval. Patients whose disease progressed while on ipilimumab or a BRAF inhibitor were randomized to investigator’s choice chemotherapy (ICC) or nivolumab. Patients receiving nivolumab demonstrated an overall response rate of 32%.25,26 Long-term data published this year from the original CheckMate-037 trial demonstrated more durable responses among patients receiving nivolumab than ICC, but no difference was noted in overall survival (15.7 vs. 14.4, respectively). However, the absence of a difference in overall survival may be accounted for by a higher incidence of brain metastases, elevated LDH, and lower incidence of crossover treatments among patients receiving nivolumab vs. ICC.27 These two classes of immunotherapeutics have revolutionized the treatment of metastatic melanoma and led to a significant number of clinical trials, regulatory approvals, and basic science research around immunotherapeutics.
Following the success of both CTLA-4 and PD-1 inhibitors, combination immunotherapy trials ensued. Phase I and II trials demonstrated better outcomes with combination nivolumab and ipilimumab in patients with advanced melanoma, regardless of BRAF mutation status or prior treatment, compared to monotherapy with ipilimumab. The randomized phase III CheckMate-067 trial, completed in 2015, demonstrated that patients with previously untreated malignant melanoma receiving combination ipilimumab plus nivolumab had a higher objective response rate, higher rates of complete response, and longer progression-free survival compared to monotherapy with either ipilimumab or nivolumab.28 However, the incidence of severe (grade 3 or 4) adverse events was significantly higher among combination therapy (54%) as opposed to monotherapy with ipilimumab (24%).28 Updated results from the CheckMate-067 trial were recently published.29 While no change was noted in the safety profile during the 3-year period, there were significant differences in survival.29 With a minimum of approximately 36 months of follow-up, median overall survival was 19.9 months among patients receiving ipilimumab, 37.6 months in patients receiving nivolumab, and was not reached on the combination arm.29 Overall survival rate at 3 years had a similar pattern, with the combination group having a survival rate of 58%, and 52% and 34 % on the nivolumab and ipilimumab arms, respectively. Given the similar overall survival rate among patients receiving combination nivolumab plus ipilimumab vs. nivolumab alone, though the study was not powered for this comparison, further studies are needed to help elucidate predictors for treatment response and identify the patient population who would benefit from combination therapy vs. anti-PD-1 monotherapy. This is crucial given the significantly lower rate of toxicity with nivolumab compared to combination therapy (21% vs. 59% treatment-related grade 3-4 adverse events).29 Recent data from a retrospective analysis of patients who discontinued combination nivolumab and ipilimumab due to adverse events during treatment induction had not reached a median overall survival, and demonstrated an objective response rate and progressionfree survival similar to patients who continued treatment.30 Data from this study highlights the importance of identifying predictors of treatment response, and exploring treatment regimens that maximize clinical response but minimize adverse events. A recent phase Ib trial was completed in which standard dose pembrolizumab plus reduced dose ipilimumab (1 mg/ kg rather than the standard 3 mg/kg) every 3 weeks for four doses, followed by pembrolizumab every 3 weeks represented a promising modified dose combination therapy with a manageable toxicity profile and anti-tumor activity.31 Modified dose regimes are another area of clinical research needing to be explored, as few studies have looked to this area to help manage the adverse events associated with combination therapy.
Studies comparing first-line BRAF-targeted therapy to immunotherapy, with cross-over at progression, are pending results (NCT02224781). Thus, current first-line recommendations for advanced melanoma suggest either combination MEK/BRAF inhibition (in BRAF mutated patients) or immunotherapy with combination anti-PD-1/CTLA-4 or anti-PD-1 monotherapy.
Immunotherapeutics for Adjuvant Therapy
Checkpoint immunotherapy and MEK/BRAF inhibition have also shown significant benefits in overall survival and recurrence-free survival in the adjuvant setting. Prior to checkpoint immunotherapy and MEK/BRAF inhibition, interferon was the only approved adjuvant treatment, and provided only modest benefit with significant toxicities.32 A study comparing a higher dose of ipilimumab (10 mg/kg) to placebo for 3 years demonstrated significant benefits.33 Three-year recurrence-free survival among patients receiving ipilimumab was 46.5% compared to 34.8% in the placebo group.34 The median recurrence-free survival was significantly higher in the ipilimumab group compared to the placebo group, at 26.1 vs. 17.1 months, respectively. Of note, there were five deaths related to adverse events associated with ipilimumab and 46% of patients had grade 3 or higher adverse events leading to approximately 40% of patients discontinuing therapy before starting maintenance therapy.33 Recently published updated results demonstrated a 5-year overall survival rate of 65.4% in the ipilimumab arm, compared to 54.4% for placebo (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001).34 Due to the significant number of patients who discontinued ipilimumab after induction, there may be potential for greater benefit if patients continued with maintenance therapy.
In late 2017, the Food and Drug Administration in the United States approved nivolumab for adjuvant treatment in patients with melanoma and completely resected lymph nodes or metastases (stage IIIb/c or IV), based on the CheckMate-238 trial.35 This randomized, phase III trial compared 1 year of treatment with nivolumab or ipilimumab in patients with resected melanoma.35 The recurrence-free survival in patients who received nivolumab was 70.5%, compared to 60.8% in the ipilimumab arm. Six months after discontinuation of therapy (18 months after starting), recurrence-free survival in patients treated with nivolumab was 66.4% compared to 52.7% with ipilimumab.35 Patients who received nivolumab had a considerably lower frequency of grade 3 or greater adverse events, 14.4% vs. 45.9% with ipilimumab. The discontinuation rate related to adverse events, regardless of severity, was only 9.7% with nivolumab compared to 42.6% with ipilimumab.35 CheckMate-238 is presently ongoing and plans to assess longterm survival.
Combination MEK/BRAF inhibitors have also been studied in the adjuvant setting, with stage III BRAFV600E/V600K mutation positive melanoma. In the COMBI-AD trial, patients received dabrafenib and trametinib or placebo for 1 year.36 With a median followup of 2.8 years, disease recurrence occurred in 37% of patients receiving dabrafenib and trametinib compared to 57% of patients in the placebo group, with a 3-year recurrence-free survival rate of 58% and 39%, respectively.36 The 3-year overall survival among patients receiving active therapy was 86% vs. 77% in the placebo group.36 Patients receiving combination treatment had a significantly reduced rate of distant metastases or deaths (25%) compared to those receiving placebo (35%).36
The treatment of unresectable or metastatic melanoma has changed over the last 7 years. There has been remarkable progress after years of poor outcomes from treatments that have limited clinical efficacy. PD-1 and CTLA-4 are just two proteins in a complex network of immune regulation that have been exploited to help utilize the body’s natural ability to clear cancerous cells. Over the last decade, there has been an explosion of new immunotherapeutics that have been approved or are in clinical and pre-clinical trials, which will hopefully continue to expand our arsenal in the treatment of melanoma and other previously difficult to treat malignancies.
- Melanoma skin cancer statistics 2017. Canadian Cancer Society. Available at: http://www.cancer.ca/en/cancer-information/cancer-type/skin-melanoma/statistics/?region=on. Accessed November 25, 2018.
- Canadian Cancer Statistics Advisory Committee. Canadian Cancer Statistics 2018. Toronto, ON: Canadian Cancer Society; 2018. Available at: cancer.ca/Canadian-Cancer-Statistics-2018-EN. Accessed November 25, 2018.
- Bosserhoff, AK (ed). Melanoma development: molecular biology, genetics and clinical application, 2nd edition. p. VIII, 447 p. 36 illus., 26 illus. in color. Cham, Switzerland: SpringerLink (Online service), 2017.
- Rozeman EA, Dekker TJA, Haanen J, et al. Advanced melanoma: current treatment options, biomarkers, and future perspectives. Am J Clin Dermatol. 2018 Jun;19(3):303-17.
- Delea TE, Amdahl J, Wang A, et al. Cost effectiveness of dabrafenib as a first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma in Canada. Pharmacoeconomics. 2015 Apr;33(4):367-80.
- Aksenenko MB, Kirichenko AK, Ruksha TG. Russian study of morphological prognostic factors characterization in BRAF-mutant cutaneous melanoma. Pathol Res Pract. 2015 Jul;211(7):521-7.
- McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014 Mar;15(3):323-32.
- 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 Jul 28;380(9839):358-65.
- 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 Jul 28;380(9839):358-65.
- Ascierto PA, McArthur GA, Dreno B, 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 Sep;17(9):1248-60.
- Long GV, Flaherty KT, Stroyakovskiy D, 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 Jul 1;28(7):1631-9.
- Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, doubleblind, phase 3 randomised controlled trial. Lancet. 2015 Aug 1;386(9992):444-51.
- Long GV, Atkinson V, Cebon JS, et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE- 029): an open-label, phase 1b trial. Lancet Oncol. 2017 Sep;18(9):1202-10.
- Iwai Y, Hamanishi J, Chamoto K, et al. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci. 2017 Apr 4;24(1):26.
- Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017 8:561.
- Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016 Feb;39(1):98-106.
- Khan AA, Srivastava R, Chentoufi AA, et al. Therapeutic immunization with a mixture of herpes simplex virus 1 glycoprotein D-derived “asymptomatic” human CD8+ T-cell epitopes decreases spontaneous ocular shedding in latently infected CD8+ exhausted T cells. J Virol. 2015 Jul;89(13):6619-32.
- Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res. 2011 Nov 15;17(22):6958-62.
- Fellner C. Ipilimumab (Yervoy) prolongs survival in advanced melanoma: serious side effects and a hefty price tag may limit its use. PT. 2012 Sep;37(9): 503-30.
- Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23.
- Maio M, Grob JJ, Aamdal S, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol. 2015 Apr 1;33(10):1191-6.
- Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44.
- Robert C, Ribas A, Hamid O, et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. J Clin Oncol. 2016 May;34(15 suppl):9503 (abstract).
- Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32.
- Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-62.
- Raedler LA. Opdivo (Nivolumab): second PD-1 inhibitor receives FDA approval for unresectable or metastatic melanoma. Am Health Drug Benefits. 2015 Mar;8(Spec Feature):180-3.
- Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):375-84.
- Larkin J, Minor D, D’Angelo S, et al. Overall survival in patients with advanced melanoma who received nivolumab versus investigator’s choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial. J Clin Oncol. 2018 Feb 1;36(4):383-90.
- Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015 May 21;372(21):2006-17.
- Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017 Oct 5; 377(14):1345-56.
- Schadendorf D, Wolchok JD, Hodi FS, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017 Dec 1;35(34):3807-14.
- Long GV, Atkinson V, Cebon JS, et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol. 2017 Sep;18(9):1202-10.
- Ives NJ, Suciu S, Eggermont AMM, et al. Adjuvant interferon-alpha for the treatment of high-risk melanoma: An individual patient data meta-analysis. Eur J Cancer. 2017 Sep;82:171-83.
- Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30.
- Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-35.
- Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017 Nov 9;377(19):1813-23.