The treatment landscape for metastatic melanoma has recently undergone a remarkable transformation. Prior to 2011, clinicians and patients were presented with difficult decisions between therapies without proven survival benefit. Now, similarly difficult but much more hopeful choices are posed among multiple potentially effective therapies (as well as promising clinical trials). Although outcomes are still far from optimal, we are now in a position to compare between clinically active agents.
Promising New Therapies
Treatment options for advanced melanoma include genetically targeted agents and immune therapies. Selective small-molecule inhibitors blocking BRAF and MEK have improved clinical outcomes for the 40% to 50% of patients harboring a BRAF mutation, and MEK inhibitors are showing activity in other genetic subsets.1-3 Perhaps more promising, new immune therapies cause durable antitumor responses in some patients by unleashing suppressed immune responses.
Ipilimumab (Yervoy), a monoclonal antibody to cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), was the first of these novel therapeutics to receive regulatory approval, based on its survival benefit in patients with advanced melanoma who experienced disease progression on prior therapies.4 Antibodies blocking the interaction of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have more recently displayed clinical activity. Pembrolizumab (Keytruda) and nivolumab (Opdivo) were both U.S. Food and Drug Administration (FDA)-approved, largely based on randomized studies that demonstrated improved clinical outcomes compared with chemotherapy for patients who had previously received ipilimumab.5,6 In addition, nivolumab produced superior response rates and overall survival compared with chemotherapy in a randomized phase III study in treatment-naive, BRAF–wild-type melanoma patients.7
These and other early-phase studies, in fact, suggested that anti–PD-1 agents have favorable efficacy and safety compared to ipilimumab. However, until recently, these agents had not been compared against one another, and the optimal sequence had been unclear.
KEYNOTE-006
As reviewed in this issue of The ASCO Post, Robert and colleagues have begun to address some of these questions. In the randomized phase III KEYNOTE-006 clinical trial, which they recently reported in The New England Journal of Medicine, two schedules of pembrolizumab were compared with ipilimumab in 834 patients.8 Both pembrolizumab arms were superior to ipilimumab in terms of response rate (33.7% and 32.9% vs 11.9%), median progression-free survival (5.5 months and 4.1 months vs 2.8 months), and 12-month overall survival (74.1% and 68.4% vs 58.2%).
Pembrolizumab improved clinical outcomes across all prespecified subgroups, with the possible exception of PD-L1–nonexpressing tumors. Consistent with prior studies, immune-related adverse events and other severe drug-related toxicities occurred less often in the pembrolizumab arms, despite more prolonged exposure. This study is the first to demonstrate superiority of an anti–PD-1 agent compared to ipilimumab and establishes that pembrolizumab (and likely nivolumab) should be preferred over ipilimumab as front-line therapy.
Remaining Questions
Several questions remain, particularly in light of the smaller, randomized study published concurrently in The New England Journal of Medicine by Postow and colleagues.9 This study compared the combination of nivolumab and ipilimumab with ipilimumab alone and noted superior overall survival and objective response rates for the combination. Nivolumab and ipilimumab produced a 61% response rate and 22% complete response rate in the BRAF–wild-type cohort—unprecedented activity for immune therapies. For several reasons, however, it would be premature to conclude that the combination is superior to anti–PD-1 monotherapy.
First, the trial by Postow and colleagues was comparatively small, enrolling 142 patients (with 95 receiving combination therapy). Second, negative prognostic features were less common in this study than in KEYNOTE-006, including stage IV M1c disease (46% vs 65%), prior brain metastases (3% vs 9%), and prior therapies for metastatic disease (0% vs 34%). Third, grade 3 or 4 immune-related adverse events and other toxicities occurred much more frequently with the combination, although they were manageable with corticosteroids in most cases.
Still, the activity of nivolumab and ipilimumab in combination appears quite impressive, with rapid and deep responses occurring even after just one cycle of therapy.10 Ongoing randomized trials will clarify whether an anti–PD-1 agent should be given alone or in combination with ipilimumab.
Biomarkers Needed
These studies also highlight the need for predictive molecular biomarkers to assist with treatment selection. An accurate marker for anti–PD-1 therapy would be particularly useful to clinicians. Such a marker could be envisioned to stratify patients to single-agent pembrolizumab or nivolumab if positive or immune combinations or genetically targeted therapy if negative. This “precision immunotherapy” type of approach could maximize therapeutic benefits and allow avoidance of more toxic combination regimens.
Initially, great excitement surrounded stratifying patients based on PD-L1 expression by tumor cells.11 Several subsequent studies, however, have diminished enthusiasm for using PD-L1 in treatment decision-making. While response rates are generally higher in the PD-L1–positive cohort, a large number of PD-L1–negative patients still benefit. Furthermore, PD-L1 status has essentially no predictive capacity for patients treated with nivolumab and ipilimumab.9 Although PD-L1 expression may have utility in other malignancies or in combination with other predictors, it is unlikely to have a major role in guiding melanoma treatment selection.
Several promising strategies may help identify more accurate predictive markers of anti–PD-1 response. Snyder and colleagues profiled melanomas treated with ipilimumab and found an array of neoantigens generated by tumor mutations present only in patients who benefited from ipilimumab.12 Individual mutant peptides may represent specific targets for activated T cells and therefore may predict anti–PD-1 response as well. Tumeh and colleagues reported that tumor-infiltrating CD8-positive T cells, particularly at the invasive margin, correlated with pembrolizumab responses.13 In this same study, pretreatment clonal expansion of infiltrating T cells, likely representing a preexisting tumor-specific T-cell population, also predicted benefit from pembrolizumab.
Closing Thoughts
Pembrolizumab has now demonstrated superior efficacy and tolerability compared with ipilimumab in a randomized phase III clinical trial. Pembrolizumab, therefore, should be strongly considered as a preferred front-line treatment option for patients with metastatic melanoma. We also eagerly await the results from ongoing randomized clinical trials that will elucidate the role of combination treatment with anti–PD-1 agents and ipilimumab. ■
Disclosure: Dr. Johnson reported no potential conflicts of interest.
References
1. Chapman PB, Hauschild A, Robert C, et al: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507-2516, 2011.
2. Robert C, Karaszewska B, Schachter J, et al: Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372:30-39, 2014.
3. Ascierto PA, Schadendorf D, Berking C, et al: MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: A non-randomised, open-label phase 2 study. Lancet Oncol 14:249-256, 2013.
4. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010.
5. 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 16:375-384, 2015.
6. 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 384:1109-1117, 2014.
7. Robert C, Long GV, Brady B, et al: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320-330, 2015.
8. Robert C, Schachter J, Long GV, et al: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. April 19, 2015 (early release online).
9. Postow MA, Chesney J, Pavlick AC, et al: Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. April 20, 2015 (early release online).
10. Chapman PB, D’Angelo SP, Wolchok JD: Rapid eradication of a bulky melanoma mass with one dose of immunotherapy. N Engl J Med. April 20, 2015 (early release online).
11. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012.
12. Snyder A, Makarov V, Merghoub T, et al: Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189-2199, 2014.
13. Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568-571, 2014.
Dr. Johnson is Assistant Professor of Medicine at Vanderbilt University Medical Center and a hematologist/oncologist at Vanderbilt-Ingram Cancer Center, Nashville.
