As reported in this issue of The ASCO Post, Robert and colleagues recently published a phase III study comparing the anti–programmed death 1 (PD-1) antibody nivolumab with the standard melanoma chemotherapy dacarbazine in the front-line treatment of patients with advanced BRAF wild-type melanoma.1 In this study, nivolumab was shown to be superior to dacarbazine in improving overall survival, progression-free survival, and objective response rate. Nivolumab was also associated with a lower rate of high-grade side effects than dacarbazine. Of importance, this study is the first to demonstrate that nivolumab, and any anti–PD-1 antibody, improves overall survival compared with a standard comparator in a large, well-conducted, randomized, placebo-controlled phase III study.
The high response rate and favorable toxicity profile of nivolumab and pembrolizumab (Keytruda), another anti–PD-1 antibody, in patients with melanoma have been well known from large, previously published, early-phase studies.2-5 Yet how these anti–PD-1 antibodies perform in randomized studies against standard chemotherapy (dacarbazine or carboplatin/paclitaxel) has only recently begun to emerge.
As reported by Drs. Jeffrey Weber and Sandra D’Angelo at the 2014 European Society for Medical Oncology (ESMO) meeting, nivolumab demonstrated a superior response rate compared with chemotherapy for patients with melanoma that had progressed after treatment with ipilimumab (Yervoy).6 In a similar patient population, pembrolizumab resulted in improved progression-free survival compared with chemotherapy, as demonstrated by results presented by Dr. Antoni Ribas at the Society for Melanoma Research meeting.7 The overall survival effects of nivolumab and pembrolizumab for patients with ipilimumab-refractory melanoma in randomized studies are not yet known, but results are eagerly expected, once the length of follow-up is more mature. Nivolumab and pembrolizumab are believed to be similarly effective.
The study by Robert and colleagues is the first formally reported randomized study of an anti–PD-1 agent in the front-line setting. The study involved only melanoma patients who did not have a BRAF mutation. We expect that the favorable results for nivolumab over dacarbazine would be similar in patients with BRAF-mutant melanoma. In other studies, both nivolumab and pembrolizumab have demonstrated efficacy in patients with BRAF-mutant melanoma.2,6 Other immune checkpoint antibodies, such as ipilimumab, have similarly shown equal response rates in patients with melanoma, with and without BRAF mutations.8 Anti–PD-1 antibodies should be considered for patients regardless of their BRAF status.
Expression of PD-L1, one of the ligands for PD-1, on tumor cells has been associated with favorable response rates in prior, early-phase studies of nivolumab.9 In this study, however, patients with tumors classified as PD-L1–negative/indeterminate also had improved overall survival with nivolumab compared with dacarbazine. PD-L1 was therefore not found to be a predictive biomarker for overall survival, and the results do not support using tumor PD-L1 status to select patients for nivolumab. PD-L1 expression can be heterogeneous, even within individual patients,10 further complicating ongoing research in this area.
Questions Remain
Despite the tremendous advance this study provides for our patients with melanoma, several essential questions remain about the best use of nivolumab and other anti–PD-1 antibodies. First, whether nivolumab or pembrolizumab improves overall survival compared with ipilimumab remains unknown. Second, combining nivolumab with ipilimumab has shown high response rates in patients with melanoma, but whether it will ultimately be preferable to administer nivolumab in combination with ipilimumab or in a particular sequence remains to be determined. An ongoing randomized phase III study (Checkmate 67) comparing nivolumab, ipilimumab, and the combination of both completed accrual earlier in 2014 and should help to address this question.
Third, since PD-L1 as a single biomarker was not found to be predictive for overall survival with nivolumab, additional investigations into biomarkers that may be more predictive remain of great interest. It is possible that a model incorporating many immunologic factors, including the presence of infiltrating CD8-positive T cells in a tumor, may better capture the complexities of the tumor microenvironment relevant to benefit with PD-1 blockade.11 The presence of mutations in the tumor that produce immunogenic neoantigens may also be important, as was recently found in patients treated with ipilimumab.12
Finally, we are encouraged by the low rate of toxicity of nivolumab in this study and the lack of cumulative side effects with it in other, longer-term studies.5 As treatment with nivolumab and other anti–PD-1 antibodies is continuous every several weeks, however, the optimal duration of treatment remains unknown. Many patients who respond to anti–PD-1 antibodies and discontinue treatment due to side effects continue to respond to treatment. We should investigate whether treatment can be safely discontinued in other patients, particularly to ease the logistical challenges many patients face and to be mindful of the current environment of escalating health-care costs.
In summary, the expectation that nivolumab would improve overall survival based upon its high durable response rate was confirmed in a front-line phase III study compared with dacarbazine. As anti–PD-1 antibodies have already demonstrated superiority to dacarbazine in randomized studies of ipilimumab-refractory patients—and have now demonstrated success for the first time in a randomized, controlled, front-line setting—we expect that therapeutic regimens containing an anti–PD-1 antibody may ultimately be the first treatment considered in patients with advanced melanoma. ■
Disclosure: Dr. Postow has received a research grant from Bristol-Myers Squibb. Dr. Wolchok is a paid consultant and has received research funding from Bristol-Myers Squibb and Merck.
References
1. Robert C, Long GV, Brady B, et al: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. November 6, 2014 (early release online).
2. 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.
3. Hamid O, Robert C, Daud A, et al: Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134-144, 2013.
4. Weber JS, Kudchadkar RR, Yu B, et al: Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol 31:4311-4318, 2013.
5. Topalian SL, Sznol M, McDermott DF, et al: Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32:1020-1030, 2014.
6. Weber JS, Minor DD, D’Angelo, S, et al: A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy. 2014 ESMO Congress. Abstract LBA3.
7. Ribas A, Pzanov I, Dummer R, et al: A randomized controlled comparison of pembrolizumab and chemotherapy in patients with ipilimumab-refractory (IPI-R) melanoma (MEL). Society for Melanoma Research 2014 Congress. Presented November 16, 2014.
8. Shahabi V, Whitney G, Hamid O, et al: Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother 61:733-737, 2012.
9. 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.
10. Madore J, Vilain R, Menzies AM, et al: PD-L1 expression in melanoma shows marked heterogeneity within and between patients: Implications for anti-PD-1/PD-L1 clinical trials. Pigment Cell Melanoma Res. December 5, 2014 (early release online).
11. Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568-571, 2014.
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.
Drs. Postow and Wolchok are medical oncologists at Memorial Sloan Kettering Cancer Center, New York.
