The activity and safety of multiple antibodies blocking programmed cell death protein 1 (PD-1) or its ligand PD-L1 has been reported in multiple meetings and in high-profile journals over the past 4 years. The PD-1/PD-L1 pathway is important in suppressing the activity of activated lymphocytes, and therefore, blockade of the pathway in patients is predicted to result in de-repression of tumor-specific T-cells within the tumor microenvironment, in turn, causing lymphocyte-mediated tumor destruction.
Several types of immune therapies produce clinical activity in metastatic melanoma and renal cancer, so activity of the PD-1/PD-L1 antagonists in these diseases was not a great surprise; the substantial excitement over the emerging clinical data was based on higher than expected levels of activity in melanoma and renal cancer, and also on activity in other cancers that were felt to be ”unresponsive” to immune therapy such as non-small cell lung cancer. Moreover, the safety profile for all of the anti-PD1 or anti-PD-L1 agents was very favorable; the agents were well tolerated in most patients, the incidence of immune-related adverse events was low, and adverse events were easily managed using algorithms established for ipilimumab in all but a few patients. So far, follow-up for the patients in trials of anti-PD1 or anti-PD-L1 was relatively short.
In a recent issue of the Journal of Clinical Oncology, however, my co-authors and I reported on data from 107 previously treated patients with metastatic melanoma that were enrolled in a phase 1 multidose trial of nivolumab (anti-PD-1) with a minimum follow-up of approximately 14 months and up to approximately 4 years.1 Because of the longer follow-up in this trial, we were able to assess the durability of responses, overall survival, and long-term adverse effects of the agent. The median duration of response among the 31% achieving an objective response was 24 months, median overall survival was 16.8 months, and the 2-year survival rate was 43%. Many of the responders continued to be progression-free after anti-PD1 therapy was stopped, suggesting that, in some patients, nivolumab could produce long-term unmaintained remissions. The adverse-event profile of nivolumab did not change with longer follow-up; the drug was well-tolerated even with prolonged treatment up to 2 years.
Similar data with shorter follow-up were recently reported for MK-3475 (anti-PD1). Together, the trials of anti-PD1 show remarkable activity in metastatic melanoma, and suggest that overall survival is improved (although phase 3 data are pending), that a subset of patients can achieve durable long-term remissions, and that the risk/benefit ratio is excellent. For both nivolumab and MK-3475, a total of five randomized phase 3 trials have recently been completed. If the phase 3 results confirm the prior data, anti-PD1 would likely become the standard front-line treatment for many if not most patients with metastatic melanoma. Although controversy still exists over treatment choice in the first-line setting for patients with metastatic melanoma with BRAF mutations, anti-PD1 will likely be favored over targeted agents in many patients because of the possibility of inducing long-term unmaintained remissions and, in aggregate, fewer potential adverse events, which will ultimately improve patient quality of life.
The phase 3 data to come will provide more clarity on the value of tumor PD-L1 expression as a predictive biomarker. Combinations with PD-1/PD-L1 antagonists are being developed rapidly—a combination with ipilimumab produced promising results in a phase 1 trial and was included as an arm in one of the phase 3 trials. Although combinations are likely to produce greater toxicity, the increased efficacy may justify their use in many patients, and incorporation of toxicity management guidelines will minimize adverse consequences. PD-1/PD-L1 pathway antagonists are likely to become the cornerstone for treatment of metastatic melanoma for many years to come. Exploration of these agents in the adjuvant setting is only just beginning.
- 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. 2014;32(10):1020-1031.
- Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-133.