The news is good from the longest follow-up survival study of patients with advanced melanoma who were treated with the anti–programmed cell death protein 1 (PD-1) agent nivolumab (Opdivo).¹ Thirty-four percent of patients who received the drug in a phase I trial (CA909-003) were alive 5 years later. This study, which was presented at the 2016 Annual Meeting of the American Association for Cancer Research (AACR), enrolled heavily pretreated patients with advanced melanoma.

Durable Survival

Further, updated follow-up showed that patients who respond to nivolumab and go off treatment but then have a recurrence can be retreated with nivolu­mab and are alive at 5 years. Prior to the introduction of newer immunotherapies, median survival of patients with advanced melanoma was about 11 months.

F. ­Stephen Hodi, MD

“Based on this analysis, survival appears to plateau at around 48 months and then stays durable. If you make it to 48 months, your chances of survival are excellent. This represents the longest survival follow-up of patients who received anti–PD-1 [programmed cell death protein 1] therapy in a clinical trial, and long-term survival is durable,” said lead author F. ­Stephen Hodi, MD, of Dana-Farber Cancer Center and Ludwig Center at Harvard, Boston.

Study Details

Nivolumab is an anti–PD-1 immune checkpoint inhibitor approved for first-line treatment of advanced melanoma as monotherapy and in combination with ipilimumab (Yervoy), an anti–cytotoxic T-lymphocyte–associated antigen (CTLA)-4 inhibitor.

The study enrolled 107 patients with advanced melanoma (including ocular and mucosal melanoma) who had received one to five prior systemic therapies. About two-thirds of patients were treated with a prior immunotherapy but not anti–CTLA-4, anti–PD-1, or anti–PD-L1 [programmed cell death ligand 1] therapy. Forty-two percent had received prior interleukin-2 (Proleukin). The majority of patients had visceral metastasis, and one-third had elevated lactate dehydrogenase.

At baseline, the median age was 61 years, 67% of patients were male, and 97% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were treated with five different dose levels (0.1, 0.3, 1, 3, or 10 mg/kg) of nivolumab every 2 weeks for a maximum of 96 weeks beginning in October 2008.

Key Findings

Median overall survival was 17.3 months for all patients enrolled in the trial. Median overall survival was 20.3 months for those treated at the 3-mg/kg dose level, and this is the dose level selected for going forward in phase II and III trials. At 12 months, the overall survival rate was 63% for all patients and 65% for those treated at the 3-mg/kg dose.

Retreatment with nivolumab was allowed for patients who achieved disease control on treatment and had subsequent disease progression, if they did not experience a dose-limiting toxicity prior to retreatment, did not reach 1 year of follow-up without progressive disease, and had not already undergone retreatment.

Five patients who were off treatment for at least 100 days met these criteria and were retreated at their originally assigned dose. An exploratory analysis showed that all five achieved durable disease control (one had a complete response) over time and were alive at 5 years.

No new nivolumab-related safety signals emerged over long-term follow-up. The most common treatment-related adverse events (of any grade) were fatigue, pruritus, rash, and diarrhea. No study drug–related deaths were reported.

Data in Context

When looking at these findings in the context of other trials of checkpoint inhibitors, they compare favorably with pooled data for 1,861 patients treated with ipilimumab, which showed that 22% achieved a long-term durable survival benefit. Survival data are not yet in for the phase III CheckMate 066 trial of nivolumab in 210 previously untreated patients, Dr. Hodi said.

This represents the longest survival follow-up of patients who received anti–PD-1 therapy in a clinical trial, and long-term survival is durable.

— F. Stephen Hodi, MD

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“These data suggest that both ipilimumab and nivolumab can induce ‘memory responses’ that lead to long-term survival,” Dr. Hodi said.

“Anti–CTLA-4 and PD-L1 agents have nonoverlapping mechanisms and could be synergistic. This has incredible importance for the future.” ■

Disclosure: Dr. Hodi has been a consultant for or has received research support from Bristol-Myers Squibb, Genentech, Novartis, Amgen, and Merck.

Reference

1. Hodi FS, Kluger HM, Sznol M, et al: Durable, long-term survival in previously treated patients with advanced melanoma who received nivolumab monotherapy in a phase I trial. 2016 AACR Annual Meeting. Abstract CT001. Presented April 17, 2016.