The 5-year outcomes of the ­CheckMate 066 trial, reported in the Journal of Clinical Oncology by Caroline Robert, MD, PhD, of Gustave Roussy, Villejuif, France,and colleagues, show continued benefit of first-line nivolumab vs dacarbazine in advanced BRAF wild-type melanoma and support evidence that nivolumab can be associated with long-term survival in this setting.¹

Study Details

In the double-blind trial, 418 patients with unresectable stage III/IV disease were randomly assigned to receive nivolu­mab at 3 mg/kg every 2 weeks (n = 210) or dacarbazine at 1,000 mg/m² (n = 208) every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. Treatment after disease progression was permitted for patients who continued to exhibit clinical benefit. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and objective response rate.

Caroline Robert, MD, PhD

In a 3-year analysis, median overall survival was 37.5 months in the nivolumab group vs 11.2 months in the dacarbazine group, with 3-year rates of 52% vs 22%.

5-Year Overall Survival

Patients were followed for a minimum of 60 months from the last patient randomly assigned in the trial. At 5 years, median overall survival was 37.3 months (95% confidence interval [CI] = 25.4–51.6 months) in the nivolumab group vs 11.2 months (95% CI = 9.6–13.0 months) in the dacarbazine group (hazard ratio [HR] = 0.5, 95% CI = 0.40–0.63, P < .0001), with 5-year rates of 39% vs 17%. A post hoc analysis of restricted mean survival time showed that there was an average survival time difference of 14.3 months (95% CI = 9.9–18.7 months) for nivolumab (34.8 months, 95% CI = 31.5–38.1 months) vs dacarbazine (20.5 months, 95% CI = 17.6–23.4 months).

In subgroup analyses, overall survival at 5 years was 48% vs 24% among 244 patients with normal lactate dehydrogenase and 27% vs 7% among 153 patients with lactate dehydrogenase above the upper limit of normal. Overall survival at 5 years was 52% vs 17% among 120 patients with PD-L1 expression ≥ 5% (staining of ≥ 5% of tumor cells) and 34% vs 20% among 244 patients with PD-L1 expression < 5%.

In the nivolumab and dacarbazine groups, 48% and 65% of patients received subsequent systemic therapy. Among 71 patients in the nivolumab group who received subsequent therapy that included ipilimumab, 5-year overall survival was 13%. Overall survival at 5 years was 38% among 37 patients in the dacarbazine group who received subsequent therapy including nivolumab and 23% among 91 patients who received subsequent therapy including ipilimumab. Subsequent radiotherapy was received by 26% vs 31% and subsequent surgery by 16% vs 17%.

Median progression-free survival was 5.1 months in the nivolumab group vs 2.2 months in the dacarbazine group (HR = 0.4, P < .0001), with 5-year rates of 28% vs 3%. Five-year rates were 43% vs 4% in patients with PD-L1 expression ≥ 5% and 21% vs 3% in patients with PD-L1 expression < 5%.

Effect of Response on Survival

Among all patients, the objective response rates were 42% in the nivolumab group vs 14% in the dacarbazine group. Median duration of response was not reached (95% CI = 47.2 months to not reached) in the nivolumab group vs 6 months (95% CI = 3.9–30.4 months) in the dacarbazine group. Overall, 27 (30%) of 89 responders in the nivolumab group vs none of 30 responders in the dacarbazine group had a response lasting at least 60 months. Among 78 patients from the nivolumab group alive at 5 years, objective response had been achieved in 63 (81%). Among 33 patients from the dacarbazine group alive at 5 years, objective response had been observed in 13 (39%).

Among 42 patients in the nivolumab group who had complete response, 37 (88%) were alive at 5 years; among 47 with partial response, 26 (55%) were alive at 5 years. In a landmark 12-month analysis in the nivolumab group according to individual patient response, Kaplan-Meier estimates of overall survival at 5 years were 84% in patients with complete response, 72% in those with partial response, 27% in those with stable disease, and 27% in those with progressive disease. Progression-free survival at 5 years was 75%, 67%, and 30%, respectively, in patients with response or stable disease.

Among 75 patients in the nivolumab group alive and evaluable at 5-year analysis, 62 (83%) had not received subsequent therapy, 17 (23%) were still on study treatment, and 45 (60%) were treatment free.

Updated Toxicity

Among 42 nivolumab group patients who were on randomized treatment for at least 3 years, treatment-related adverse events of any grade at 5 years, excluding those reported at 3-year analysis, had occurred in 21 (50%), the most common being fatigue in 3 (7%), increased amylase in 2 (5%), and increased lipase in 2 (5%).

The investigators concluded: “Results from this 5-year analysis confirm the significant benefit of nivolumab over dacarbazine for all endpoints and add to the growing body of evidence supporting long-term survival with nivolumab monotherapy. Survival is strongly associated with achieving a durable response, which can be maintained after treatment discontinuation, even without subsequent systemic therapies.” 

DISCLOSURE: The study was supported by Bristol Myers Squibb. Dr. Robert has served in a consulting or advisory role for Amgen, Biothera, Bristol-Myers Squibb, CureVac, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi.

REFERENCE

1. Robert C, Long GV, Brady B, et al: Five-year outcomes with nivolumab in patients with wild-type BRAF advanced melanoma. J Clin Oncol September 30, 2020 (early release online).