Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma

Abstract

Purpose: The CheckMate 066 trial investigated nivolumab monotherapy as first-line treatment for patients with previously untreated BRAF wild-type advanced melanoma. Five-year results are presented herein.

Patients and methods: In this multicenter, double-blind, phase III study, 418 patients with previously untreated, unresectable, stage III/IV, wild-type BRAF melanoma were randomly assigned 1:1 to receive nivolumab 3 mg/kg every 2 weeks or dacarbazine 1,000 mg/m² every 3 weeks. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.

Results: Patients were followed for a minimum of 60 months from the last patient randomly assigned (median follow-up, 32.0 months for nivolumab and 10.9 months for dacarbazine). Five-year OS rates were 39% with nivolumab and 17% with dacarbazine; PFS rates were 28% and 3%, respectively. Five-year OS was 38% in patients randomly assigned to dacarbazine who had subsequent therapy, including nivolumab (n = 37). ORR was 42% with nivolumab and 14% with dacarbazine; among patients alive at 5 years, ORR was 81% and 39%, respectively. Of 42 patients treated with nivolumab who had a complete response (20%), 88% (37 of 42) were alive as of the 5-year analysis. Among 75 nivolumab-treated patients alive and evaluable at the 5-year analysis, 83% had not received subsequent therapy; 23% were still on study treatment, and 60% were treatment free. Safety analyses were similar to the 3-year report.

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

Trial registration: ClinicalTrials.gov NCT01721772.

FIG 1.

Kaplan-Meier plot of (A) overall survival (OS) and (B) progression-free survival (PFS) in patients who received nivolumab (NIVO) or dacarbazine (DTIC). Median survival time was 37.3 months (95% CI, 25.4 to 51.6 months) in the NIVO group and 11.2 months (95% CI, 9.6 to 13.0 months) in the DTIC group. Median time to progression or death was 5.1 months (95% CI, 3.5 to 12.2 months) in the NIVO group and 2.2 months (95% CI, 2.1 to 2.5 months) in the DTIC group. Rates at earlier time points are based on 5-year analysis and, therefore, may differ slightly from those available for previous reports.

FIG 2.

Kaplan-Meier plot of overall survival (OS) in patients who received nivolumab (NIVO) or dacarbazine (DTIC) with (A) lactate dehydrogenase (LDH) ≤ the upper limit of normal (ULN), (B) LDH > ULN, (C) programmed death-ligand 1 (PD-L1) < 5%, and (D) PD-L1 ≥ 5%. For LDH ≤ ULN, median survival time was 53.4 months (95% CI, 37.6 months to not reached [NR]) in the NIVO group and 18.4 months (95% CI, 13.0 to 22.9 months) in the DTIC group, and for LDH > ULN, median survival time was 12.8 months (95% CI, 8.4 to 25.5 months) in the NIVO group and 6.5 months (95% CI, 4.2 to 8.4 months) in the DTIC group. For PD-L1 < 5%, median survival time was 27.5 months (95% CI, 18.2 to 38.0 months) in the NIVO group and 11.6 months (95% CI, 9.3 to 13.0 months) in the DTIC group, and for PD-L1 ≥ 5%, median survival time was NR (95% CI, 42.4 months to NR) in the NIVO group and 9.7 months (95% CI, 6.7 to 13.5 months) in the DTIC group.

FIG 3.

Kaplan-Meier plot of progression-free survival (PFS) in patients who received nivolumab (NIVO) or dacarbazine (DTIC) with (A) lactate dehydrogenase (LDH) ≤ the upper limit of normal (ULN), (B) LDH > ULN, (C) programmed death-ligand 1 (PD-L1) < 5%, and (D) PD-L1 ≥ 5%. For LDH ≤ ULN, median time to progression or death was 12.2 months (95% CI, 5.0 to 22.8 months) in the NIVO group and 2.4 months (95% CI, 2.1 to 3.4 months) in the DTIC group, and for LDH > ULN, median time to progression or death was 2.1 months (95% CI, 2.0 to 3.3 months) in the NIVO group and 2.1 months (95% CI, 1.9 to 2.4 months) in the DTIC group. For PD-L1 < 5%, median time to progression or death was 4.7 months (95% CI, 2.2 to 7.6 months) in the NIVO group and 2.2 months (95% CI, 2.1 to 3.3 months) in the DTIC group, and for PD-L1 ≥ 5%, median time to progression or death was 32.7 months (95% CI, 5.1 months to not reached) in the NIVO group and 2.1 months (95% CI, 2.0 to 2.4 months) in the DTIC group.

FIG 4.

(A) Response to treatment in all patients and proportion alive at 5 years of follow-up and Kaplan-Meier plots of (B) overall survival (OS) and (C) progression-free survival (PFS) from landmark 12-month analyses by individual response in patients on nivolumab (NIVO). Median survival time was not reached (NR) in patients with a complete response (CR) or partial response (PR), 42.4 months (95% CI, 28.19 to 52.01 months) in patients with stable disease (SD), and 26.9 months (95% CI, 22.34 to 47.11 months) in patients with progressive disease (PD). Median time to progression or death was NR (95% CI, 54.44 months to NR) in patients with a CR, NR in patients with a PR, and 22.8 months (95% CI, 17.51 months to NR) in patients with SD. ^aIntention to treat (ITT; NIVO): objective response rate (ORR), 42%; response in patients not evaluable, 23 (11%) of 210. ^bPatients alive at 5 years (NIVO): ORR, 80%; response in patients not evaluable, two (3%) of 78. ^cITT (DTIC): ORR, 14%; response in patients not evaluable, 31 (15%) of 208. ^dPatients alive at 5 years (DTIC): ORR, 39%; response in patients not evaluable, zero of 33.