In the phase 3 CheckMate-067 trial, a durable and sustained clinical benefit was achieved with nivolumab (NIVO) plus ipilimumab (IPI) and NIVO alone compared with IPI at the 5-year mark of follow-up. Overall survival (OS) rates for NIVO plus IPI, NIVO alone, and IPI alone were 52%, 44%, and 26%, respectively. Progression-free survival (PFS) rates for NIVO plus IPI, NIVO alone, and IPI alone were 36%, 29%, and 8%, respectively.1 At the American Society of Clinical Oncology 2021 Annual Meeting, the investigators reported 6.5-year efficacy and safety outcomes.2
Eligible patients with previously untreated unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio and stratified by PD-L1 status, BRAF mutation status, and metastasis stage. Patients received NIVO 1 mg/kg plus IPI 3 mg/kg every 3 weeks for 4 doses followed by NIVO 3 mg/kg every 2 weeks (n = 314), NIVO 3 mg/kg every 2 weeks plus placebo (n = 316), or IPI 3 mg/kg every 3 weeks for 4 doses plus placebo (n = 315) until progression or unacceptable toxicity. Co-primary end points were PFS and OS with NIVO plus IPI or NIVO alone compared with IPI alone. Secondary end points included objective response rate (ORR), descriptive efficacy assessments of NIVO plus IPI compared with NIVO alone, and safety.
With a minimum follow-up of 6.5 years, median OS was 72.1 months with NIVO plus IPI, 36.9 months with NIVO alone, and 19.9 months with IPI alone. The median time from randomization to subsequent systemic therapy was not reached (NR; 95% confidence interval [CI], 59.6-NR) with NIVO plus IPI, 25.2 months (95% CI, 16.0-43.2) with NIVO alone, and 8.0 months (95% CI, 6.5-8.7) with IPI alone. For NIVO plus IPI, NIVO alone, and IPI alone, 36%, 49%, and 66% of patients, respectively, received any subsequent systemic therapy.
The median treatment-free interval (excluding patients who discontinued follow-up before starting subsequent systemic therapy) was 27.6 months (0-83.0 months) for NIVO plus IPI, 2.3 months (0.2-81.6 months) for NIVO alone, and 1.9 months (0.1-81.9 months) for IPI alone. Of the patients who were still alive and in follow-up, 81% of the NIVO plus IPI group, 74% of the NIVO-alone group, and 43% of the IPI-alone group were off treatment and never received subsequent systemic therapy.
Grade 3/4 treatment-related adverse events were reported in all groups: 59% of the NIVO plus IPI group, 24% of the NIVO group, and 28% of the IPI group. Since the primary analysis, no new safety signals were observed, and no additional treatment-related deaths occurred.
This 6.5-year analysis is the longest follow-up from a phase 3 melanoma trial investigating checkpoint inhibitor combination therapy. The results show durable improved outcomes with NIVO plus IPI and NIVO alone compared with IPI alone in patients with advanced melanoma, with improvement in OS, PFS, and ORR with NIVO plus IPI compared with treatment with NIVO alone.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535-1546.
- Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. Presented at: American Society of Clinical Oncology Annual Meeting 2021; June 4-8, 2021. Abstract 9506.