Adjuvant Nivolumab Displays Survival Benefits in High-Risk Resected Melanoma

Adjuvant nivolumab (Opdivo) demonstrated clinically meaningful improvements in relapse-free survival (RFS), overall survival (OS), and distant metastasis-free survival (DMFS) vs placebo in patients with high-risk resected melanoma, even after accounting for disease stage and post-recurrence survival, supporting the use of the anti–PD-1 antibody as a standard adjuvant therapy, according to findings from an indirect treatment comparison of the phase 3 CheckMate-238 and EORTC 18071 trials that were presented during the 2020 SITC Annual Meeting.

Because the trials differed in staging, a subset indirect treatment comparison analysis accounted only for patients with stage IIIB and IIIC disease, which were common populations in both trials. Among patients with stage IIIB or IIIC disease, nivolumab was associated with significant improvements in RFS excluding new primary melanomas (HR, 0.53), RFS including new primary melanomas (HR, 0.54), OS (HR, 0.67), and DMFS (HR, 0.62) vs placebo.

“The results of this indirect treatment comparison suggest that adjuvant nivolumab is associated with clinically meaningful improvements in relapse-free, overall, and distant metastasis-free survival in patients with high-risk resected melanoma vs placebo, which for us as clinicians is the proxy for a watch-and-wait trial,” said Jeffrey S. Weber, MD, PhD, lead study author, and deputy director of the NYU Langone Health’s Perlmutter Cancer Center, in a virtual presentation of the data. 

“These findings demonstrate the need for adjuvant therapy in high-risk resected melanoma and support the use of nivolumab, the PD-1–blocking antibody as a standard-of-care adjuvant strategy in melanoma.”

Nivolumab and ipilimumab are each approved for patients with high-risk resected melanoma, based on prior findings from the CheckMate-238 and EORTC 18071 trials, respectively.

In CheckMate-238, nivolumab, given as 3 mg/kg every 2 weeks for up to 1 year, demonstrated a significant improvement in RFS vs ipilimumab, given as 10 mg/kg every 3 weeks for 4 doses and every 12 weeks thereafter for up to 1 year. In EORTC 18071, ipilimumab, given as 10 mg/kg every 3 weeks for 4 doses and every 12 weeks thereafter for up to 3 years, demonstrated significant improvements in RFS and OS vs placebo. 

Specifically, in CheckMate-238, nivolumab led to a 29% reduction in the risk of relapse or death vs ipilimumab (Yervoy; HR, 0.71; 95% CI, 0.59-0.85), whereas ipilimumab led to a 23% reduction in the risk of relapse or death vs placebo in EORTC 18071 (HR, 0.77; 95% CI, 0.65-0.91).

Regarding OS, nivolumab led to a 13% reduction in the risk of death vs ipilimumab in CheckMate-238 (HR, 0.87; 95% CI, 0.66-1.14), whereas ipilimumab led to a 28% reduction in the risk of death vs placebo in EORTC 18071 (HR, 0.72; 95% CI, 0.58-0.88). 

Prior to the approvals of immunotherapy, a watch-and-wait strategy had been the standard of care for patients with high-risk resected melanoma. Although no studies have directly compared nivolumab with a watch-and-wait strategy, ipilimumab has been compared with placebo, which is the proxy for a watch-and-wait strategy. 

In a prior indirect treatment comparison when OS data from CheckMate-238 were not yet available, nivolumab demonstrated significant improvements in RFS and DMFS.

To confirm the signal that was reported previously, investigators conducted an indirect treatment comparison of nivolumab vs placebo with data from the intention-to-treat (ITT) populations in the CheckMate-238 and EORTC 18071 trials, with a minimum follow-up of 4 and 4.5 years, respectively. RFS, OS, and DMFS served as primary end points of the comparison. 

RFS excluding new primary melanomas was defined as the time from randomization to recurrence or death, and RFS including new primary melanomas included the development of new primary melanomas in CheckMate-238.

In the ITT populations, nivolumab was associated with significant improvements in RFS and OS vs placebo, similar to the results in the stage IIIB and IIIC comparison. RFS excluding new primary melanomas in CheckMate-238, RFS including new primary melanomas in CheckMate-238, and OS all favored nivolumab vs placebo, respectively (HR, 0.54; HR, 0.55; HR, 0.62).

After adjusting for an average post-recurrence survival increase of 63% in the placebo arm of EORTC 18071, nivolumab was associated with a significant improvement in OS vs placebo (HR, 0.65; 95% CI, 0.45-0.91), similar to the results of the unadjusted analysis.

To account for the effect of subsequent therapy on survival, a sensitivity analysis determined the average increase in post-recurrence survival in the ipilimumab arm in CheckMate-238 vs the ipilimumab arm in EORTC 18071. Results were also similar when applying post-recurrence survival increases of 63% to the ipilimumab arm and 53%, 73%, and 83% to the placebo arm in EORTC 18071. 

In CheckMate-238, the median OS was not reached (NR) with nivolumab, nor was the median OS reached with the adjusted placebo in EORTC 18071 (HR, 0.65; 95% CI, 0.45-0.91).

The indirect treatment comparison adjusted for post-recurrence survival favored nivolumab for OS vs placebo on all accounts (HR, 0.63; HR, 0.65; HR, 0.66; HR, 0.69).

“Results were similar after accounting for disease stage and post-recurrence survival. This indirect treatment comparison is the only available survival comparison of an anti–PD-1 antibody with a watch-and-wait strategy in high-risk resected melanoma,” concluded Weber. 

Reference

Weber JS, Ascierto PA, Middleton MR, et al. Indirect treatment comparison of nivolumab versus placebo as adjuvant treatment for melanoma. Presented at: 2020 SITC Annual Meeting; November 9-14, 2020; virtual. Abstract 308.