ASCO 2018-ADJUVANT NIVOLUMAB FOR MELANOMA PATIENTS

Two-year results from the CheckMate-238 trial bolster support for use of adjuvant nivolumab over ipilimumab following resection of stage IIIB/C or IV melanoma. Extended findings of the randomized phase III trial showed that not only did nivolumab yield a higher rate of recurrence-free survival (RFS) at 24 months compared with high-dose ipilimumab (63% vs. 50%; p < 0.0001), it did so regardless of patients’ disease stage, PD-L1 expression levels, or BRAFmutation status (Abstract 9502).

“These more mature data continue to demonstrate durable clinical benefit with nivolumab,” stated Jeffrey S. Weber, MD, PhD, of the New York University Perlmutter Cancer Center.

In the absence of adjuvant therapy, approximately 50% to 80% of patients with high-risk stage III or IV melanoma who underwent surgical resection experienced disease recurrence within 5 years. To reduce these recurrence rates, CheckMate-238 was designed to compare the efficacy and safety of two different immunotherapies in the adjuvant setting: the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which was the standard of care when the trial was designed.

CheckMate-238 was open to patients who had undergone complete resection of stage IIIB/C or IV melanoma and who had no prior systemic therapy. Following stratification by disease stage and PD-L1 expression, the 906 enrolled patients entered into the trial were randomly assigned to receive either nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks starting at week 24. Patients continued to take their assigned therapy for up to 1 year or until they developed disease recurrence or unacceptable toxicity. Sixty-one percent of patients assigned to nivolumab and 27% assigned to ipilimumab succeeded in completing a full year of treatment.

The median RFS reached 30.8 months with nivolumab versus 24.1 months with ipilimumab—a 34% reduction in the risk of disease recurrence, new primary melanoma, or death (HR 0.66, 95% CI [0.54, 0.81]; p < 0.0001). Distant metastases represented the most common type of recurrence in both groups. Across all prespecified subgroups analyzed—based on age, sex, disease stage, presence of ulceration, lymph node involvement, PD-L1 expression level, and BRAF mutation status—nivolumab consistently outperformed ipilimumab at prolonging RFS, although the results did not reach statistical significance in some of the smaller subgroups.

An exploratory analysis also revealed that nivolumab yielded a significantly higher rate of distant metastasis–free survival (DMFS) versus ipilimumab. In patients with stage III disease, the DMFS rate at 2 years was 71% with nivolumab versus 64% with ipilimumab (HR 0.76, 95% CI [0.59, 0.98]; p = 0.0340). Median DMFS has yet to be reached in either arm.

Because the primary RFS endpoint in CheckMate-238 was met, the trial will continue to track overall survival, a secondary endpoint. Dr. Weber noted that five deaths have been recorded in the ipilimumab arm versus none in the nivolumab arm. “

Discussant April K. S. Salama, MD, of Duke University, believes the melanoma field has entered the era where adjuvant therapy should be recommended for all patients with resected stage IIIB/C and IV disease. Given the expanding number of adjuvant options, toxicity is a key factor that Dr. Salama will use to guide treatment selection.

Safety was not evaluated in the current CheckMate-238 analysis because all patients had been off study treatment for more than 100 days. However, in a prior analysis conducted after a minimum follow-up of 18 months, nivolumab demonstrated better tolerability compared with ipilimumab based on the rates of treatment discontinuation (9.7% vs. 42.6%) and grade 3/4 immune-related adverse events (14.4% vs. 45.9%).

“This makes anti–PD-1–based therapy the preferred immunotherapy regimen in [patients with BRAF wild-type melanoma],” Dr. Salama said. The decision is a bit more complicated for patients with BRAF-mutated melanoma, where adjuvant targeted therapy with dabrafenib/trametinib is also an option. In the absence of a head-to-head study, the choice between options in the latter scenario should ultimately be left to the patient following an informed discussion.