Adjuvant immunotherapy with PD-1 inhibitors (nivolumab or pembrolizumab) in resected stage III/IV melanoma reduces the risk of recurrence by approximately 40% and is the established standard of care. Patients without lymph node involvement, but with high-risk features in their primary tumor, including depth of invasion or ulceration (stage IIB or IIC), are at increased risk of recurrence and have a similarly poor prognosis as stage III melanoma. However, currently, adjuvant therapy is not standard for these patients. Nevertheless, the efficacy and favorable toxicity profile of adjuvant anti-PD-1 therapy in stage III melanoma provides hope that patients with stage II disease may also benefit from adjuvant immunotherapy. This is currently being evaluated in phase III clinical trials.

At the 2021 ESMO Congress, Dr. Jason J. Luke (UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, US) presented results from the phase III, randomized, double-blind KEYNOTE-716 trial, which is the first study to evaluate the efficacy and safety of pembrolizumab versus placebo in patients with resected stage IIB or IIC melanoma. The study included adjuvant and rechallenge/crossover parts. Only data from the adjuvant part were presented where 976 patients were randomized to receive either pembrolizumab or placebo for up to 1 year. Patients were stratified according to T-category (3b, 4a, and 4b) and pediatric status, although accrual of pediatric patients was low. At a median follow-up of 14 months, the median recurrence-free survival (RFS), which was the study’s primary endpoint, was not reached (NR) in either arm. At 12 months, the RFS rate was 90.5% for pembrolizumab and 83.1% for placebo (HR, 0.65; P=0.00658). The benefit of pembrolizumab was demonstrated across all key subgroups. The majority of patients did not have a recurrence with pembrolizumab (88.9%) or placebo (83.2%), but in those who had a recurrence, pembrolizumab reduced the distant recurrence rate by nearly half (4.7% vs. 7.8%).

As expected, treatment-related adverse events (TRAEs) were higher with pembrolizumab (93.0%) than with placebo (89.1%). The safety profile of adjuvant pembrolizumab was consistent with that seen in previous clinical trials. Grade 3-4 TRAEs were 16.1% with pembrolizumab and 4.3% with placebo. In addition, discontinuation due to TRAEs was more frequent with pembrolizumab (15.3% vs. 2.5%). Hypo- and hyperthyroidism were the most common AEs of interest with pembrolizumab, most of which were grade 1 or 2. Of interest, thyroid-related AEs were also seen at a rate of 4-5% with placebo. Approximately 20% of patients with endocrine AEs in the pembrolizumab arm required long-term hormonal therapy to manage endocrine toxicities (13.9% for thyroid toxicity). Nevertheless, pembrolizumab therapy did not negatively impact quality of life.

Dr. Luke concluded that patients with resected stage IIB and IIC melanoma are at a high risk of early recurrence, and that adjuvant pembrolizumab is an effective treatment option, with a favorable benefit-risk profile for these patients. A discussant of the trial, Dr. Omid Hamid (The Angeles Clinic and Research Institute, Cedars-Sinai Medical Institute, LA, California, US), pointed out that the marked decrease in distant recurrence seen with pembrolizumab is ‘’enough to push this for the right patients into a standard’, while awaiting the overall survival data from this trial. In addition, he stressed the need for predictive biomarkers to identify those patients who would benefit from treatment while avoiding unnecessary toxicity for others. Furthermore, he noted several issues that are currently being investigated in ongoing clinical trials, including the assessment of benefit of adjuvant immunotherapy in stage I melanoma, reduced frequency and intensity of immunotherapy, and the role of vaccines and adjuvant combination approaches in stage II disease.

Reference:
Luke J, et al. ESMO 2021; Abstract LBA3.