Discussion
death, pembrolizumab, melanoma, immune-mediated adverse, primary melanomas, T4b melanoma, resected stage IIB/C disease, resected stage IIB/C
RECURRENCES, RECURRENCE, METASTASIS, MELANOMA, DISEASE, EVENT, MELANOMA IN SITU, ADVERSE EVENT, EVENTS, METASTASES
CheckMate 76K met its primary endpoint of RFS. Nivolumab demonstrated a statistically significant and clinically meaningful 58% reduction in the risk of recurrence or death versus placebo in patients with resected stage IIB/C melanoma (HR = 0.42; 95% CI: 0.30–0.59; In this trial, nivolumab reduced the risk of disease recurrence or death by 58% and reduced the risk of distant metastasis by 53% in the intention-to-treat population. The improved outcomes with adjuvant nivolumab in this population follow those reported in KEYNOTE-716, where pembrolizumab reduced the risk of recurrence by 35% (HR = 0.65; 95%: CI: 0.46–0.92) and the risk of distant metastasis by 36% (HR = 0.64; 95% CI: 0.47–0.88)Although there is debate about whether new primary melanomas, particularly melanoma in situ, should be considered as recurrence events, the sensitivity analysis excluding these events demonstrated a nearly identical HR (0.39 (95% CI: 0.27–0.57)), indicating that the inclusion of new primary melanomas in the definition of RFS did not impact the magnitude of observed benefit with adjuvant nivolumab. The rate of new primary melanomas was low among patients with a recurrence. However, regular skin surveillance is still needed given the high risk of subsequent primary melanomas in this patient populationRFS benefit from nivolumab was observed across subgroups, including disease stage and T category. Although the initial RFS results from KEYNOTE-716 showed an HR for pembrolizumab versus placebo in patients with T4b melanoma of 0.94 (95% CI: 0.56–1.59)Fewer distant as well as local and regional recurrences were observed with nivolumab compared with placebo. Location of first recurrence (locoregional and distant combined) in both groups was predominately skin, lung and lymph node, as expected for melanoma. Fewer patients treated with adjuvant nivolumab experienced metastases at each of these sites versus those treated with placebo. Too few recurrences have occurred thus far at other distant sites to assess trends in the impact of adjuvant nivolumab on reducing metastases to other specific sites. In addition, a lower proportion of patients treated with nivolumab had multiple lesions detected at first recurrence versus those treated with placebo (3.4% versus 9.1%).The nivolumab safety profile observed here for patients with resected stage IIB/C disease was similar to that observed in patients with resected stage III or stage IV disease, including time to onset and time to resolution of immune-mediated adverse events, and was similar to that in pembrolizumab-treated patients with resected stage IIB/C diseaseThe melanoma field has changed considerably from the time when adjuvant therapy was first considered for patients with resected stage IIB/C disease, in the period from 1995 to 2017, when the only available therapy was interferon alpha (IFNα), which was substantially less effective and more toxic than anti-PD-1 immunotherapyAlthough OS benefit with anti-PD-1 immunotherapy has been established in patients with unresectable or metastatic melanomaFindings from CheckMate 76K were robust, although potential limitations should be acknowledged. Due to the pre-specified nature of this interim analysis, long-term outcomes (such as OS, as previously discussed) could not be evaluated. In addition, the lack of a blinded independent central review could be viewed as a limitation. However, although efficacy outcomes were assessed by investigators, the inclusion of only patients with completely resected disease, along with the requirement of objective confirmation of recurrence (preferably by biopsy), minimized potential variability in determining whether a recurrence event had occurred. Another trial specification that could be viewed as a limitation is the 2:1 patient randomization because unequal patient allocation may raise concerns of potentially reduced statistical powerIn conclusion, adjuvant nivolumab significantly improved RFS in patients with resected stage IIB/C melanoma by 58% compared with placebo, with clinical benefit observed across disease subgroups, including all T categories. Adjuvant nivolumab also demonstrated substantial improvements in DMFS compared with placebo in this patient population. The observed adverse event profile of nivolumab was similar to the established anti-PD-1 monotherapy profile, which should be taken into account when making treatment decisions with patients. Based on these findings, the European Medicines Agency has approved the use of nivolumab as an adjuvant treatment option for patients ≥12 years of age with completely resected stage IIB/C melanoma. Nivolumab is an effective adjuvant treatment in resected stage IIB/C melanoma.