Preclinical studies suggest that treatment with neoadjuvant immune checkpoint blockade is associated with enhanced survival and antigen-specific T cell responses over adjuvant treatment1; however, optimal regimens have not been defined.,Herein, we report results from a randomized phase II study of neoadjuvant nivolumab versus combined ipilimumab with nivolumab in 23 patients with high-risk resectable melanoma (NCT02519322).,RECIST overall response rates (ORR), pathologic complete response rates (pCR), treatment-related adverse events (trAEs), and immune correlates of response were assessed.,Treatment with combined ipilimumab and nivolumab yielded high response rates (RECIST ORR 73%, pCR 45%) but substantial toxicity (73% grade 3 trAEs), whereas treatment with nivolumab monotherapy yielded modest responses (ORR 25%, pCR 25%) and low toxicity (8% grade 3 trAEs).,Immune correlates of response were identified, demonstrating higher lymphoid infiltrates in responders to both therapies and a more clonal and diverse T cell infiltrate in responders to nivolumab monotherapy.,These results are the first to describe the feasibility of neoadjuvant immune checkpoint blockade in melanoma and emphasize the need for additional studies to optimize treatment regimens and to validate putative biomarkers.
Both the combination of nivolumab + ipilimumab and single‐agent anti‐PD‐1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma.,As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti‐PD‐1 immunotherapy are needed to understand who benefits most from the combination.,Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy.,To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single‐center, retrospective analysis of patients with advanced melanoma who received nivolumab + ipilimumab either as part of a clinical trial (n = 122) or commercial use (n = 87).,Baseline routine laboratory values were correlated with overall survival (OS) and overall response rate (ORR).,Kaplan-Meier estimation and Cox regression were performed.,Median OS was 44.4 months, 95% CI (32.9, Not Reached).,A total of 110 patients (53%) responded (CR/PR).,Significant independent variables for favorable OS included the following: high relative eosinophils, high relative basophils, low absolute monocytes, low LDH, and a low neutrophil‐to‐lymphocyte ratio.,These newly identified factors, along with those previously reported to be associated with anti‐PD‐1 monotherapy outcomes, should be studied in the randomized trials of nivolumab + ipilimumab versus anti‐PD‐1 monotherapies to determine whether they help define the patients who benefit most from the combination versus anti‐PD‐1 alone.