Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial

Abstract

PURPOSE Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti–PD-1 in the neoadjuvant setting for resectable MCC. METHODS In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies. RESULTS Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received ≥ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions ≥ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation. CONCLUSION Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.

Unknown primary Merkel cell carcinoma with cutaneous spread

“…Pembrolizumab and nivolumab have shown similar efficacy in metastatic disease, and their approval in this setting is a certainty. Although there are no head-to-head trials comparing checkpoint inhibitors with CT, the results of this new immunotherapy-based approach compare favourably with historical data for CT in advanced MCC, especially in terms of safety features and durability of response 9–11…”

Somatostatin Receptors in Merkel-Cell Carcinoma: A Therapeutic Opportunity Using Somatostatin Analog Alone or in Association With Checkpoint Inhibitors Immunotherapy. A Case Report

“…When used in a first-line setting, PD-1/PD-L1 inhibitors including avelumab, pembrolizumab, and nivolumab are even more promising as objective responses were observed in ∼50-70% of patients with a 2-year survival rate of about 70%. Due to these results, PD-1/PD-L1 inhibitors are considered the standard of care in advanced MCC and are currently being investigated in the adjuvant and neoadjuvant settings (9)(10)(11).…”

“…In both studies, an objective response rate over 50% was reported. Of note, responses were observed in both patients with virus-positive tumors and those with virus-negative tumors (9)(10)(11).…”

“…Other two antiPD-1 antibodies have also been investigated in advanced MCC. Pembrolizumab was tested as first-line treatment in advanced MCC (9) whereas nivolumab was proposed as neoadjuvant therapy in patients with resectable MCC (10). In both studies, an objective response rate over 50% was reported.…”

Advanced Merkel cell carcinoma—A focus on medical drug therapy

“…Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had a tumor reduction ≤30%. During a median follow‐up of 20.3 months, median recurrence‐free survival (RFS) and OS were not reached 28 …”