Neoadjuvant anti-PD-1 alone or in combination with anti-TIGIT or an oncolytic virus in resectable stage IIIB–D melanoma: a phase 1/2 trial
Reinhard Dummer, Caroline Robert, Richard A. Scolyer, Janis M. Taube, Michael T. Tetzlaff, Alexander M. Menzies, Andrew F. Hill, Jean‐Jacques Grob, David C. Portnoy, Célèste Lebbé, Muhammad A. Khattak, Jonathan Cohen, Gil Bar‐Sela, Inderjit Mehmi, Ronnie Shapira‐Frommer, Nicolás Meyer, Andrea L. Webber, Yixin Ren, Mizuho Fukunaga‐Kalabis, Clemens Krepler, Georgina V. Long
Abstract
Neoadjuvant immunotherapies have shown antitumor activity in melanoma. Substudy 02C of the global, rolling-arm, phase 1/2, adaptive-design KEYMAKER-U02 trial is evaluating neoadjuvant pembrolizumab (anti-PD-1) alone or in combination, followed by adjuvant pembrolizumab, for stage IIIB-D melanoma. Here we report results from the first three arms: pembrolizumab plus vibostolimab (anti-TIGIT), pembrolizumab plus gebasaxturev (coxsackievirus A21) and pembrolizumab monotherapy. Pathologic complete responses occurred in 10 of 26 patients (38%) with pembrolizumab plus vibostolimab, 7 of 25 (28%) with pembrolizumab plus gebasaxturev and 6 of 15 (40%) with pembrolizumab monotherapy. Major pathologic responses occurred in 13 (50%), 10 (40%) and 7 (47%) patients, respectively. Safety was manageable. Treatment-related adverse events occurred in 24 of 26 patients (92%) with pembrolizumab plus vibostolimab, 21 of 25 (84%) with pembrolizumab plus gebasaxturev and 12 of 15 (80%) with pembrolizumab monotherapy; grade 3 or 4 treatment-related adverse events occurred in 2 (8%), 7 (28%) and 1 (7%) patient in each arm, respectively. No deaths due to adverse events occurred. Exploratory objective responses per RECIST v1.1 were observed in 13 (50%), 8 (32%) and 4 (27%) patients, in each arm, respectively. In a post hoc analysis, scores for tumor mutational burden and an 18-gene T cell-inflamed gene expression profile were generally higher in patients with major pathologic response. Longer follow-up will provide insight into the incremental benefit of combining neoadjuvant pembrolizumab with other therapies in stage IIIB-D melanoma. ClinicalTrials.gov registration: NCT04303169 .