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

Authors

Reinhard Dummer
Caroline Robert
Richard A. Scolyer
Janis M. Taube
Michael T. Tetzlaff
Alexander M. Menzies
Andrew Hill
Jean Jacques Grob
David C. Portnoy
Celeste Lebbe
Muhammad A. Khattak, Edith Cowan UniversityFollow
Jonathan Cohen
Gil Bar-Sela
Inderjit Mehmi
Ronnie Shapira-Frommer
Nicolas Meyer
Andrea L. Webber
Yixin Ren
Mizuho Fukunaga-Kalabis
Clemens Krepler
Georgina V. Long

Document Type

Journal Article

Publication Title

Nature Medicine

Volume

31

Issue

1

First Page

144

Last Page

151

PubMed ID

39775043

Publisher

Nature

School

School of Medical and Health Sciences

RAS ID

77418

Funders

Merck Sharp & Dohme LLC / National Health and Medical Research Council

Grant Number

NHMRC Number : 2022/GNT2018514

Comments

Dummer, R., Robert, C., Scolyer, R. A., Taube, J. M., Tetzlaff, M. T., Menzies, A. M., ... & Long, G. V. (2025). 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. Nature Medicine, 31, 144-151. https://doi.org/10.1038/s41591-024-03411-x

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.

DOI

10.1038/s41591-024-03411-x

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