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
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 .
Authors
- Inderjit Mehmi (ORCID: https://orcid.org/0000-0002-2253-2206)
- Mizuho Fukunaga‐Kalabis (ORCID: https://orcid.org/0000-0001-5699-6941)
- Andrew F. Hill (ORCID: https://orcid.org/0000-0001-5581-2354)
- Alexander Maxwell Menzies (ORCID: https://orcid.org/0000-0001-5183-7562)
- Célèste Lebbé (ORCID: https://orcid.org/0000-0002-5854-7290)
- David C. Portnoy (ORCID: https://orcid.org/0009-0000-1614-1383)
- Janis M. Taube (ORCID: https://orcid.org/0000-0002-8273-4395)
- Clemens Krepler
- Andrea L. Webber (ORCID: https://orcid.org/0000-0003-2463-0878)
- Ronnie Shapira‐Frommer (ORCID: https://orcid.org/0000-0001-6170-080X)
- Jean‐Jacques Grob (ORCID: https://orcid.org/0000-0002-0667-153X)
- Nicolás Meyer (ORCID: https://orcid.org/0000-0003-4519-8666)
- Georgina Venetia Long (ORCID: https://orcid.org/0000-0001-8894-3545)
- Gil Bar‐Sela (ORCID: https://orcid.org/0000-0001-6579-1841)
- Jonathan Cohen (ORCID: https://orcid.org/0000-0001-8120-3827)
- Richard A. Scolyer (ORCID: https://orcid.org/0000-0002-8991-0013)
- Yixin Ren (ORCID: https://orcid.org/0000-0002-8499-4545)
- Reinhard Dummer (ORCID: https://orcid.org/0000-0002-2279-6906)
- Caroline Robert (ORCID: https://orcid.org/0000-0002-9493-0238)
- Muhammad A. Khattak
- Michael T. Tetzlaff
Institutions
- Edith Cowan University (AU)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- The University of Sydney (AU)
- Bloomberg (United States) (US)
- Technion – Israel Institute of Technology (IL)
- University of California, San Francisco (US)
- Université Paris Cité (FR)
- Aix-Marseille Université (FR)
- Université Paris-Saclay (FR)
- Emek Medical Center (IL)
- Royal Prince Alfred Hospital (AU)
- Sheba Medical Center (IL)
- Hadassah Medical Center (IL)
- Royal North Shore Hospital (AU)
- Fiona Stanley Hospital (AU)
- Institut Gustave Roussy (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- University Hospital of Zurich (CH)
- Angeles Clinic and Research Institute (US)
- Sidney Kimmel Cancer Center (US)
- West Cancer Center (US)
- Melanoma Institute Australia (AU)
- Médipole Garonne (FR)
- Hôpital Saint-Louis (FR)
- Hôpital de la Timone (FR)
Publication Details
- Journal
- Nature Medicine
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1038/s41591-024-03411-x
- Citations
- 28
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 29.27
Funders
- Amgen
- Bristol-Myers Squibb
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- F. Hoffmann-La Roche
- Regeneron Pharmaceuticals
- Society for Immunotherapy of Cancer
- Les Laboratories Pierre Fabre
- Myriad Genetics
- SkylineDx
- Moderna
- Sun Pharma
- Qbiotics
- NeraCare
- MSD Australia
- Medical Research Council
- National Health and Medical Research Council