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 Hill; Jean-Jacques Grob; David C Portnoy; Celeste Lebbe; Muhammad A Khattak; 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

doi:10.1038/s41591-024-03411-x

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

Nat Med. 2025 Jan 7. doi: 10.1038/s41591-024-03411-x. Online ahead of print.

Authors

Reinhard Dummer¹, Caroline Robert², Richard A Scolyer³, Janis M Taube⁴, Michael T Tetzlaff⁵, Alexander M Menzies⁶, Andrew Hill⁷, Jean-Jacques Grob⁸, David C Portnoy⁹, Celeste Lebbe¹⁰, Muhammad A Khattak¹¹, Jonathan Cohen¹², Gil Bar-Sela^{13

14}, Inderjit Mehmi¹⁵, Ronnie Shapira-Frommer¹⁶, Nicolas Meyer¹⁷, Andrea L Webber¹⁸, Yixin Ren¹⁸, Mizuho Fukunaga-Kalabis¹⁸, Clemens Krepler¹⁸, Georgina V Long⁶

Affiliations

¹ University Hospital Zurich, Zurich, Switzerland. [email protected].
² Gustave Roussy and Paris-Saclay University, Paris, France.
³ Melanoma Institute Australia, The University of Sydney; Faculty of Medicine and Health, The University of Sydney; Royal Prince Alfred Hospital and NSW Health Pathology; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.
⁴ Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA.
⁵ University of California, San Francisco, CA, USA.
⁶ Melanoma Institute Australia, The University of Sydney; Faculty of Medicine and Health, The University of Sydney; and Mater and Royal North Shore Hospitals, Sydney, New South Wales, Australia.
⁷ Tasman Health Care, Southport, Queensland, Australia.
⁸ Aix-Marseille University Hôpital de la Timone, Marseille, France.
⁹ West Cancer Center and Research Institute, Germantown, TN, USA.
¹⁰ Université Paris Cité, Dermato-Oncology and CIC Hôpital Saint-Louis AP-HP, Cancer Institute AP-HP Nord-Université Paris Cité, Paris, France.
¹¹ Fiona Stanley Hospital and Edith Cowan University, Perth, Western Australia, Australia.
¹² Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
¹³ Emek Medical Center, Afula, Israel.
¹⁴ Technion-Israel Institute of Technology, Haifa, Israel.
¹⁵ Angeles Clinic and Research Institute, a Cedars-Sinai affiliate, Los Angeles, CA, USA.
¹⁶ Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat Gan, Israel.
¹⁷ Dermatology, Clinique Médipole Garonne, Toulouse, France.
¹⁸ Merck & Co. Inc., Rahway, NJ, USA.

PMID: 39775043
DOI: 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 .

Associated data

ClinicalTrials.gov/NCT04303169