PURPOSE: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma. METHODS: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis. RESULTS: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm. CONCLUSION: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

Amgen Inc South San Francisco CA

Amgen Inc Thousand Oaks CA

Biotherapy of Tumors Unit Department of Experimental Oncology European Institute of Oncology IRCCS Milan Italy

Dana Farber Cancer Institute Boston MA

Department of Dermatology Barcelona University Barcelona IDIBAPS CIBER de Enfermedades Raras ISCIII Madrid Spain

Department of Dermatology Medical University of Vienna Vienna Austria

Department of Dermatology University Hospital Regensburg Regensburg Germany

Department of Hematology Oncology West Cancer Center and Research Institute Memphis TN

Department of Immunology Faculty of Health Sciences University of Pretoria Pretoria South Africa

Department of Medical Oncology Alfred Hospital Melbourne Australia

Division of Oncology Yonsei University College of Medicine Seoul Korea

Huntsman Cancer Institute University of Utah Health Salt Lake City UT

Jonsson Comprehensive Cancer Center at the University of California Los Angeles Los Angeles CA

Maria Sklodowska Curie National Research Institute of Oncology Warsaw Poland

Medizinische Hochschule Hannover Hannover Germany

Melanoma Institute Australia The University of Sydney Sydney NSW Australia

Merck and Co Inc Kenilworth NJ

Mühlenkreiskliniken Minden Ruhr University Bochum Bochum Germany

N N Blokhin Russian Cancer Research Center Moscow Russia

National and Kapodistrian University of Athens Athens Greece

Netherlands Cancer Institute Amsterdam the Netherlands

Roswell Park Comprehensive Cancer Center Buffalo NY

Royal North Shore and Mater Hospitals Sydney NSW Australia

The Medical Oncology Centre of Rosebank Johannesburg South Africa

University Hospital Královské Vinohrady Prague Czech Republic

University Hospital of Zurich Zurich Switzerland

University of Chicago Medical Center Chicago IL

UofL Health Brown Cancer Center University of Louisville Louisville KY

UPMC Hillman Cancer Center Pittsburgh PA

Ann Transl Med. 2023 Aug 30;11(10):369. doi: 10.21037/atm-2023-5. PubMed

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