940TiP - INTerpath-007: A phase II/III, adaptive, randomized study of neoadjuvant and adjuvant pembrolizumab (pembro) with V940 (mRNA-4157) for treatment of resectable locally advanced (LA) cutaneous squamous cell carcinoma (cSCC)

Background

Pembro is approved for recurrent or metastatic cSCC not curable by surgery or radiation. cSCC is an immunogenic cancer driven by high tumor mutation burden, UV signature, and tumor antigen overexpression. V940 (mRNA-4157) is a novel individualized neoantigen therapy encoding up to 34 neoantigens specifically tailored to each patient (pt), derived from their tumor-specific mutational profile. V940 + pembro showed improved recurrence-free survival over pembro alone for completely resected, high-risk, stages IIIB-D and IV cutaneous melanoma. INTerpath-007 is an open-label, randomized, phase II/3 trial (NCT06295809) evaluating the efficacy and safety of neoadjuvant and adjuvant pembro with or without V940 for resectable LA cSCC.

Trial design

Pts with histologically confirmed resectable stage II-IV (M0) cSCC with adequate tumor sample suitable for next-generation sequencing will be enrolled. In phase II, 600 pts will be randomly assigned 5:5:2 to Arm A (pembro + V940), Arm B (surgery), or Arm C (pembro alone). Pts in Arm A will receive pembro 400 mg IV Q6W (2 neoadjuvant + 9 adjuvant doses) + V940 1 mg IM Q3W (2 neoadjuvant + 7 adjuvant doses). Pts in Arm C will receive pembro 400 mg IV Q6W (2 neoadjuvant + 9 adjuvant doses). Pts in Arm B will proceed straight to surgery. Radiation will be allowed per investigator’s discretion after surgery in all arms. If the trial expands to phase III, an additional 412 pts will be randomly assigned 1:1 to Arms A and B. Imaging will be performed at screening, 6 weeks, 3-6 weeks post-surgery, day 1 of adjuvant period, then Q12W thereafter for Arms A and C, and at screening, 3-6 weeks post-surgery, with subsequent imaging calculated from the first imaging assessment, for Arm B. The primary end point is event-free survival by investigator assessment. The key secondary end points are pathological complete response assessed by blinded independent central review (BICR) and overall survival. Other secondary end points include ORR per RECIST v1.1 by investigator assessment, pathological partial response by BICR, disease-free survival by investigator assessment, and safety.

Clinical trial identification

NCT06295809; release date: March 6, 2024.

Editorial acknowledgement

Medical writing and editorial assistance was provided by Mallory Campbell, PhD, and Robert Steger, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc.

Funding

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc.

Disclosure

R. Ladwa: Financial Interests, Personal and Institutional, Advisory Board, Invited Speaker, Research Grant: MSD; Financial Interests, Personal, Advisory Board, Invited Speaker: Sanofi. D. Davar: Financial Interests, Personal, Advisory Board: ACM Bio, Ascendis, Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Immunitas, Medical Learning Group (MLG), Replimmune, Trisalus, Xilio Therapeutics; Financial Interests, Personal, Stocks/Shares: Zola; Financial Interests, Institutional, Other, US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, Dec 11, 2020: None; Financial Interests, Institutional, Royalties, US Patent 63/208,719, “Compositions and Methods For Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021: None; Financial Interests, Institutional, Coordinating PI: Arcus, Immunocore, Merck, Regeneron Pharmaceuticals Inc, Tesaro/GSK. J. Lee: Financial Interests, Personal, Advisory Board, Invited Speaker, Research Grant: MSD; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Sponsor/Funding: Novartis. A.W. Silk: Financial Interests, Institutional, Advisory Board: Natera, Regeneron; Financial Interests, Institutional, Advisory Role, Consultant: Merck; Financial Interests, Institutional, Speaker, Consultant, Advisor: Leerink; Financial Interests, Institutional, Stocks/Shares: Illumina. M.A. Khattak: Financial Interests, Personal, Advisory Board: Moderna; Financial Interests, Personal, Invited Speaker: MSD, Evaxion; Financial Interests, Personal, Other, Conference sponsorship: Evaxion; Financial Interests, Personal, Other, Advisory role: One Clinical Research. R. Meehan: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Moderna. T. Posadas: Financial Interests, Institutional, Full or part-time Employment, Sponsor/Funding: Moderna. A. Wang, J. Yuan: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Merck. S. Koyfman: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck, BMS, Galera Therapeutics, Regeneron; Financial Interests, Institutional, Research Funding: Merck, Regeron, BMS, Castle Biosciences. D. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, MSD, Merck Serono, Sanofi, Neracare, SunPharma; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Immunocore, Pierre Fabre, Sanofi/Regeneron, Pfizer, Philogen, Neracare, InFlarX, BioAlta, Daiichi Sanyko, NoviGenix, Anaveon, AstraZeneca, PamGene, BioNTech, Immatics, CureVac, Erasca, Formycon, Replimune, Seagen, SunPharma, Ultimovacs; Financial Interests, Personal, Steering Committee Member: Novartis, BMS, MSD; Financial Interests, Institutional, Coordinating PI: Novartis, BMS, MSD, Pierre Fabre; Financial Interests, Institutional, Research Grant: BMS, MSD; Financial Interests, Institutional, Local PI: Sanofi, Philogen; Non-Financial Interests, Member of Board of Directors: EORTC-MG; Non-Financial Interests, Leadership Role, Founding member and SC chair: European Melanoma Registry (EuMelaReg). All other authors have declared no conflicts of interest.