2021TiP - INTerpath-005: Phase II study of pembrolizumab (pembro) with V940 (mRNA-4157) versus pembro with placebo (pbo) for adjuvant treatment of resected high-risk muscle-invasive urothelial carcinoma (MIUC)

Background

The randomized phase 3 AMBASSADOR trial demonstrated that adjuvant pembro improved disease-free survival (DFS) in patients (pts) with high-risk MIUC with or without neoadjuvant cisplatin-based chemotherapy (NAC) (HR 0.69, 95% CI 0.54-0.87, P<0.001). V940 (mRNA-4157) is an individualized neoantigen therapy consisting of an mRNA encoding up to 34 tumor neoantigens. V940 is hypothesized to work in synergy with immune checkpoint inhibitors by generating de novo tumor-specific T-cell activity. V940 has exhibited a manageable safety profile and improved recurrence-free survival when combined with pembro as adjuvant therapy in a phase 2 trial of pts with high-risk melanoma, which has led to an ongoing phase 3 trial in melanoma. The randomized, double-blind, phase 2, global INTerpath-005 (NCT06305767) trial was initiated to evaluate the efficacy and safety of adjuvant pembro plus V940 versus pembro plus pbo in pts with resected high-risk MIUC.

Trial design

Eligible pts are aged ≥18 years with predominant urothelial carcinoma, high-risk pathologic disease (ypT2-4a and/or ypN+ after NAC; pT3-4a and/or pN+ without NAC) after radical resection, and an ECOG PS of 0-2. Pts must have undergone surgery for MIBC ≤8 weeks before providing informed consent and ≤16 weeks before randomization. Pts must provide a blood sample and adequate formalin-fixed, paraffin-embedded tumor sample for tumor-informed circulating tumor (ct)-DNA molecular residual disease assessment and DNA and RNA sequencing for HLA-subtype informed for neoantigen selection. Approximately 200 pts will be randomly assigned 1:1 to receive pembro 400 mg (intravenously Q6W for 9 cycles) plus V940 1 mg (intramuscularly Q3W for 9 doses) or pembro 400 mg plus pbo. Pts will be stratified by ctDNA status and prior NAC. Radiographic imaging is performed Q12W up to 2 years, then Q24W thereafter until disease recurrence outside the urothelial tract. The primary end point is investigator assessed DFS. The secondary end points are overall survival, investigator-assessed distant metastasis-free survival, and safety and tolerability.

Clinical trial identification

NCT06305767.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and Moderna, Inc., Cambridge, MA, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and Moderna, Inc., Cambridge, MA, USA.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and Moderna, Inc., Cambridge, MA, USA.

Disclosure

G.P. Sonpavde: Financial Interests, Personal, Advisory Board: EMD Serono, Bristol Myers Squibb, Genentech, Merck, Seattle Genetics, Exelixis, Janssen, Bicycle Therapeutics, Gilead, Scholar Rock, G1 Therapeutics, Loxo Oncology, Lucence, Tempus, Syapse, Astellas, Pfizer, Atkis, Kura, Syncorp, Vial, PrecisCa; Financial Interests, Personal, Advisory Board, Editor of Bladder cancer virtual center of excellence for Practice Update: Elsevier; Financial Interests, Personal, Other, Member of data safety monitoring board: Mereo; Financial Interests, Personal, Other, Author of chapter: Uptodate; Financial Interests, Personal, Invited Speaker: Research to practice, Seattle Genetics, Gilead, Exelixis, Janssen, Astellas, Merck, Aveo, Pfizer, Natera, Bayer, PeerView, Ideology Health, Grand Rounds in Urology, Onviv; Financial Interests, Personal, Advisory Board, to develop a trial in bladder cancer: Servier Pharmaceuticals; Financial Interests, Personal, Advisory Board, Investigational drug development for HER2+ cancers: Daiichi-Sankyo/Astrazeneca; Financial Interests, Institutional, Research Grant: Gilead, EMD Serono, Jazz Pharma; Financial Interests, Institutional, Local PI: BMS; Non-Financial Interests, Principal Investigator, Steering committee of trial: Bristol Myers Squibb; Non-Financial Interests, Other, steering committee of trial: Merck; Other, Spouse employment: Myriad Genetics; Other, Travel: BMS, Astellas. B. Perez Valderrama: Financial Interests, Personal, Advisory Board: Pfizer, Astellas Pharma, Bristol Myers Squibb, Ipsen, EUSA Pharma, Merck, MSD, Astra-Zeneca, AAA, Recordati; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Bayer, MSD, Merck, Pfizer, Astellas Pharma, AAA, Almirall pharma; Other, Travel/accommodations: Bristol Myers Squibb, Pfizer. K. Chamie: Financial Interests, Personal, Advisory Board: Merck & Co., Inc.. S. Gupta: Financial Interests, Personal, Advisory Board: Seattle Genetics, BMS, Pfizer, Bayer, Merck, Gilead, Loxo Oncology, Guardant, Foundation one; Financial Interests, Personal, Other, Speaker's Bureau: Janssen; Financial Interests, Personal, Other, Consultant: EMD Sorono; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Stocks/Shares: BioNTech, Moderna; Financial Interests, Personal, Steering Committee Member: BMS, Merck, Seattle Genetics, Acrivon; Financial Interests, Institutional, Local PI: EMD Serono, Gilead, Roche, QED, Exelixis, Moderna, Pfizer. M. De Santis: Financial Interests, Personal, Advisory Board, Advisory functions, invited speaker,: Bioclin; Financial Interests, Personal, Advisory Board: AAA, Amgen, 4D, EISAI, Basilea, Merck/Serono, Bayer, BMS, Sanofi, Ipsen, Novartis/Sandoz, Immunomedics/Gilead, Roche, Ferring, Seagen, Gilead; Financial Interests, Personal, Advisory Board, invited speaker, advisory function: Astellas; Financial Interests, Personal, Advisory Board, invited speaker, steering committee member: AstraZeneca; Financial Interests, Personal, Advisory Board, invited speaker, advisory function, local PI: MSD; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Advisory Board, Speaker fees: Pierre Fabre Oncology; Financial Interests, Personal, Steering Committee Member, Steering committee, advisory Board: AAA; Financial Interests, Personal, Steering Committee Member, advisory function: Amgen; Financial Interests, Personal and Institutional, Steering Committee Member, advisory function, honoraria: Astellas, 4D, Bayer, Novartis, Ipsen, Janssen; Financial Interests, Personal and Institutional, Coordinating PI, advisory function, honoraria: AstraZeneca; Financial Interests, Personal and Institutional, Local PI, advisory function, honoraria trial fees: EISAI; Financial Interests, Personal and Institutional, Steering Committee Member, local PI, honoraria for advisory function, trial fees: Basilea; Financial Interests, Institutional, Local PI: Calithera; Financial Interests, Personal and Institutional, Steering Committee Member, advisory function, local PI, honoraria, trial fees: MSD; Financial Interests, Personal and Institutional, Steering Committee Member, advisory function, honoraria,: Merck/Serono; Financial Interests, Personal and Institutional, Steering Committee Member, Advisory function, honoraria, travel funding: BMS; Financial Interests, Institutional, Local PI, trial fees: Nektar; Financial Interests, Personal and Institutional, Steering Committee Member, advisory function, honoraria: Sanofi; Financial Interests, Personal and Institutional, Steering Committee Member, Advisory function, honoraria: Roche/Genentech; Financial Interests, Personal, Steering Committee Member, advisory function, honoraria: Sandoz; Financial Interests, Personal and Institutional, Steering Committee Member, advisory function, local PI: Immunomedics/Gilead; Financial Interests, Personal and Institutional, Steering Committee Member, advisory function, honoraria, local PI: Seagen; Financial Interests, Personal, Other, advisory function, honoraria: Ferring; Financial Interests, Personal and Institutional, Steering Committee Member, advisory function, honoraria, local and coordinating PI: Pierre Fabre; Financial Interests, Personal and Institutional, Steering Committee Member, advisory function and PI: Gilead; Non-Financial Interests, Member, writing and discussing guidelines for treatment and diagnostics: EAU Guidelines group prostate cancer; Non-Financial Interests, Member, Guidelines for bladder cancer treatment: S3 Leitlinie Blasenkrebs; Non-Financial Interests, Member: ESMO Clinical practice guidelines panel bladder cancer. R. Meehan: Financial Interests, Personal, Full or part-time Employment: Moderna Inc. T. Posadas: Financial Interests, Personal, Full or part-time Employment: Moderna Inc. Y. Ren: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. A. Bavle: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc. T.B. Powles: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Merck, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, MSD; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Roche, Pfizer, MSD, AstraZeneca, Ipsen; Financial Interests, Personal, Other, Sponsorship for Uromigos Podcast: Mashup Ltd; Financial Interests, Institutional, Other, honoraria: Gilead; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck, MSD, Seattle Genetics, Novartis, Pfizer, Merck Serono, Astellas, Johnson & Johnson, Eisai; Financial Interests, Institutional, Other, Honoraria: Gilead.