2364MO - Durvalumab (D) +/- tremelimumab (T) in combination with dose-dense MVAC (ddMVAC) as neoadjuvant treatment in patients with muscle-invasive bladder carcinoma (MIBC): Results of NEMIO, a randomized phase I-II trial

Background

Neoadjuvant cisplatin-based chemotherapy (NAC) regimen followed by local therapy is the standard of care for MIBC. However, 60-75% of these patients (pts) have residual disease after NAC. Preclinical data suggest that the use of ddMVAC regimen may induce higher immunogenic death and pathological complete response (pCR) in the NAC setting as compared to gemcitabine cisplatin regimen (GC). Thus, we aimed to evaluate the efficacy and safety of ddMVAC + D +/- T combination in a phase I/II trial.

Methods

NEMIO (NCT03549715) is a multicenter open-label randomized non-comparative phase 1/2 trial evaluating neoadjuvant ddMVAC + D +/- T in pts with cT2-4N0-1 eligible for radical cystectomy (RC). The pts received 4 cycles of ddMVAC every 2 weeks with D (1500 mg) +/- T (75 mg) every 4 weeks. The co-primary endpoints were locally assessed pCR rate (ypT0N0) and grade ≥ 3 treatment related adverse events (TRAE). We assumed a pCR rate ≥ 45% to consider trial as positive.

Results

Between November 2018 and April 2022, 121 pts were enrolled in 16 centers and 119 received at least one dose of ddMVAC + D +/- T. The median age was 64 years (IQR: 58-70) with predominant ECOG PS 0 (74%). Clinical tumor stage at diagnosis was cT2, cT3 and cT4 in 86 (89%), 9 (9%) and 1 (1%), respectively, while 5 (5%) pts were cN1. Only 6 pts (6%) did not undergo RC (4 refusal and 2 progressive disease). Among the 113 pts with RC, the pCR was 47.8% (Table). All pts had at least one TRAE and 41% a G≥3 TRAE including neutropenia (12.6%) anemia (9.2%), and acute kidney injury (6.7%). ddMVAC or D +/- T were discontinued in 21 pts (17.6%), mostly due to TRAE (90.5%). Table: 2364MO

Conclusions

NEMIO is a positive trial showing one of the highest pCR achieved in the neoadjuvant setting with the use of ddMVAC + D. Nonetheless, the benefit of adding T on pathological response appears limited, pending survival outcomes.

Clinical trial identification

NCT03549715.

Editorial acknowledgement

Legal entity responsible for the study

Association pour la Recherche de Thérapeutiques innovantes en Cancérologie.

Funding

AstraZeneca.

Disclosure

C. Thibault: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Sanofi, Ipsen, Pfizer, Merck, MSD, BMS, AstraZeneca, AAA; Financial Interests, Personal, Expert Testimony: Seagen; Financial Interests, Institutional, Funding: AstraZeneca, Sanofi. A. Flechon: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Pfizer, Merck, Gilead, BMS, Astellas. G. Gravis: Financial Interests, Institutional, Invited Speaker: AAA, Amgen, Astellas, BMS, Janssen, MSD, Pfizer, Ipsen, AstraZeneca, alliance Merck Pfizer, Bayer, Eisai, BMS; Financial Interests, Institutional, Advisory Board: Alliance Merck-Pfizer, BMS, Janssen, Pfizer, Ipsen, Bayer, Eisai; Financial Interests, Institutional, Funding: Janssen; Non-Financial Interests, Principal Investigator: Ipsen, BMS, Merck. D. Pouessel: Financial Interests, Personal, Advisory Board: Ipsen, BMS, AstraZeneca, Astellas Pharma, MSD Oncology, Pfizer/Astellas, Pfizer; Financial Interests, Institutional, Funding: Merck Sharp & Dohme, Roche, BMS, AstraZeneca, Seagen. P. Combe: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Eisai, Sanofi, Novartis, Daiichi Sankyo, Clovis Oncology, GSK, Amgen; Non-Financial Interests, Institutional, Principal Investigator: MSD, Novartis, AstraZeneca, BMS. D. Borchiellini: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, Ipsen, Janssen, Merck, Pfizer; Financial Interests, Institutional, Advisory Board: MSD; Financial Interests, Institutional, Invited Speaker, Clinical Research: Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, Exelixis, Infinity, Janssen, MSD, Roche, Taiho Oncology. Y. Loriot: Financial Interests, Personal, Advisory Board: Merck Kga, Pfizer, Gilead, Seattle Genetics, Taiho; Financial Interests, Personal, Other, lectures, advisory boards: MSD, AstraZeneca, Astellas, Janssen; Financial Interests, Personal, Other, lectures, advisroy boards: Roche, BMS; Financial Interests, Institutional, Research Grant: Janssen, Sanofi, MSD, Roche, Celsius; Financial Interests, Institutional, Invited Speaker: Janssen, Pfizer, Janssen, MSD, Janssen, Exelexis, AstraZeneca, Pfizer, Merck Kga, BMS, Astellas, Gilead, Incyte; Financial Interests, Invited Speaker: MSD, Astellas, Gilead/Immunomedics, Taiho; Financial Interests, Personal, Invited Speaker: Basilea; Non-Financial Interests, Member: ESMO, ASCO, AACR; Non-Financial Interests, Other, scientific committee: ARC. B. Laguerre: Financial Interests, Personal, Other, ASCO GU symposium 2023 (travel and registration): Pfizer; Financial Interests, Personal, Other, honoraria: Astellas, Janssen, Pfizer; Financial Interests, Personal, Other, registration ASCO virtual meeting 2022: BMS; Financial Interests, Personal, Other, registration ASCO GU symposium 2022 (virtual): MSD. P. Barthelemy: Financial Interests, Personal, Advisory Board: BMS, MSD, Merck, Pfizer, Ipsen, Bayer, Janssen Cilag, Astellas, Novartis, Amgen, Gilead; Financial Interests, Personal, Invited Speaker: AstraZeneca, Seagen. M. Gross Goupil: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Astellas, MSD, Ipsen, Eisai, Pfizer; Financial Interests, Personal, Invited Speaker: BMS, Astellas, Amgen, MSD, Janssen, Eisai; Financial Interests, Institutional, Coordinating PI: Pfizer; Non-Financial Interests, Principal Investigator: Pfizer, Ipsen, Gilead, Roche, Bayer, Astellas, Janssen, BMS, MSD. C. Helissey: Financial Interests, Personal, Invited Speaker: Janssen, Roche, Astellas, AstraZeneca, Sanofi; Non-Financial Interests, Principal Investigator: Janssen, Sanofi, Roche, Astellas. O. Huillard: Financial Interests, Personal, Invited Speaker: Sanofi, Ipsen, Novartis; Financial Interests, Personal, Advisory Board: Janssen, Bristol Myers Squibb, AstraZeneca, Pfizer, Eisai, Bayer, AAA. M. Cancel: Financial Interests, Personal, Invited Speaker: Janssen, Sanofi, BMS; Financial Interests, Institutional, Research Grant: Ipsen; Financial Interests, Institutional, Invited Speaker: Janssen. L. Campedel: Financial Interests, Personal, Advisory Board: Pfizer, Bayer, Ipsen, Janssen, BMS, MSD; Financial Interests, Personal, Invited Speaker: Janssen. F. Audenet: Financial Interests, Personal, Invited Speaker: VitaDX, Astellas, BMS, Ipsen, Pfizer; Financial Interests, Personal, Advisory Board: UroDiag. S. Oudard: Financial Interests, Personal, Advisory Board, consultancy, advisory role: Sanofi; Financial Interests, Personal, Invited Speaker, public speaking and advisory role: Janssen; Financial Interests, Personal, Advisory Board, advisory role and public speaking: AstraZeneca, MSD, Merck, Astellas, Ipsen, Pfizer, Roche, Genetech; Financial Interests, Personal, Advisory Board, Advisory board and public speaking: BMS, Bayer, Novartis. All other authors have declared no conflicts of interest.