Addition of nintedanib or placebo to neoadjuvant gemcitabine and cisplatin in locally advanced muscle-invasive bladder cancer (NEOBLADE): a double-blind, randomised, phase 2 trial.

BACKGROUND

Recurrence is common after neoadjuvant chemotherapy and radical treatment for muscle-invasive bladder cancer. We investigated the effect of adding nintedanib to neoadjuvant chemotherapy on response and survival in muscle-invasive bladder cancer.

METHODS

NEOBLADE was a parallel-arm, double-blind, randomised, placebo-controlled, phase 2 trial of neoadjuvant gemcitabine and cisplatin chemotherapy with nintedanib or placebo in locally advanced muscle-invasive bladder cancer. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 15 hospitals in the UK. Patients were randomly assigned (1:1) to nintedanib or placebo using permuted blocks with random block sizes of two or four, stratified by centre and glomerular filtration rate. Treatments were allocated using an interactive web-based system, and patients and investigators were masked to treatment allocation throughout the study. Patients received oral nintedanib (150 mg or 200 mg twice daily for 12 weeks) or placebo, in addition to usual neoadjuvant chemotherapy with intravenous gemcitabine 1000 mg/m

FINDINGS

Between Dec 4, 2014, and Sept 3, 2018, 120 patients were recruited and were randomly allocated to receive nintedanib (n=57) or placebo (n=63). The median follow-up for the study was 33·5 months (IQR 14·0-44·0). Pathological complete response in the intention-to-treat population was reached in 21 (37%) of 57 patients in the nintedanib group and 20 (32%) of 63 in the placebo group (odds ratio [OR] 1·25, 70% CI 0·84-1·87; p=0·28). Grade 3 or worse toxicities were observed in 53 (93%) of 57 participants who received nintedanib and 50 (79%) of 63 patients in the placebo group (OR 1·65, 95% CI 0·74-3·65; p=0·24). The most common grade 3 or worse adverse events were thromboembolic events (17 [30%] of 57 patients in the nintedanib group vs 13 [21%] of 63 patients in the placebo group [OR 1·63, 95% CI 0·71-3·76; p=0·29]) and decreased neutrophil count (22 [39%] in the nintedanib group vs seven [11%] in the placebo group [5·03, 1·95-13·00; p=0·0006]). 45 treatment-related serious adverse events occurred in the nintedanib group and 43 occurred in the placebo group. One treatment-related death occurred in the placebo group, which was due to myocardial infarction.

INTERPRETATION

The addition of nintedanib to chemotherapy was safe but did not improve the rate of pathological complete response in muscle-invasive bladder cancer.

FUNDING

Boehringer Ingelheim.

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests SAH reports fees for consulting or honoraria from Janssen, Roche, Merck, Bristol-Myers Squibb (BMS), AstraZeneca, Pfizer, Astellas, GlaxoSmithKline, and Eisai; grants from Boehringer Ingelheim, Roche, Janssen, and AstraZeneca; and support for attending meetings or travel from Janssen, Boehringer Ingelheim, Pfizer, Roche, BMS, AstraZeneca, and Merck Sharp & Dohme (MSD) Oncology. SJC reports fees for consulting from Astellas, Roche, AstraZeneca, MSD, and Pfizer; grants from AstraZeneca, Astex Pharmaceuticals, Roche, and Clovis Oncology; speaker honoraria from AstraZeneca, Roche, MSD, and Astellas; payment for expert testimony from MSD and Pfizer; and support for attending meetings or travel from BMS, MSD, and Roche. RAH reports leading the Cancer Centre London; honoraria from Janssen Oncology; fees for consulting or an advisory role from BMS, Janssen Oncology, MSD, Nektar, and Roche; speakers' bureau fees from MSD and Roche; research funding from BMS, Janssen, MSD, and Roche; royalties from Janssen; and payment for travel, accommodation, and expenses from MSD and Roche. NV reports grants or contracts from BMS; consulting fees from Merck Serono and 4D Pharma; and honoraria: EUSA Pharma, IPSEN, and BMS. AJB reports consulting fees from Janssen, Merck, Pfizer, Astellas, and BMS; honoraria from Janssen, Pfizer, Astellas, Roche, and MSD; support for attending meetings or travel from Janssen; and participation on a data safety monitoring board or advisory board for Janssen, Astellas, Merck, and Pfizer. MDL reports grants or contracts from BMS, Shionogi, and AstraZeneca; consulting fees from BioNTech, Bicycle Therapeutics, Janssen, Merck Sorano, Pfizer, and ADC Therapeutics; honoraria from AstraZeneca and Pfizer; and support for attending meetings or travel from MSD, Janssen, and Bayer. IBR reports support for attending meetings or travel from the American Society of Clinical Oncology; and a patent planned, issued, or pending for a Living Evidence Synthesis platform for creating living systematic reviews and meta-analysis. JWFC reports grants or contracts from Roche; consulting fees from AstraZeneca, BMS, Gilead, QED Therapeutics, Roche, Ferring, Steba Biotech, UroGen, Janssen, and Photocure; payment or honoraria from BMS, AstraZeneca, and Roche; and a leadership or fiduciary role in Fight Bladder Cancer UK. TP reports grants or contracts from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai; consulting fees or honoraria from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Incyte, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai; and payment for travel, accommodation, or expenses from Roche, Pfizer, MSD, AstraZeneca, and Ipsen. RJJ reports consulting fees from Janssen, Astellas, Bayer, Novartis, Pfizer, Merck, Serono, MSD, Roche, Ipsen, and BMS; research grants from Exelixis, Astellas, Clovis, and Bayer; speaker honoraria from Janssen, Astellas, Bayer, Pfizer, Merck, Serono, MSD, Roche, Ipsen, BMS; support for travel and attending meetings from Bayer; and participation on a data safety monitoring board or advisory board for Roche. All other authors declare no competing interests.