Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study.

BACKGROUND

IMvigor130 demonstrated statistically significant investigator-assessed progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial carcinoma. Overall survival was not improved in interim analyses. Here we report the final overall analysis for group A versus group C.

METHODS

In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) with previously untreated locally advanced or metastatic urothelial cancer and who had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), with a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin risk factor score, and investigator's choice of platinum-based chemotherapy, to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo (ie, group A and group C) and atezolizumab monotherapy (group B) was open label. For groups A and C, all patients received gemcitabine (1000 mg/m

FINDINGS

Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 851 were assigned to group A (n=451) and group C (n=400). 338 (75%) patients in group A and 298 (75%) in group C were male, 113 (25%) in group A and 102 (25%) in group C were female, and 346 (77%) in group A and 304 (76%) in group C were White. At data cutoff (Aug 31, 2022), after a median follow up of 13·4 months (IQR 6·2-30·8), median overall survival was 16·1 months (95% CI 14·2-18·8; 336 deaths) in group A versus 13·4 months (12·0-15·3; 310 deaths) in group C (stratified hazard ratio 0·85 [95% CI 0·73-1·00]; one-sided p=0·023). The most common grade 3-4 treatment-related adverse events were anaemia (168 [37%] of 454 patients who received atezolizumab plus chemotherapy vs 133 [34%] of 389 who received placebo plus chemotherapy), neutropenia (167 [37%] vs 115 [30%]), decreased neutrophil count (98 [22%] vs 95 [24%]), thrombocytopenia (95 [21%] vs 70 [18%]), and decreased platelet count (92 [20%] vs 92 [24%]). Serious adverse events occurred in 243 (54%) patients who received atezolizumab plus chemotherapy and 196 (50%) patients who received placebo plus chemotherapy. Treatment-related deaths occurred in nine (2%; acute kidney injury, dyspnoea, hepatic failure, hepatitis, neutropenia, pneumonitis, respiratory failure, sepsis, and thrombocytopenia [n=1 each]) patients who received atezolizumab plus chemotherapy and four (1%; unexplained death, diarrhoea, febrile neutropenia, and toxic hepatitis [n=1 each]) who received placebo plus chemotherapy.

INTERPRETATION

Progression-free survival benefit with first-line combination of atezolizumab plus platinum-based chemotherapy did not translate into a significant improvement in overall survival in the ITT population of IMvigor130. Further research is needed to understand which patients might benefit from first-line combination treatment. No new safety signals were observed.

FUNDING

F Hoffmann-La Roche.

Informations de copyright

Copyright © 2023 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests EG has received grants or contracts from Astellas, AstraZeneca, Ipsen, Lexicon, Merck KGaA, MTEM/Threshold/Tersera, Nanostring Technologies, Pfizer, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Advanced Accelerator Applications, Amgen, Angelini, Astellas, AstraZeneca, Bayer, Blueprint, BMS, Caris Life Sciences, Celgene, Clovis Oncology, Dr Reddy's, Eisai, Esteve, EUSA Pharma, Genetracer, GSK, Guardant Health, HRA Pharma, Ipsen, ITM Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, OncoDNA (Biosequence), Palex, Pfizer, PharmaMar, Pierre Fabre, Raffo, Roche, Sanofi-Genzyme, Servier, Taiho, Tecnofarma, Thermo Fisher Scientific, and Zodiac; support for attending meetings or travel from AstraZeneca, Ipsen, Janssen, Merck KGaA, MSD, Pfizer, and Roche; and has participated on a data safety monitoring board or advisory board with Faron and Roche. EG was previously affiliated with Hospital Ramon y Cajal, Madrid, Madrid, Spain, during the time of study conduct. JAA has received consulting fees (to self) from Astellas, Bayer, BMS, Pfizer, Merck, and MSD; received payment or honoraria (to self) for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, Merck, and MSD; and has patents planned, issued, or pending with BMS and MSD. MDS has received consulting fees (to self) from AAA, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, BMS, Eisai, Ferring, Immunomedics/Gilead Sciences, Ipsen, Janssen, Merck, MSD, Novartis, Orion, Pfizer, Pierre Fabre Oncology, Roche, Sandoz, Sanofi, and SeaGen; payment or honoraria (to self) for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AAA, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, BMS, Eisai, Ferring, Immunomedics/Gilead Sciences, Ipsen, Janssen, Merck, MSD, Novartis, Orion, Pfizer, Pierre Fabre Oncology, Roche, Sandoz, Sanofi, and SeaGen; support (to self) for attending meetings or travel from AAA, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, BMS, Eisai, Ferring, Immunomedics/Gilead Sciences, Ipsen, Janssen, Merck, MSD, Novartis, Orion, Pfizer, Pierre Fabre Oncology, Roche, Sandoz, Sanofi, and SeaGen; has participated on a data safety monitoring board for Orion, Aurora trial, GUSTO trial, and Thermosome_TS-DM-STS-101; participated on an advisory board with AAA, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, BMS, Eisai, Ferring, Immunomedics/Gilead Sciences, Ipsen, Janssen, Merck, MSD, Novartis, Orion, Pfizer, Pierre Fabre Oncology, Roche, Sandoz, Sanofi, and SeaGen; and has a leadership or fiduciary role in other board, society, committee, or advocacy group that developed the European Association of Urology Prostate Cancer Guidelines, ESMO Clinical Practice Guideline–Bladder Cancer, and S3-Leitlinie Blasenkarzinom. AB has received grants or contracts from AstraZeneca, BMS, and Pfizer; consulting fees from BMS, Roche, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, MSD, and Pfizer; and has participated on a data safety monitoring board or advisory board with BMS and Excelya. EK has received honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, AstraZeneca, BMS, Chugai, Ferring, Kissei, Merck Bio Pharma, MSD, Nippon Kayaku, Nippon Shinyaku, Pfizer, and Taiho. EK was previously affiliated with Keio University Hospital, Tokyo, Japan, during the time of study conduct. XGdM has received support for the present manuscript from Roche; consulting fees (to self) from BMS, Deciphera, EUSA Pharma, Eisai, GSK, Ipsen, Lilly, Merck, Pfizer, PharmaMar, and Roche; payment or honoraria (to self) for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas Pharma, Eisai, and Pfizer; and support for attending meetings or travel from Merck and Pfizer. SHP declares honoraria from Merck, Ono Pharmaceuticals and Pfizer; a consulting or advisory role with Janssen Oncology, and research funding from Ono Pharmaceutical and Sanofi. UDG has received consulting fees (to self) from Amgen, Astellas Pharma, AstraZeneca, Bayer, BMS Clovis Oncology, Dompé Farmaceutici, Eisai, Ipsen, Janssen, Merck KGaA, MSD, Novartis, Pfizer, and PharmaMar; support (to self) for attending meetings or travel from AstraZeneca, Ipsen, and Pfizer; and other financial or non-financial interests (to institution) from AstraZeneca, Roche, and Sanofi. BA has received support for the present manuscript from Roche; consulting fees from Astellas, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche; and support for attending meetings or travel from Astellas, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, MSD, Pfizer, and Roche. MM has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Janssen, Pfizer, and Roche; and has participated on a data safety monitoring board or advisory board for Astellas, Merck, Pfizer, and Roche. KI has received support for the present manuscript from Chugai Pharmaceutical. FAS has received support for the present manuscript from Roche; consulting fees from Adium/Tecnofarma, Astellas, Bayer, BMS, Ipsen, Janssen, MSD, and Pfizer; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Adium/Tecnofarma, Astellas, Bayer, BMS, Ipsen, Janssen, MSD, Pfizer; and support for attending meetings or travel from Adium/Tecnofarma, Ipsen, Janssen, and MSD. JP has received study funding from Roche; consulting fees from Pfizer and Roche; honoraria for lectures presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, BMS, Eisai, Janssen, Merck, MSD, and Pfizer; support for travel for attending meetings from Janssen, Merck, and Pfizer; and has participated on an advisory board for AstraZeneca, BMS, Janssen, Merck, MSD, and Pfizer. J-RL declares no competing interests. PHO has received honoraria (to self) from Astellas Pharma, Axiom Healthcare Strategies, CLD, Curio Science, EMD Serono, EnquiringMinds, FirstWord Publications, Great Debates and Updates, IntrinsiQ Specialty Solutions, ISMIE, MedLearning Group, Merck, MJH Life Sciences, NAMCP, Peerview, Pfizer, Research to Practice, Seagen, Vaniam Group; research funding (to institution) from Acerta Pharma, Astellas Pharma, AstraZeneca/MedImmune, Boehringer Ingelheim, BMS, Genentech/Roche, Janssen, Merck, and Seagen; provided expert testimony (self) to Oregon Health & Science University (OHSU); received travel fees, accommodations, or expenses (to self) from Curio Science; and has served (in a compensated capacity) on data safety and monitoring boards for Dragonfly Therapeutics, G1 Therapeutics, Janssen, Nektar, and the National Institutes of Health. ARK has stock and other ownership interests in ECOM Medical; has received fees (to self) for a consulting or advisory role for Amgen, Astellas/Medivation, AstraZeneca, AVEO, Bayer, BMS, Eisai, EMD Serono, Exelixis, Genentech/Roche, Gilead Sciences, Immunomedics, Janssen, Merck, Myovant Sciences, Novartis, Pfizer, Sanofi, and Seagen/Astellas; research funding (to institution) from Amgen, Arvinas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, BeyondSpring, BioClin, BMS, Clovis, Eisai, Epizyme, Exelixis, Genentech, Immunomedics, Janssen, MacroGenics, Merck, Mirati, Novartis, POINT Biopharma, and Seagen; and support (to self) for attending meetings or travel from Astellas/Medivation, AstraZeneca, Bayer, Eisai, Exelixis, Genentech, Janssen, Novartis, Pfizer, and Prometheus. ARK was previously affiliated with Norton Cancer Institute (Louisville, KY, USA), during the time of study conduct. DY declares no competing interests. SM is an employee and stockholder of Genentech/Roche and declares a patent on the invention of atezolizumab. FBT is an employee of and has employee stock options from Hoffman-La Roche. SB is an employee of and has employee stock options from Roche. CL was an employee of Roche Products (Welwyn Garden City, UK), during the time of study conduct, and is a stockholder of Roche. IDD has been a member of the IMvigor130 steering committee (uncompensated); served as director and chair of the ANZUP Cancer Trials Group (uncompensated); reports salaried employment with Eastern Health (Melbourne, VIC, Australia) and Monash University (Melbourne, VIC, Australia). MDG has received research funding (to institution) for the present manuscript from Genentech; research funding (to institution) from AstraZeneca, BMS, Dendreon, Genentech, Merck, and Novartis; and consulting fees (to self) from AbbVie, Alligator, Analog Devices, Asieris, AstraZeneca, Basilea, Bicycle, BMS, Curis, Dragonfly, EMD Serono, Fujifilm, Genentech, Gilead, GSK, Janssen, Merck, Numab, Pfizer, Rappta Therapeutics, SeaGen, Silverback, UroGen, and Veracyte.