Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial

Abstract

Background: Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma.

Method: In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2-4a or ypN+ tumours following neoadjuvant chemotherapy or pT3-4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients.

Findings: Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2-29·8). Median disease-free survival was 19·4 months (95% CI 15·9-24·8) with atezolizumab and 16·6 months (11·2-24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74-1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group.

Interpretation: To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time.

Funding: F Hoffmann-La Roche/Genentech.

Conflict of interest statement

Declaration of interests

All authors report editorial support from F Hoffmann-La Roche. J Bellmunt received institutional research funding from Millennium, Pfizer/EMD Serono, and Sanofi, advisory or consulting fees from Astellas Pharma, AstraZeneca/MedImmune, Bristol-Myers Squibb, Genentech, Merck, Novartis, Pfizer, and Pierre Fabre, honoraria from UpToDate, stock ownership of Rainier, and travel, accommodation, or expenses support from Ipsen, MSD Oncology, and Pfizer. MH received research funding from AstraZeneca, Bayer, Genentech, and Pfizer, honoraria or advisory fees from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Genentech, PER, Pfizer, Projects in Knowledge, Research to Practice, and Sanofi/Genzyme, and travel, accommodation, or expenses support from Astellas Pharma, Bayer, Genentech/Roche, and Pfizer. MH also has two pending patents and one licensed patent with Imbio to disclose. JEG received consulting fees or honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen-Cilag, Merck, MSD, Pfizer, and Roche. PA received advisory/consulting fees and honoraria from MSD Oncology, Sanofi, and Roche/Genentech. SO received research funding from Ipsen and Sanofi, advisory/consulting fees and honoraria from Astellas, Bayer, Bristol Myers Squibb, Eisai, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi, and travel, accommodations, or expenses support from Bayer, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Novartis, and Pfizer. DC received consulting fees from Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen Oncology, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Sanofi, research funding support from Janssen Oncology, and travel, accommodation, or expenses support from AstraZeneca Spain, Bristol Myers Squibb, Pfizer, and Roche/Genentech. SD received honoraria from Ferring, MDxHealth Olympus, Pacific Edge, Photocure, QED Therapeutics, , and Spectrum Pharmaceuticals, advisory/consulting fees from Ferring, Photocure, QED Therapeutics, and Taris, and research funding, travel accommodation, or expenses support from Photocure. HN received research funding support from Ono and Chugai, advisory/consulting fees from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Janssen, and MSD, and participated in speakers’ bureaus for Astellas Pharma, AstraZeneca, Chugai, and MSD. MM is an employee of Genentech and has stock ownership of Roche. VD is an employee of Genentech and has stock ownership of Roche. SM is an employee of Genentech and has stock ownership of Roche. PG received consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Driver, EMD Serono, Exelixis, Foundation Medicine, GlaxoSmithKline, Genentech, Genzyme, Heron Therapeutics, Janssen, Merck, Mirati Therapeutics, Pfizer, Roche, Seattle Genetics and QED Therapeutics, participation in an educational program for Bristol Myers Squibb; and institutional research funding support from AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Clovis Oncology, Debiopharm, Genentech, GlaxoSmithKline, Immunomedics, Kure It Cancer Research, Merck, Mirati Therapeutics, OncoGenex, Pfizer and QED Therapeutics. YS is an employee of Genentech and has stock ownership of Roche. AD received consulting fees from AstraZeneca and Nektar and advisory fees from Genentech, Merck, Seattle Genetics, PACT Pharma, and Janssen. PHO received honoraria from Astellas Pharma, Atheneum Partners, Dedham Group, FirstWord Publication, Genentech/Roche, Health Advances, Janssen, Merck, OncLive, Schlesinger Associates, and Seattle Genetics, advisory fees from Merck, research funding support from Acerta Pharma, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Janssen, Merck, and Seattle Genetics, travel, accommodations and expenses support from Genentech/Roche, Janssen, Merck, and Seattle Genetics/Astellas, and other support from Janssen, Nektar and NIH. JER has stock ownership of Illumina and Merck, honoraria from Chugai Pharma, advisory fees from Adicet Bio, Astellas Pharma, AstraZeneca, Bayer, BioClin Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, GlaxoSmithKline, Inovio Pharmaceuticals, Janssen Oncology, Lilly, Merck, Mirati Therapeutics, Pfizer, Pharmacyclics, QED Therapeutics, Roche/Genentech, Seattle Genetics, research funding support from Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Incyte, Novartis, QED Therapeutics, Seattle Genetics, and travel, accommodations, and expenses support from Bristol Myers Squibb and Genentech/Roche. JER also declares an institutional patent. DMG received grants to the institution from Genentech, Merck, Calithera, and Astellas and consulting fees or honoraria from Seattle Genetics/Astellas, Pfizer, Eisai, Merck, and Exelixis. DPP has stock ownership of Bellicum Pharmaceuticals and TYME, received consulting fees from Advanced Accelerator Applications, Amgen, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Exelixis, Incyte, Ipsen, Janssen, Lilly, Pfizer, Pharmacyclics, Roche, Seattle Genetics, and UroGen Pharma, research funding support from Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Endocyte, Genentech, Innocrin Pharma, Lilly, MedImmune, Merck, Novartis, Pfizer, Progenic, Roche, Sanofi, and Seattle Genetics, and personal fees for expert testimony from Celgene and Sanofi. JH-C received research support from Foundation Medicine and Genentech. J Bedke received consulting fees and honoraria from AstraZeneca, Astellas, Bristol Myers Squibb, Eisai, EUSA, Ipsen, Novartis, Roche, Pfizer, Merck, and Janssen. ARK has stock ownership from ECOM Medical, received consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, EMD Serono, Exelixis, Genentech, Novartis, and Pfizer, and has participated in speakers’ bureaus with Amgen, Astellas Medivation, AstraZeneca, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Janssen, Merck, Novartis, Pfizer, and Sanofi, research funding support from Astellas Pharma, AstraZeneca, Bavarian Nordic, Bayer, BeyondSpring Pharmaceuticals, BioClin Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, Epizyme, Exelixis, Genentech/Roche, Immunomedics, Janssen, Macrogenics, and Seattle Genetics, and travel, accommodations, and expenses support from Astellas Medivation, AstraZeneca, Bayer, Eisai, Exelixis, Genentech/Roche, Janssen, Novartis, Pfizer, and Prometheus. YZ has served on an advisory board for Amgen, Roche Diagnostics, Novartis, Janssen, Eisai, Exelixis, Castle Bioscience, Array, Bayer, Pfizer, Clovis, and EMD Serono, received institutional grant or research support for clinical trials from NewLink Genetics, Pfizer, Exelixis, and Eisai, and has served on a data and safety monitoring committee for Janssen Research and Development. MSvdH received research support from Bristol Myers Squibb, AstraZeneca, and Roche and consultancy fees to the institution from Bristol Myers Squibb, Merck/MSD, Roche, AstraZeneca, Seattle Genetics, and Janssen. CNS received honoraria from Astellas Pharma, AstraZeneca, Ipsen, Janssen, Pfizer, Sanofi Genzyme, Bayer, Bristol Myers Squibb, Clovis Oncology, Eisai, Incyte, Merck, MSD, Novartis, Roche, UroToday and Medscape. NND is an employee of Genentech, has stock ownership of Roche, and has received travel, accommodation, and expenses support from Genentech. TP received honoraria and consulting fees from Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono (EMD Serono), MSD, Novartis, Pfizer, Roche, and Seattle Genetics, research funding support from Astellas, AstraZeneca, Bristol Myers Squibb, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono (EMD Serono), MSD, Novartis, Pfizer, Seattle Genetics, , and Roche, and received travel, accommodation, or expenses support from AstraZeneca, MSD, Ipsen, Pfizer, and Roche.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1.

Randomisation and trial populations. *For patients who were screened more than once, reasons for ineligibility refer to the first screening. For patients who were initially ineligible but later re-screened and became eligible, reasons are not included.

Figure 2.

Kaplan-Meier plots for (A) investigator-assessed disease-free survival and (B) overall survival in the intention-to-treat population. HR, hazard ratio. *Stratified by post-resection tumour stage, nodal status, and programmed death-ligand 1 status. †Two-sided.

Figure 3.

Forest plot analyses of disease-free survival in key subgroups. Median follow-up in the intention-to-treat population was 21·9 months (interquartile range 13·2-29·8); thus, observed median disease-free survival durations longer than 21·9 months may be unstable and subject to change with longer follow-up. Tumor stage after resection refers to pathologic staging at cystectomy or nephroureterectomy. DFS, disease-free survival; HR, hazard ratio; IHC, immunohistochemistry; NE, not estimable; PD-L1, programmed death-ligand 1. *Unstratified analyses. †Per interactive voice/web response system. ‡Per electronic case report form.