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

Abstract

Summary 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 evaluated atezolizumab as adjuvant therapy in the phase 3 IMvigor010 study. Methods In this multicentre, open-label, randomised phase 3 trial, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and 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 postsurgical radiation or prior adjuvant chemotherapy was allowed. Patients were randomised 1:1 using a permuted block method and interactive voice-web response system to receive atezolizumab 1200 mg given intravenously every 3 weeks or up to 1 year or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathologic nodal status, tumour stage, and PD-L1 expression on tumor-infiltrating immune cells. The primary endpoint was disease-free survival, tested in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients. Findings Between October 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned atezolizumab, and 403 were assigned observation. Median follow-up was 21·9 months (interquartile range: 13·2–29·8). Median disease-free survival with atezolizumab and observation was 19·4 (95% CI: 15·9–24·8) and 16·6 (11·2–24·8) months, respectively; the hazard ratio was 0·89 (95% CI, 0·74–1·08; P=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (occurring in 31 of 390 [8%)] treated patients in the atezolizumab and 20 [5%] of 397 in the observation arm), as well as pyelonephritis (in 12 (3%]) vs 14 (4%]) and anaemia (in 8 [2%] vs 7 [2%]). Serious adverse events occurred in 122 patients (31%) who received atezolizumab and 71 (18%) who underwent observation. Sixty-three patients who received atezolizumab (16%) had a treatment-related grade 3 or 4 adverse event. One treatment-related grade 5 adverse event of acute respiratory distress syndrome was observed in the atezolizumab arm. Interpretation IMvigor010—to our knowledge the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma—did not meet its primary endpoint of improved disease-free survival 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 Ltd./Genentech, Inc.