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/m2 intravenously; day 1 and day 8 of each 21 -day cycle), plus investigator's choice of carboplatin (area under curve 4 center dot 5 mg/mL per min or 5 mg/mL per min; intravenously) or cisplatin (70 mg/m2 intravenously), plus either atezolizumab (1200 mg intravenously) or placebo on day 1 of each cycle. Co -primary endpoints of the study were investigator -assessed progression -free survival and overall survival for group A versus group C in the intention -to -treat (ITT) population (ie, all randomised patients), and overall survival for group B versus group C, tested hierarchically. Final overall survival and updated safety outcomes (safety population; all patients who received any amount of any study treatment component) for group A versus group C are reported here. The final prespecified boundary for significance of the overall survival analysis was one-sided p=0 center dot 021. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting. 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 center dot 4 months (IQR 6 center dot 2-30 center dot 8), median overall survival was 16 center dot 1 months (95% CI 14 center dot 2-18 center dot 8; 336 deaths) in group A versus 13 center dot 4 months (12 center dot 0-15 center dot 3; 310 deaths) in group C (stratified hazard ratio 0 center dot 85 [95% CI 0 center dot 73-1 center dot 00]; one-sided p=0 center dot 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.