Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial
Arjun V Balar 1 , Matthew D Galsky 2 , Jonathan E Rosenberg 3 , Thomas Powles 4 , Daniel P Petrylak 5 , Joaquim Bellmunt 6 , Yohann Loriot 7 , Andrea Necchi 8 , Jean Hoffman-Censits 9 , Jose Luis Perez-Gracia 10 , Nancy A Dawson 11 , Michiel S van der Heijden 12 , Robert Dreicer 13 , Sandy Srinivas 14 , Margitta M Retz 15 , Richard W Joseph 16 , Alexandra Drakaki 17 , Ulka N Vaishampayan 18 , Srikala S Sridhar 19 , David I Quinn 20 , Ignacio Durán 21 , David R Shaffer 22 , Bernhard J Eigl 23 , Petros D Grivas 24 , Evan Y Yu 25 , Shi Li 26 , Edward E Kadel 3rd 26 , Zachary Boyd 26 , Richard Bourgon 26 , Priti S Hegde 26 , Sanjeev Mariathasan 26 , AnnChristine Thåström 26 , Oyewale O Abidoye 26 , Gregg D Fine 26 , Dean F Bajorin 3 , IMvigor210 Study Group
Background: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.
Methods: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression.
The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652.
Findings: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2).
Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.
Interpretation: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer.
Funding: F Hoffmann-La Roche, Genentech.
Trial registration: ClinicalTrials.gov NCT02302807 NCT02807636 NCT02108652.