Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial

Abstract

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.

Figure 1. Change from baseline tumour burden by PD-L1 status

Spider plots depict changes from baseline tumour burden, defined as the sum of target lesion diameters, in patients who received atezolizumab, based on baseline PD-L1 status on immune cells of (A) IC2/3, (B) IC1, and (C) IC0. Grey colour denotes progressive disease; blue denotes stable disease; green denotes complete and partial responses (per RECIST v1.1). Data cutoff: July 4, 2016. PD-L1=programmed death-ligand 1. IC=tumour-infiltrating immune cell.

Figure 2. Overall survival in patients treated with atezolizumab

Kaplan-Meier estimates of overall survival according to PD-L1 status on immune cells. A total of 59 events occurred in all patients by the data cutoff date (18 in IC2/3 patients; 41 in IC0/1 patients). Data cutoff: July 4, 2016. PD-L1=programmed death-ligand 1. NE=not estimable. IC=tumour-infiltrating immune cell.

Figure 3. Associations among TCGA subtype, mutation load, and clinical activity

(A) Response as a function of The Cancer Genome Atlas subtype. (B) Kaplan-Meier plot of overall survival by subtype (luminal I, papillary-like; luminal II; basal III, squamous-like; and basal IV). (C) Mutation load as a function of response (Wilcoxon rank sum p=0·0180 for responding vs non-responding patients). (D) Mutation load versus response disaggregated by subtype or PD-L1 IC score. (E) Kaplan-Meier estimate of overall survival according to estimated mutation load (per megabase), binned into quartiles (log-rank p=0·0041 for a difference in overall survival between quartiles 1 to 3 and quartile 4). P values are for descriptive purposes only. TCGA=The Cancer Genome Atlas. PD-L1=programmed death-ligand 1. Data cutoff: July 4, 2016. IC=tumour-infiltrating immune cell. Lum=luminal. Bas=basal. RECIST=Response Evaluation Criteria In Solid Tumors. NE=not estimable. PD=progressive disease. SD=stable disease. PR=partial response. CR=complete response. MB=megabase.