Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study

Abstract

Importance: The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval.

Objective: To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC.

Design, setting, and participants: This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein.

Intervention: Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects.

Main outcomes and measures: Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1).

Results: A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis).

Conclusions and relevance: Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC.

Trial registration: clinicaltrials.gov Identifier: NCT01693562.

Figure 1.. Study Profile

The overall population included 17 different tumor-specific cohorts; 2367 patients were screened, of whom 1355 were screen failures. ≥2L indicates second-line or greater; Q2W, every 2 weeks; PD-L1, programmed cell death ligand-1. ^aA large portion of screen failures were based on their PD-L1 status and eligibility criteria requiring a specific PD-L1 status for enrollment. ^bThese included 6 patients from the dose-escalation phase of the study. ^cPD-L1 expression status was unknown (owing to insufficient tumor in biopsy) or unavailable (as testing had not been processed at data cutoff) for 14 patients.

Figure 2.. Antitumor Activity and Kaplan-Meier Estimates of Overall Survival in the Cohort With Urothelial Carcinoma by PD-L1 Expression Status

Programmed cell death ligand-1 (PD-L1) expression status was unknown (owing to insufficient tumor in biopsy) or unavailable (as testing had not been processed at data cutoff) for 14 patients. A, Time to response and duration of response (DoR) by blinded independent central review (BICR). B, Best percentage change from baseline in tumor size by BICR (patients with target lesions at baseline and ≥1 postbaseline scan). One patient in the PD-L1 high subgroup with confirmed complete response was excluded from the figure owing to lack of a target lesion at baseline per BICR. For patients with lymph nodes included in their target lesions, complete response may not equate with a 100% decrease from baseline according to Response Evaluation Criteria in Solid Tumors, version 1.1. C, Overall survival (OS). Given limited follow-up, OS data were considered immature at the time of data cutoff. CR indicates complete response; NE, not evaluable; neg, negative; PR, partial response.