Atezolizumab (MPDL3280A) Monotherapy for Patients With Metastatic Urothelial Cancer: Long-term Outcomes From a Phase 1 Study

Abstract

Importance: Atezolizumab (anti-programmed death ligand 1) has demonstrated safety and activity in advanced and metastatic urothelial carcinoma, but its long-term clinical profile remains unknown.

Objective: To report long-term clinical outcomes with atezolizumab therapy for patients with metastatic urothelial carcinoma.

Design, setting, and participants: Patients were enrolled in an expansion cohort of an ongoing, open-label, phase 1 study. Median follow-up was 37.8 months (range, >0.7 to 44.4 months). Enrollment occurred between March 2013 and August 2015 at US and European academic medical centers. Eligible patients had measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Eastern Cooperative Oncology Group performance status 0 to 1, and a representative tumor sample. Programmed death ligand 1 expression on immune cells was assessed (VENTANA SP142 assay).

Interventions: Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects, protocol nonadherence, or loss of clinical benefit.

Main outcomes and measures: Primary outcome was safety. Secondary outcomes included objective response rate, duration of response, and progression-free survival. Response and overall survival were assessed in key baseline subgroups.

Results: Ninety-five patients were evaluable (72 [76%] male; median age, 66 years [range, 36-89 years]). Forty-five (47%) received atezolizumab as third-line therapy or greater. Nine patients (9%) had a grade 3 to 4 treatment-related adverse event, mostly within the first treatment year; no serious related adverse events were observed thereafter. One patient (1%) discontinued treatment due to a related event. No treatment-related deaths occurred. Responses occurred in 26% (95% CI, 18%-36%) of patients. Median duration of response was 22.1 months (range, 2.8 to >41.0 months), and median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months). Median overall survival was 10.1 months (95% CI, 7.3-17.0 months); 3-year OS rate was 27% (95% CI, 17%-36%). Response occurred in 40% (95% CI, 26%-55%; n = 40) and 11% (95% CI, 4%-25%; n = 44) of patients with programmed death ligand 1 expression of at least 5% tumor-infiltrating immune cells (IC2/3) or less than 5% (IC0/1), respectively. Median overall survival in patients with IC2/3 and IC0/1 was 14.6 months (95% CI, 9.0 months to not estimable) and 7.6 months (95% CI, 4.7 to 13.9 months), respectively.

Conclusions and relevance: Atezolizumab remained well tolerated and provided durable clinical benefit to a heavily pretreated metastatic urothelial carcinoma population in this long-term study.

Trial registration: clinicaltrials.gov Identifier: NCT01375842.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Petrylak has ownership interest in Bellicum Pharmaceuticals and Tyme, Inc, has received honoraria from Astellas Pharma, Bayer, Bellicum Pharmaceuticals, Exelixis, Ferring, Genentech, Johnson & Johnson, Medivation, Merck Serono, Millennium, Pfizer, Progenics, and Sanofi, and has had consultancies with Bayer, Bellicum Pharmaceuticals, Dendreon, Exelixis, Ferring, Johnson & Johnson, Medivation, Millennium, Pfizer, and Sanofi. Dr Powles has received research funding from Roche and AstraZeneca as well as honoraria from Roche, Bristol-Myers Squibb, and Merck. Dr Bellmunt has received institutional funding from Millennium and Sanofi, has had consultancies with Astellas, Genentech, Merck, Novartis, Pfizer, and Pierre Fabre, and has received fees for travel accommodations from MSD Oncology and Pfizer. Dr Braiteh has received honoraria for speakers’ bureaus from Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Roche-Genentech, Incyte, INSYS, Ipsen, Merck, and Pfizer and has had consultancies or advisory board roles with Amgen, AstraZeneca, Eli Lilly, and Roche-Genentech. Dr Loriot has received grants from Sanofi and fees for consulting or advisory roles from Astellas, AstraZeneca, Janssen, MSD, Roche, and Sanofi. Dr Kim has received research funding from Immune Design and has had consulting or advisory roles with Dendreon, TRM Oncology, and Voluntis. Drs Ding, Kaiser, Fassò, and O’Hear are employees of Roche-Genentech and own Roche stock. No other disclosures are reported.

Figures

Figure 1.. Duration of Treatment and Response in Patients With Metastatic Urothelial Cancer Treated With Atezolizumab

Time in study is plotted for patients with confirmed, investigator-assessed Response Evaluation Criteria in Solid Tumors version 1.1 responses. Bar color indicates treatment or retreatment status, and symbols, response assessments. Thin bars indicate off-treatment periods. Ongoing response indicates no observation of progressive disease (PD) or death. CR indicates complete response; and PR, partial response. a Subsequent, postretreatment response calculated after rebaselining of target lesion diameters at time of retreatment. No PD or death following subsequent response. b Patient is deceased.

Figure 2.. Overall Survival (OS) by Programmed Death Ligand 1 (PD-L1) Status and Key Clinical Subgroups

A, Kaplan-Meier estimates of OS in all patients and based on PD-L1 status on tumor-infiltrating immune cells (ICs). Plus signs indicate censoring. One patient with unknown PD-L1 IC immunohistochemical status is included in the all-patient curve. B, Median OS by baseline characteristics. Error bars indicate 95% CIs; BCG, bacille Calmette-Guérin; ECOG, Eastern Cooperative Oncology Group; and NE, not estimable. aIndicates time from last prior chemotherapy to first administration of atezolizumab. bIndicates baseline ECOG performance status 1 or greater, baseline liver metastasis, baseline hemoglobin level less than 10 g/dL (to convert to grams per liter, multiply by 10.0), and time since prior chemotherapy 3 months or less. cThe upper 95% CI is NE.