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Atezolizumab (MPDL3280A) monotherapy for patients with metastatic urothelial cancer

  • Daniel P. Petrylak,
  • Thomas Powles,
  • Joaquim Bellmunt,
  • Fadi Braiteh,
  • Yohann Loriot,
  • Rafael Morales-Barrera,
  • Howard A. Burris,
  • Joseph W. Kim,
  • Beiying Ding,
  • Constanze Kaiser,
  • Marcella Fassò,
  • Carol O’Hear,
  • Nicholas J. Vogelzang

Publication: JAMA Oncol. , April 2018

DOI: 10.1001/jamaoncol.2017.5440

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

Expert's summary

In this open label, phase 1 study, metastatic urothelial cancer patients diagnosed between March 2013 and August 2015 were enrolled at united states and European academic medical centers. Patients were treated with Atezolizumab intravenously every 3 weeks until unacceptable toxic effects, protocol nonadherence or loss of clinical benefit. Primary outcome was safety, while secondary outcomes included objective response rate, duration of response and progression free survival. Overall, 95 patients were evaluable and 45 received atezolizumab as third line therapy or greater. High grade 3 to 4 treatment related adverse event was recorded in 9% of patients, mostly within the first treatment year. No serious event was observed thereafter. Responses occurred in 26% of the treated patients, with a median duration of response of 22.1 months and a median progression free survival of 2.7 months. Median overall survival was 10.1 months and 3-year overall survival rate was 27%. Response occurred in 40% and 11% of patients with PDL1 expression of at least 5% of tumor infiltrating immune cells or less than 5%, respectively. Authors conclude that atezolizumab remained well tolerated and provided durable clinical benefit to a heavily pretreated metastatic urothelial carcinoma. 

Expert's comment

While platinum based therapy is the established first line treatment for metastatic urothelial cancer, no definitive consensus exists regarding the treatment of patients with more advanced disease. In this phase 1 study, authors showed excellent survival outcomes and safety for metastatic urothelial patients treated with atezolizumab. Given these excellent results, research on immune check point inhibitors should be encouraged even in the first line.