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

By A. Balar, M. Galsky, J. Rosenberg, T. Powles, D. Petrylak, J. Bellmunt, Y. Loriot, A. Necchi, J. Hoffman-Censits, J. Pérez-Gracia and 25 more. The Lancet, 2016

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Summary Background First-line chemotherapy for patients with cisplatin-ineligible locally-advanced or metastatic urothelial carcinoma (mUC) is associated with short response duration, poor survival, and high toxicity. This multicenter, 2-cohort phase 2 study evaluated atezolizumab (anti–programmed death-ligand 1 [PD-L1]) as treatment for mUC in this setting, as well as in later lines. Methods In a cohort of previously untreated patients who were cisplatin ineligible, atezolizumab was given 1200 mg every 3 weeks until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria In Solid Tumors v1.1 (central review), evaluated in pre-specified subgroups based on PD-L1 expression and in all patients. Secondary endpoints included response duration, progression-free survival, overall survival, and safety. Exploratory analyses included biomarker correlates of response and survival. This study is registered with ClinicalTrials.gov, number NCT02108652. Findings Of 119 patients who received atezolizumab in the first-line setting, 83 (70%) had baseline renal impairment, and 24 (20%) had Eastern Cooperative Oncology Group performance status 2. At 17·2 months’ median follow-up, the objective response rate was 23% (95% CI 16–31), the complete response rate was 9%, 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. Median overall survival was 15·9 months. Tumour mutation load was associated with response. Treatment-related adverse events ≥10% were fatigue, diarrhoea, and pruritus. One treatment-related death (sepsis) occurred. Nine patients (8%) had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. Interpretation Atezolizumab demonstrated encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated mUC. Funding F. Hoffmann-La Roche Ltd./Genentech, Inc., a member of the Roche Group.

Subfields: Oncology, Pulmonary and Respiratory Medicine, Surgery

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Citations in the corpus

Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “In advanced or metastatic urothelial carcinoma, atezolizumab is also approved as a first-line treatment, where increased PD-L1 expression on immune cells can enhance the responses to Atezolizumab [349].”
T Cell Dysfunction in Cancer (2018, background): “…2014, 2015), non-small-cell lung cancer (NSCLC) (Borghaei et al., 2015; Brahmer et al., 2015; Fehrenbacher et al., 2016), renal cancer (RCC) (Motzer et al., 2015), urothelial cancer (Balar et al., 2017; Rosenberg et al., 2016), and head and neck squamous cell cancer (HNSCC) (Seiwert et al., 2016).”
European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2020 Update. (2020, neutral): “In addition, the role of immunotherapy has been evaluated in the first-line setting for cisplatin-ineligible UTUC patients, but limited data on pembrolizumab and atezolizumab are available in the literature [201,202].”