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

Abstract

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.

PD-L2 amplification and durable disease stabilization in patient with urothelial carcinoma receiving pembrolizumab

“…19 Previous clinical data indicate that an improved ORR to atezolizumab amongst urothelial carcinoma patients is associated with >5% positive staining for PD-L1 (as assessed by the SP142 assay) on tumor-infiltrating immune cells. 10 , 18 Conversely, PD-L1 positivity by neoplastic or immune cells (as assessed by the 22C3 assay) reportedly fails to correlate with improved objective responses to pembrolizumab in urothelial carcinoma patients. 7 This patient exhibited a durable disease stabilization on pembrolizumab (associated with an increase in survival as compared to expectations) despite no PD-L1 positivity in tumor-infiltrating immune cells and no membranous PD-L1 expression by malignant cells.…”

“…15-17 Specifically, the IMvigor 210 trial (NCT02108652) demonstrated that urothelial carcinoma patients treated with atezolizumab exhibit an increased objective response rate (ORR) when their lesions stain positively (>5% of cells) for PD-L1. 10 , 18 Nonetheless, ORR never exceeded 26%, even amongst patients with the highest IHC score for PD-L1 expression. 10 , 18 In the same setting, whole-exon DNA-seq on a subset of patients demonstrated an increased likelihood for response amongst subjects with high MuB, although a considerable overlap existed between this group and individuals with low MuB.…”

“…10 , 18 Nonetheless, ORR never exceeded 26%, even amongst patients with the highest IHC score for PD-L1 expression. 10 , 18 In the same setting, whole-exon DNA-seq on a subset of patients demonstrated an increased likelihood for response amongst subjects with high MuB, although a considerable overlap existed between this group and individuals with low MuB. 10 , 18 These findings led to the development of IHC-based companion diagnostics for the detection of PD-L1 expression levels in tumor biopsies, including the SP142 assay 19 from Ventana Medical Systems (Tucson, AZ, USA) and the 22C3 assay 20 from Dako Inc. (Santa Clara, CA, USA).…”

“…10 , 18 In the same setting, whole-exon DNA-seq on a subset of patients demonstrated an increased likelihood for response amongst subjects with high MuB, although a considerable overlap existed between this group and individuals with low MuB. 10 , 18 These findings led to the development of IHC-based companion diagnostics for the detection of PD-L1 expression levels in tumor biopsies, including the SP142 assay 19 from Ventana Medical Systems (Tucson, AZ, USA) and the 22C3 assay 20 from Dako Inc. (Santa Clara, CA, USA). Neither of these assays, however, is currently approved by the US FDA as a companion diagnostic for predicting responses to ICBs amongst urothelial carcinoma patients (22C3 is approved for predicting responses to pembrolizumab amongst non-small cell lung carcinoma and gastroesophageal carcinoma patients; source https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm).…”

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

“…Patients with MMR deficiency are associated with a higher mutational burden and tumor neoantigen load than MMR-proficient patients, and these features could be driving clinical benefit of ICBs [33,97,98]. In fact, tumor mutational burden, known to enhance neoantigen formation, has been shown to be associated with increased response to ICBs, and in some cases improved OS as well, across tumor types such as melanoma [99,100], NSCLC [101], and UC [54,56,102]. Baseline gene expression profiling has also been correlated with response to ICBs; specifically, interferon gamma (IFNγ) signature, which is indicative of an inflammatory tumor microenvironment, is associated with responsiveness to ICBs in several tumor types, including melanoma [103], UC [32,54,104,105], NSCLC [58,106], HNSCC [103], and gastric cancer [103].…”