Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study

Abstract

Purpose We assessed the safety and antitumor activity of avelumab, a fully human anti-programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma. Methods In this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), progression-free survival, overall survival (OS), and PD-L1-associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells. Results Forty-four patients were treated with avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-related adverse events of any grade were fatigue/asthenia (31.8%), infusion-related reaction (20.5%), and nausea (11.4%). Grades 3 to 4 treatment-related adverse events occurred in three patients (6.8%) and included asthenia, AST elevation, creatine phosphokinase elevation, and decreased appetite. The confirmed objective response rate by independent central review was 18.2% (95% CI, 8.2% to 32.7%; five complete responses and three partial responses). The median duration of response was not reached (95% CI, 12.1 weeks to not estimable), and responses were ongoing in six patients (75.0%), including four of five complete responses. Seven of eight responding patients had PD-L1-positive tumors. The median progression-free survival was 11.6 weeks (95% CI, 6.1 to 17.4 weeks); the median OS was 13.7 months (95% CI, 8.5 months to not estimable), with a 12-month OS rate of 54.3% (95% CI, 37.9% to 68.1%). Conclusion Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.

Fig 1.

Clinical activity of avelumab. (A) Time to response, duration of treatment, and duration of response to avelumab (eight confirmed responses and four unconfirmed responses as of data cutoff), with programmed death-ligand 1 (PD-L1) expression status indicated (on the basis of a ≥ 5% staining threshold on tumor cells; nonevaluable specimens [n = 7] included those that were missing, of poor quality, or otherwise not available to provide results). The vertical dotted line represents 1 year from the initiation of treatment. (B) Plot of tumor regression from baseline as measured by Response Evaluation Criteria in Solid Tumors (RECIST) in all assessable patients (n = 38), with PD-L1 expression status indicated (on the basis of a ≥ 5% staining threshold on tumor cells). Eastern Cooperative Oncology Group (ECOG) performance status, presence of nonlymph node metastasis, and albumin and hemoglobin levels at baseline are shown for each patient. The upper dotted line represents progression at 20% and the lower dotted line represents the RECIST boundary for complete response or partial response at 30%. (C) Percentage change in sum of target lesion diameters from baseline over time for all assessable patients (n = 38), defined as those patients with baseline tumor assessments and at least one postbaseline assessment. The upper dotted line represents progression at 20% and the lower dotted line represents the RECIST boundary for complete response or partial response at 30%.

Fig 2.

Progression-free survival (PFS) and overall survival (OS). Kaplan-Meier estimate of PFS (A) and OS (B) for the overall study population (N = 44). Kaplan-Meier estimate of PFS (C) and OS (D) on the basis of programmed death-ligand 1 (PD-L1) expression on tumor cells (n = 37). Vertical lines show censored events. Positive PD-L1 expression was defined as ≥ 5% of tumor cells expressing PD-L1 at any intensity. ne, not estimable.