AS REPORTED in The Lancet Oncology by Manish R. Patel, MD, of Florida Cancer Specialists/Sarah Cannon Research Institute, and colleagues, the anti–programmed cell death ligand 1 (PD-L1) antibody avelumab (Bavencio) produced durable responses in patients with locally advanced or metastatic urothelial carcinoma after failure of platinum-based therapy in two expansion cohorts of the phase I dose-expansion JAVELIN Solid Tumor study.¹ These findings support the recent approval of avelumab in this setting. 

“These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma….”

— Manish R. Patel, MD, and colleagues

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Study Details 

THE POOLED ANALYSIS of 2 expansion cohorts from the study involved 249 patients unselected for PD-L1 expression from 80 sites in the United States, Europe, and Asia enrolled between September 2014 and March 2016. Of the 249 patients, 7 were cisplatin-ineligible and had never received platinum-based treatment; these patients were excluded from the efficacy analysis. Patients had to have a life expectancy of at least 3 months and at least 1 measurable lesion. 

Treatment consisted of avelumab at 10 mg/kg via a 1-hour intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other reason for withdrawal. The primary endpoint was confirmed best overall response on Response Evaluation Criteria in Solid Tumors version 1.1 on independent review. Efficacy and safety data were evaluated at data cutoff in June 2016. 

Among all patients, the median age was 68 years (69% aged ≥ 65 years); 72% were male; 70% were from the United States, 25% were from Europe, and 5% were from Asia; 78% were white and 7% were Asian; all had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (35%) or 1 (65%); 77% had lower tract disease; 84% had visceral metastases; 81% had hemoglobin levels ≥ 100 g/L; 79% had albumin levels ≥ 35 g/L; 65% had ever smoked; 29% had received 2 and 21% at least 3 prior treatments for advanced disease; PD-L1 expression status was positive (≥ 5%) in 33% and negative in 50%; and the Bellmunt risk score was 0 in 23%, 1 in 46%, 2 in 24%, and 3 in 7%. (The Bellmunt score is based on the presence of the following risk factors: liver metastases, hemoglobin < 10 g/dL, Eastern Cooperative Oncology Group performance status score > 0, and time since completion or discontinuation of therapy < 3 months.) 

Response Rates 

AT THE TIME of data cutoff, the median duration of avelumab treatment was 12 weeks, and the median follow-up was 9.9 months. Among 161 postplatinum patients with ≥ 6 months of follow-up, complete (9 patients, 6%) or partial (18 patients, 11%) response was observed in 27 patients (17%). Stable disease was observed in an additional 23% of patients. Complete response, partial response, and stable disease rates were 10%, 14%, and 29% among PD-L1–positive patients and 3%, 11%, and 20% among PD-L1–negative patients. The median time to response was 11.4 weeks. The median duration of response was not reached at data cutoff; the estimated proportion of responses lasting ≥ 24 weeks was 96%. The median progression-free survival was 6.3 weeks, with 23% of patients free of disease progression at 6 months. The median overall survival was 6.5 months, and the 6-month overall survival was 53%. 

In post hoc exploratory analyses, the median progression-free survival was 8.3 weeks in patients with an ECOG performance status of 0 vs 6.1 weeks in those with an ECOG performance status of 1; 6.4 vs 6.1 weeks for patients with albumin levels ≥ 35 g/L vs lower levels; 6.4 vs 6.1 weeks for patients with hemoglobin levels ≥ 100 g/L vs lower levels; and 6.1 vs 23.7 weeks for patients with visceral metastases vs lymph node–only metastases. 

Adverse Events 

THE MOST COMMON treatment-related adverse events of any grade were infusion-related reaction (29%, all grade 1 or 2), fatigue (16%), and rash (14%). Grade ≥ 3 treatment-related adverse events occurred in 8% of patients, with the most common being fatigue (2%) and asthenia, elevated lipase, hypophosphatemia, and pneumonitis (1% each). Treatment-related serious adverse events occurred in 8% of patients, including infusion-related reaction, diarrhea, and pneumonitis in at least 1 patient each. Immune-related adverse events occurred in 14% of patients, including rash (10%) and hypothyroidism (4%). Avelumab was permanently discontinued due to treatment-related adverse events in 6% of patients. One patient died due to a treatment-related adverse event (pneumonitis). 

The investigators concluded: “Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma, and it has received accelerated U.S. Food and Drug Administration approval in this setting on this basis.” ■

DISCLOSURE: The study was funded by Merck KGaA and Pfizer Inc. For full disclosures of the study authors, visit www.thelancet.com. 

REFERENCE 

1. Patel MR, Ellerton J, Infante JR, et al: Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): Pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19:51-64, 2018.