FDA Approves Nivolumab for Urothelial Carcinoma

Jonathan E. Rosenberg, MD

The FDA has granted an accelerated approval to nivolumab (Opdivo) as a treatment for patients with locally advanced unresectable or metastatic urothelial carcinoma following progression on a platinum-containing therapy, based on findings from a phase II CheckMate-275 study.

In the study, which was presented at the 2016 ESMO Annual Meeting, the objective response rate (ORR) was 19.6% for nivolumab in patients with platinum-refractory metastatic urothelial carcinoma. The complete response rate was 3%. Across the 270-patient study, the median progression-free survival (PFS) was 2.0 months and the median overall survival (OS) was 8.74 months.

“A nearly 20% response rate in advanced and metastatic bladder cancer is extremely encouraging and clinically meaningful in this patient population,” Jonathan E. Rosenberg, MD, Memorial Sloan Kettering Cancer Center, said in a statement.

The open-label study enrolled 270 patients with metastatic or unresectable urothelial carcinoma. Patients had received a platinum-based agent in the metastatic setting or were within one year of neoadjuvant/adjuvant platinum therapy.

In the trial, nivolumab was administered at 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The FDA recommended a flat dose for the urothelial carcinoma indication of 240 mg intravenously every 2 weeks.

The median age of patients was 66 years and 84.1% of patients had visceral metastases at baseline. Overall, 42.2% of patients had received 1 prior therapy and 29.3% had received ≥2 prior treatment regimens in the metastatic setting. PD-L1 expression ≥1% and ≥5% was reported for 45.9% and 30.7% of patients, respectively.

After a median follow-up of 7 months, 24.4% of patients remained on therapy. The median duration of response was not yet reached, with 76.9% of responses ongoing at the time of the analysis. The median time to response was 1.9 months. Responses consisted of a complete response rate of 2.3% and a partial response rate of 17.4%. The stable disease rate was 22.6%.

In those with PD-L1 expression on ≥1% of cells (n = 122), the ORR was 23.8% with nivolumab (95% CI, 16.5-32.3). In those with PD-L1 expression on ≥5% (n = 81), the ORR was 28.4% (95% CI, 18.9-39.5). Additionally, responses were seen in patients with PD-L1-negative disease (n = 143), which was defined as PD-L1 expression on <1% of cells (ORR, 16.1%; 95% CI, 10.5-23.1).

In patients with PD-L1 expression on ≥1% of cells, the median PFS was 3.55 months and the median OS was 11.3 months. In those with PD-L1-negative tumors, the PFS was 1.87 months and the median OS was 5.95 months.

Across the full study, treatment-related adverse events (AEs) were experienced by 64.4% of patients, with 17.8% of these events being grade 3/4 in severity. Overall, 4.8% of patients discontinued therapy due to treatment-related AEs, of which 3.0% were grade 3/4 in severity. Quality-of-life, as assessed using the Global Health Status Scale, improved from baseline and remained stable over the course of the trial.

The most frequently reported all-grade AEs were fatigue (16.7%), pruritus (9.3%), diarrhea (8.9%), decreased appetite (8.1%), hypothyroidism (7.8%), nausea (7.0%), asthenia (5.9%), rash (5.9%), and pyrexia (5.6%). The most common grade 3/4 AEs were fatigue (1.9%), diarrhea (1.9%), asthenia (1.5%), and rash (1.1%).

In June 2016, the FDA granted nivolumab a breakthrough therapy designation for the treatment of patients with unresectable locally advanced or metastatic urothelial carcinoma after the failure of a platinum-containing regimen. The EMA validated a type II variation application for use of nivolumab for the same indication in September 2016.

Galsky MD, Retz M, Siefker-Radtke AO, et al. Efficacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results from the phase II CheckMate-275 study. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA31.