Following Favorable Findings, Nivolumab Receives Breakthrough Therapy Designation for mUC

The FDA has granted nivolumab a breakthrough therapy designation for the treatment of patients with resectable locally advanced or metastatic urothelial carcinoma after the failure of a platinum-containing regimen.

Jean Viallet, MD

The FDA has granted nivolumab (Opdivo) a breakthrough therapy designation for the treatment of patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) after the failure of a platinum-containing regimen, according to Bristol-Myers Squibb (BMS), the manufacturer of the PD-1 inhibitor.

The designation was primarily based on findings from the phase II CA209-275 study (NCT02387996), with additional supportive data also considered by the FDA.

“Urothelial cancer is a common type of bladder cancer where patients experience high rates of recurrence and remains an area where new treatment approaches are needed, further underscoring the importance of this designation for Opdivo,” Jean Viallet, MD, global clinical research lead, oncology, BMS, said in a statement.

“As part of our commitment to bring Opdivo to these advanced bladder cancer patients as quickly as possible, we look forward to filing a marketing application with health authorities based on results from study -275 and other supporting data in the coming months, as well as submitting the data for presentation at an upcoming medical meeting.”

Data for nivolumab in this setting from the CheckMate-032 trial1were reported at the 2016 ASCO Annual Meeting by Padmanee Sharma, MD. In the study, single-agent nivolumab had an overall response rate (ORR) of nearly 25% in patients with advanced mUC. The median progression-free survival (PFS) was 2.78 months (95% CI, 1.45-5.85) and the median overall survival (OS) was 9.72 months (95% CI, 7.26-16.16).

“In previously treated patients with mUC for whom there is no standard of care, [the CheckMate-032 data] provide the first evidence of substantial clinical activity with nivolumab, regardless of PD-L1 expression,” said Sharma, who is a professor of Immunology, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center.

CheckMate-032 included 78 patients with locally advanced or mUC of the renal pelvis, ureter, bladder, or urethra. Patients had recurrence within 1 year of completing platinum-based neoadjuvant or adjuvant treatment, or progression following at least 1 platinum-based regimen for metastatic disease.

The median patient age was 65.5 years (range, 31-85) and 69.2% of patients were male. Over half of patients (53.8%) had received 2 or 3 prior regimens, 33.3% had received 1, and 12.8% had received more than 3. All patients had an ECOG performance status of 0 (53.8%) or 1 (46.2%). Metastatic disease rates at baseline included 78.2%, 25.6%, and 16.7%, for visceral, liver, and lymph node only metastases, respectively.

As determined by by the Dako PD-L1 IHC 28-8 pharmDx kit, 67 patients had measurable PD-L1 tumor expression. Among these patients, 62.7% of had PD-L1 expression levels <1%, with 37.3% having PD-L1 expression levels ≥1%.

Patients received single-agent nivolumab at 3 mg/kg intravenously every 2 weeks. Patients could continue receiving nivolumab at progression if they had a clinical benefit and toxicity was manageable. Eligible patients also had the option to receive nivolumab combined with ipilimumab (Yervoy) at progression.

The primary endpoint was ORR. Secondary endpoints included PFS, OS, duration of response and safety.

At a minimum follow-up of 9 months, the median number of doses received was 8.5 (range, 1-46), and 23.1% of patients remained on nivolumab. The ORR was 24.4% (95% CI, 15.3-35.4), including a complete response rate of 6.4% and a partial response rate 17.9%. The 1-year OS rate was 45.6%.

Median time to response was 1.48 months and the median duration of response was not yet reached. The stable and progressive disease rates were 28.2% and 38.5%, respectively. Response status could not be determined for 9% of patients.

Among patients with PD-L1 levels ≥1%, ORR was 24% (95% CI, 9.4-45.1). Patients with PD-L1 expression <1%, had an ORR of 26.2% (95% CI, 13.9-42). “Basically, we saw that PD-L1 status was irrelevant for response rate and didn’t matter in this cohort of patients,” said Sharma.

The primary reasons for nivolumab discontinuation were disease progression (64.1%), adverse events (AEs) unrelated to treatment (5.1%), nivolumab-related AEs (2.6%), and patient request (2.6%). At progression, 23.1% of patients crossed over to combined therapy with nivolumab/ipilimumab.

The most common all-grade treatment-related AEs included fatigue (36%), pruritus (30%), elevate lipase (14%), rash (18%), nausea (13%), arthralgia (12%), and anemia (10%). Twenty-two percent of patients had grade 3/4 AEs, with the most common being elevated lipase (5%), fatigue (3%), rash (3%), and nausea (1%). There were 2 deaths related to treatment, 1 due to thrombocytopenia and 1 due to pneumonitis.

“These data indicate a favorable benefit/risk profile for nivolumab in the treatment of patients with mUC and support further development in the ongoing phase II -275 study,” Sharma said in her concluding remarks at ASCO.


  1. Sharma P, Bono P, Kim JW, et al. Efficacy and safety of nivolumab monotherapy in metastatic urothelial cancer (mUC): results from the phase I/II CheckMate 032 study.J Clin Oncol34, 2016 (suppl; abstr 4501).