EMA Validation Puts Nivolumab Under Formal Review for Bladder Cancer

A type II variation application for the use of nivolumab (Opdivo) as a treatment for patients with locally advanced unresectable or metastatic urothelial carcinoma (mUC) who have progressed following platinum-based chemotherapy is now under formal review.

Fouad Namouni, MD

Fouad Namouni, MD

A type II variation application for the use of nivolumab (Opdivo) as a treatment for patients with locally advanced unresectable or metastatic urothelial carcinoma (mUC) who have progressed following platinum-based chemotherapy is now under formal review by the Committee for Medicinal Products for Human Use. The European Medicines Agency (EMA) has validated the application, which will ultimately receive a final approval decision by the European Commission.

The application was based on findings from the open-label, single-arm CheckMate -275 study (NCT02387996), which is examining nivolumab in previously treated patients with mUC. Objective response rate (ORR) is the primary endpoint of the trial, with secondary outcome measures including overall survival (OS) and durability of response. Findings from the trial will be presented at the 2016 ESMO Annual Congress in October, according to Bristol-Myers Squibb (BMS), the manufacturer of nivolumab.

“The high frequency of metastatic urothelial carcinoma and its relapsing nature highlight the substantial need for new treatment approaches with high and durable responses,” Fouad Namouni, MD, head of development, Oncology, BMS, said in a statement. “We look forward to working with the EMA to potentially extend the use of Opdivo and bring the science of immuno-oncology to help patients in Europe fight this difficult-to-treat, advanced form of bladder cancer.”

Data for nivolumab in this setting from the CheckMate-032 trial were reported at the 2016 ASCO Annual Meeting. In the study, single-agent nivolumab had an 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 OS was 9.72 months (95% CI, 7.26-16.16).

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 (53.8%) of patients 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 the Dako PD-L1 IHC 28-8 pharmDx kit, 67 patients had measurable PD-L1 tumor expression. Among these patients, 62.7% had PD-L1 expression levels <1%, with 37.3% having PD-L1 expression levels &ge;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.

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 &ge;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).

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.

The FDA granted nivolumab a breakthrough therapy designation in June 2016 for the treatment of patients with unresectable locally advanced or metastatic mUC after the failure of a platinum-containing regimen.


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).

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