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FDA has approved Opdivo, a PD-1 checkpoint inhibitor, in previously treated locally advanced or metastatic urothelial carcinoma, a type of bladder cancer


The FDA ( Food and Drug Administration ) has approved Opdivo ( Nivolumab ) injection, for intravenous use for the treatment of patients with locally advanced or metastatic urothelial carcinoma ( mUC ) who have disease progression during or following Platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with Platinum-containing chemotherapy.
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

The recommended dose for metastatic urothelial carcinoma is 240 mg administered as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity.

In the CheckMate -275 trial, 19.6% ( 95% CI: 15.1-24.9; 53/270 ) of patients responded to treatment with Nivolumab.
The percentage of patients with a complete response was 2.6% ( 7/270 ) and the percentage of patients with a partial response was 17% ( 46/270 ).
Among responders, the median duration of response was 10.3 months ( range: 1.9+-12.0+ months ). The median time to response was 1.9 months ( range: 1.6-7.2 ).

The FDA granted the application priority review and previously granted Breakthrough Therapy Designation to Opdivo for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following Platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with Platinum-containing chemotherapy.

CheckMate -275 was a phase 2, open-label, single-arm, multicenter study evaluating Nivolumab in patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following treatment with a Platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with Platinum-containing chemotherapy.
In this study, 270 patients received Nivolumab 3 mg/kg administered intravenously every two weeks until disease progression or unacceptable toxicity.
The recommended dose was 240 mg administered as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity.
The primary endpoint was confirmed objective response rate ( ORR ) as defined by an independent radiographic review committee ( IRRC ).
The median age of patients participating in the study was 66 years ( range: 38-90 ), and 29% of patients had received greater than or equal to two prior systemic regimens in the metastatic setting prior to enrolling in the study.
Patients were included in the trial regardless of their PD-L1 status.

In the trial, efficacy was evaluated in 270 patients with 6 months follow-up by confirmed ORR as determined by an IRRC, Nivolumab demonstrated an ORR of 19.6% ( 95% CI: 15.1-24.9 ).
Additional efficacy breakdown by PD-L1 expression were as follows: PD-L1 less than 1% ( n=146 ), confirmed ORR by IRRC=15.1% ( n=22 ) versus PD-L1 greater than or equal to 1%, ORR=25.0% ( n=31 ); complete response ( CR ) rate: 0.7% ( n=1 ) vs 4.8% ( n=6 ); partial response ( PR ) rate: 14.4% ( n=21 ) versus 20.2% ( n=25 ), respectively.

The safety of Nivolumab has been studied in 270 patients in the CheckMate -275 study. Patients were treated with Nivolumab for a median of 3.3 months ( range: 0-13.4+ ).
In this study, serious adverse events occurred in 54% of patients. The most frequent serious adverse events reported in at least 2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.
The most common adverse reactions ( greater than or equal to 20% ) were fatigue ( 46% ), musculokeletal pain ( 30% ), nausea ( 22% ), and decreased appetite ( 22% ).

Nivolumab was discontinued due to adverse reactions in 17% of patients, and 46% of patients had a dose delay for an adverse reaction. Treatment-related death occurred in four patients due to pneumonitis or cardiovascular failure.

Bladder cancer, which typically begins in the cells that line the inside of the bladder, is the fifth most commonly diagnosed cancer in the United States, with an estimated 77,000 new diagnoses in 2016 and over 16,000 deaths.
Urothelial carcinoma is the most common type of bladder cancer, accounting for approximately 90% of diagnoses.
The majority of bladder cancers are diagnosed at an early stage, but rates of recurrence and progression are high and approximately 50-70% of patients will experience a recurrence within five years.
The poor durability of responses in the first-line setting presents a major challenge in the treatment of metastatic disease and there are limited treatment options in the second-line setting for advanced urothelial carcinoma. ( Xagena )

Source: BMS, 2017

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