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The FDA ( Food and Drug Administration ) has granted Breakthrough Therapy Designation to Opdivo ( Nivolumab ) for the potential indication of unresectable locally advanced or metastatic urothelial carcinoma that has progressed on or after a Platinum-containing regimen.
As part of the Breakthrough Therapy Designation submission, BMS ( Bristol-Myers Squibb ) has shared for the FDA’s review results from phase 2 study CA209-275 and other supportive data investigating Opdivo in these previously treated bladder cancer patients.

In the CheckMate-032 trial, single-agent Nivolumab had an overall response rate ( ORR ) of nearly 25% in patients with advanced metastatic urothelial carcinoma.
The median progression-free survival ( PFS ) was 2.78 months and the median overall survival ( OS ) was 9.72 months.

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.

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

The median patient age was 65.5 years ( ranging from 31 to 85 ) and 69.2% of patients were male. Over half of patients ( 53.8% ) had received two or three prior regimens, 33.3% had received one, and 12.8% had received more than three.
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 less than 1%, with 37.3% having PD-L1 expression levels at least 1%.

Patients received single-agent Nivolumab at 3 mg/kg intravenously every two 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 overall response rate. Secondary endpoints included progression-free survival, overall survival, duration of response and safety.

At a minimum follow-up of 9 months, the median number of doses received was 8.5 ( ranging from 1 to 46 ), and 23.1% of patients remained on Nivolumab.
The ORR was 24.4%, including a complete response rate of 6.4% and a partial response rate 17.9%. The one-year overall survival 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 at least 1%, ORR was 24%. Patients with PD-L1 expression less than 1%, had an ORR of 26.2%.

The primary reasons for Opdivo discontinuation were disease progression ( 64.1% ), adverse events unrelated to treatment ( 5.1% ), Opdivo-related adverse reactions ( 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 adverse effects 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 adverse effects, with the most common being elevated lipase ( 5% ), fatigue ( 3% ), rash ( 3% ) and nausea ( 1% ).
There were two deaths related to treatment, one due to thrombocytopenia and one due to pneumonitis.

Previous Breakthrough Therapy Designations granted for Opdivo by the FDA include previously treated recurrent or metastatic squamous cell carcinoma of the head and neck, Hodgkin lymphoma after failure of autologous stem cell transplant and Brentuximab vedotin, previously treated advanced melanoma, previously treated non-squamous non-small cell lung cancer, and previously treated advanced or metastatic renal cell carcinoma.

Bladder cancer, which typically begins in the cells that line the inside of the bladder, is the ninth most commonly diagnosed cancer in the world, with an estimated 430,000 new cases diagnosed per year and over 165,000 deaths per year.
Urothelial carcinoma is the most common type of bladder cancer, accounting for approximately 90% of cases.
The majority of bladder cancers are diagnosed at an early stage, but rates of recurrence and progression are high and approximately 78% of patients will experience a recurrence within five years.
Survival rates vary depending on the stage and type of the cancer and when it is diagnosed. For stage IV bladder cancer, the five-year survival rate is 15%. ( Xagena )

Source: BMS, 2016

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