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Opdivo for the adjuvant treatment of patients with high-risk urothelial carcinoma - Approved by FDA

The U.S. Food and Drug Administration ( FDA ) ha approved Opdivo ( Nivolumab ) 240 mg every two weeks or 480 mg every four weeks ( injection for intravenous use ) for the adjuvant treatment of patients with urothelial carcinoma ( UC ) who are at high risk of recurrence after undergoing radical resection, regardless of prior neoadjuvant chemotherapy, nodal involvement or PD-L1 status.

The approval is based on the phase 3 CheckMate -274 trial, which has compared Opdivo 240 mg ( n=353 ) to placebo ( n=356 ).
In the trial, among patients who received Nivolumab, median disease-free survival ( DFS ) was nearly twice as long as in those who received placebo ( 20.8 months [ 95% Confidence Interval ( CI ): 16.5 to 27.6 ] versus 10.8 months [ 95% CI: 8.3 to 13.9 ] ).
Nivolumab has reduced the risk of disease recurrence or death by 30% compared to placebo ( hazard ratio [ HR ] 0.70, 95% CI: 0.57 to 0.86; P=0.0008 ).
Among patients whose tumors express PD-L1 1% or more, median disease-free survival was not reached ( 95% CI: 21.2 to NE; n=140 ) for those who received Nivolumab versus 8.4 months ( 95% CI: 5.6 to 21.2; n=142 ) for placebo; Nivolumab has reduced the risk of disease recurrence or death by 45% ( HR 0.55, 95% CI: 0.39 to 0.77; P=0.0005 ).

Opdivo is associated with the following Warnings & Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, dermatologic adverse reactions, nephritis with renal dysfunction, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation ( HSCT ); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when Opdivo is added to a Thalidomide analogue and Dexamethasone, which is not recommended outside of controlled clinical trials.

CheckMate -274 is a randomized, double-blind, placebo-controlled, multi-center trial evaluating Nivolumab as an adjuvant treatment in patients who had undergone radical resection of urothelial carcinoma originating in the bladder or upper urinary tract and were at high risk of recurrence.
The urothelial carcinoma pathologic staging criteria that defines high risk patients was ypT2-ypT4a or ypN+ for patients who received neoadjuvant Cisplatin chemotherapy or pT3-pT4a or pN+ for patients who did not receive neoadjuvant Cisplatin and who also either were ineligible for or refused adjuvant Cisplatin chemotherapy.

Patients were randomized ( n=353 and n=356 to the Nivolumab and placebo arms, respectively ) to receive Nivolumab 240 mg or placebo by intravenous infusion over 30 minutes every two weeks until recurrence or unacceptable toxicity for a maximum treatment duration of one year.
Eligible patients were randomized in a 1:1 ratio to Nivolumab or placebo and were stratified by pathologic nodal status ( N+ vs. N0/x with less than 10 nodes removed vs. N0 with 10 or more nodes removed ), tumor cells expressing PD-L1 ( greater than or equal to 1% vs. less than 1% / indeterminate as determined by the central lab using the PD L1 IHC 28-8 pharmDx assay ), and use of neoadjuvant Cisplatin ( yes versus no ).
The major efficacy outcome measures were investigator-assessed disease-free survival in all randomized patients and in patients with tumors expressing PD-L1 greater than or equal to 1%.
Disease-free survival was defined as time to first recurrence ( local urothelial tract, local non-urothelial tract, or distant metastasis ), or death.
Additional efficacy outcome measures included overall survival.

The FDA-approved dosing for Opdivo is 240 mg every two weeks ( 30-minute intravenous infusion ) or 480 mg every four weeks ( 30-minute intravenous infusion ) until disease recurrence or unacceptable toxicity for up to one year.

Adverse reactions leading to discontinuation of Nivolumab occurred in 18% of patients.
Nivolumab was delayed for adverse reaction in 33% of patients.
Serious adverse reactions occurred in 30% of patients receiving Nivolumab.
The most frequent ( 2% or more ) serious adverse reaction in patients receiving Nivolumab was urinary tract infection.
Fatal adverse reactions occurred in 1% of patients and included pneumonitis ( 0.6% ).
The most common ( 20% or more ) adverse reactions were rash ( 36% ), fatigue ( 36% ), diarrhea ( 30% ), pruritus ( 30% ), musculoskeletal pain ( 28% ), and urinary tract infection ( 22% ).

Urothelial carcinoma, which most frequently begins in the cells that line the inside of the bladder, is the most common type of bladder cancer in adults in the United States.
Each year, 81,000 new cases of bladder cancer are diagnosed and a majority of those cases are urothelial carcinoma.
In addition to the bladder, urothelial carcinoma can occur in other parts of the urinary tract, including the ureter and renal pelvis.
Although urothelial carcinoma can be diagnosed early, the rates of recurrence and disease progression can be high.
The survival rate can vary depending on the stage and other factors when diagnosed; for patients with metastatic urothelial carcinoma, the prognosis is often poor. ( Xagena )

Source: Bristol Myers Squibb, 2021