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FDA approves Opdivo® (nivolumab) for high-risk urothelial carcinoma
24 August 2021
FDA approves Opdivo® (nivolumab) for high-risk urothelial carcinoma

Bristol Myers Squibb has announced that Opdivo®(nivolumab) was approved by the U.S. Food and Drug Administration (FDA) for the adjuvant treatment of patients with high-risk 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.1 

The approval is based on the Phase 3 CheckMate -274 trial, which compared Opdivo 240 mg (n=353) to placebo (n=356).1 This application was approved under the FDA’s Real-Time Oncology Review (RTOR) pilot program, which aims to ensure that safe and effective treatments are available to patients as early as possible.2

In the trial, among patients who received Opdivo, 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]). Opdivo 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%, median DFS was not reached (95% CI: 21.2 to NE; n=140) for those who received Opdivo versus 8.4 months (95% CI: 5.6 to 21.2; n=142) for placebo; Opdivo reduced the risk of disease recurrence or death by 45% (HR 0.55, 95% CI: 0.39 to 0.77; P=0.0005).1

“This approval is a major milestone for patients who have undergone major surgery to remove the bladder or parts of the urinary tract and are in need of additional treatment approaches that can help reduce the risk of their UC returning,” said Matthew D. Galsky, M.D., a CheckMate -274 primary investigator and Professor of Medicine, Director of Genitourinary Medical Oncology, Co-Director of the Center of Excellence for Bladder Cancer, and Associate Director for Translational Research at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai.3 “Nivolumab provides a new FDA-approved treatment shown to reduce the risk of disease recurrence or death based on the safety and efficacy findings from CheckMate -274, and has the potential to become a new standard of care option in this setting.”1

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.1

“At Bristol Myers Squibb, our leading research in immunotherapy has helped transform the way many cancers are treated, and we are continuing to bring these advancements to patients with earlier stages of disease, particularly in challenging cancers with significant unmet need,” said Adam Lenkowsky, senior vice president and general manager, U.S. Cardiovascular, Immunology and Oncology, Bristol Myers Squibb. “high-risk urothelial carcinoma is the third type of cancer where Opdivo has been the first approved PD-1 inhibitor in the adjuvant setting. Now with this advancement, we can offer new hope to the conversations between healthcare providers and their high-risk urothelial carcinoma patients where historically no approved treatment options have existed to help prevent disease recurrence post-surgery.”1

The results from the CheckMate -274 trial are confirmatory evidence for Opdivo’s accelerated approval for patients with locally advanced or metastatic UC 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 received in February 2017. These results support conversion of Opdivo’s accelerated approval to a regular approval in this setting.

About CheckMate -274

CheckMate -274 is a randomized, double-blind, placebo-controlled, multi-center trial evaluating Opdivo as an adjuvant treatment in patients who had undergone radical resection of high-risk urothelial carcinoma (UC) originating in the bladder or upper urinary tract and were at high risk of recurrence.1 The UC 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.1

Patients were randomized (n=353 and n=356 to the Opdivo and placebo arms, respectively) to receive Opdivo 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.1 Eligible patients were randomized in a 1:1 ratio to Opdivo or placebo and were stratified by pathologic nodal status (N+ vs. N0/x with <10 nodes removed vs. N0 with ≥10 nodes removed), tumor cells expressing PD-L1 (≥1% vs. <1%/indeterminate as determined by the central lab using the PD L1 IHC 28-8 pharmDx assay), and use of neoadjuvant cisplatin (yes vs. no).1 The major efficacy outcome measures were investigator-assessed DFS in all randomized patients and in patients with tumors expressing PD-L1 ≥1%.1 DFS was defined as time to first recurrence (local urothelial tract, local non-urothelial tract, or distant metastasis), or death.1 Additional efficacy outcome measures included overall survival.1 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.1

Select Safety Profile from CheckMate -274 Study

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

About Urothelial Carcinoma

Urothelial carcinoma (UC), 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.4 Each year, 81,000 new cases of bladder cancer are diagnosed and a majority of those cases are UC.4,5 In addition to the bladder, UC can occur in other parts of the urinary tract, including the ureter and renal pelvis.4 Although UC can be diagnosed early, the rates of recurrence and disease progression can be high.6,7 The survival rate can vary depending on the stage and other factors when diagnosed; for patients with metastatic UC, the prognosis is often poor.5,8

Read more news from The Bladder Interest Group

  1. OpdivoPrescribing Information. OpdivoU.S. Product Information. Last updated: August 2021. Princeton, NJ: Bristol-Myers Squibb Company.
  2. U.S. Food & Drug Administration. Real-Time Oncology Review Pilot Program. Accessed August 03, 2021.
  3. Salama A, Abdelmaksound M, Shawki A, et al. Outcome of Muscle-Invasive Urothelial Bladder Cancer After Radical Cystectomy. Clinical Genitourinary Cancer.2016;14(1):43-47.
  4. American Cancer Society. About Bladder Cancer. Accessed August 03, 2021.
  5. SEER. Cancer Stat Facts: Bladder Cancer. Accessed August 03, 2021.
  6. American Cancer Society. Can Bladder Cancer Be Found Early? Accessed August 03, 2021.
  7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines: Bladder Cancer. Updated: April 22, 2021. Accessed August 03, 2021.
  8. American Cancer Society: Survival Rates for Bladder Cancer. Accessed August 03, 2021.

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