Following Checkmate-274 trial, FDA approves adjuvant Nivolumab for high-risk Urothelial Carcinoma

Urothelial carcinoma (UC), is the most common type of bladder cancer in adults. In addition to the bladder, UC can occur in other parts of the urinary tract, including the ureter and renal pelvis. Nivolumab is a fully human IgG4 monoclonal antibody known as a programmed cell death 1 (PD-1) immune checkpoint inhibitor. The PD-1 pathway is an immune system checkpoint that may be exploited by tumour cells to escape active T-cell surveillance.

"The U.S. Food and Drug Administration (FDA) approved Nivolumab 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 on August 19, 2021."

The FDA-approved dosing for Nivolumab 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.

About the CheckMate -274 trial

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 (UC) originating in the bladder or upper urinary tract and were at high risk of recurrence.

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.

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. 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 <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). The major efficacy outcome measures were investigator-assessed DFS in all randomized patients and in patients with tumors expressing PD-L1 ≥1%.

Important findings in CheckMate -274 trial that lead to Nivolumab approval are:

• Among patients who received Nivolumab, median disease-free survival (DFS) was nearly twice as long as in those who received placebo (20.8 months)

• Nivolumab 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 for those who received Nivolumab versus 8.4 months for placebo

• Nivolumab reduced the risk of disease recurrence or death by 45%

Matthew D. Galsky, M.D., a CheckMate -274 primary investigator at the Icahn School of Medicine at Mount Sinai noted that "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."

Safety Profile of Nivolumab from CheckMate -274 Study

The most common (≥20%) adverse reactions were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%).

Indications of Nivolumab:

• As a single agent, it is indicated for the adjuvant treatment of patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

• Indicated 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.

• Adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

• Adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy.

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)

Source: Bajorin DF et al. N Engl J Med 2021; 384:2102-2114

DOI: 10.1056/NEJMoa2034442 and F.D.A