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Opdivo (Nivolumab) Demonstrates Significant Improvement in Disease-Free Survival as Adjuvant Therapy for Muscle-Invasive Urothelial Carcinoma

Jun 22, 2021 02:07 CST Updated 02:07
Bristol-Myers Squibb

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Bladder Cancer (Image source: medscape.com)

June 21, 2021 /BioonBIOON/ -- Recently, data from the pivotal Phase 3 CheckMate-274 study (NCT02632409), which evaluated Bristol-Myers Squibb's (BMS) anti-PD-1 therapy Opdivo (Chinese brand name: Ouyiwo; generic name: nivolumab) as adjuvant therapy for muscle-invasive urothelial carcinoma (MIUC), were published in The New England Journal of Medicine (NEJM). The results showed that:In high-risk MIUC patients who have undergone surgical resection, adjuvant Opdivo treatment significantly prolonged disease-free survival (DFS) compared with placebo, regardless of PD-L1 expression level.. In this study, Opdivo was generally well tolerated, and its safety profile was consistent with that previously reported in studies of Opdivo in patients with solid tumors. For detailed results, see:Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma。

Currently, the application for Opdivo as an adjuvant (postoperative) therapy for patients with high-risk MIUC following radical surgery is under review by regulatory authorities in the United States, the European Union, and Japan.If approved, Opdivo will become the first adjuvant immunotherapy regimen for the treatment of MIUC.

Patients with MIUC frequently undergo radical cystectomy as a life-saving measure, yet the risk of cancer recurrence remains approximately 50%. The CheckMate-274 study demonstrated that, among all randomized patients, DFS in the Opdivo treatment group was nearly double that of the placebo group. Based on the groundbreaking disease-free survival results from this trial, Opdivo has the potential to transform the treatment landscape for MIUC and help address the urgent need for effective and tolerable therapeutic options following surgery.

CheckMate-274 is a randomized, double-blind, multicenter Phase 3 study conducted in patients with muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence following radical surgery, evaluating the efficacy and safety of Opdivo versus placebo as postoperative adjuvant therapy. In the trial, a total of 709 patients were randomized in a 1:1 ratio to receive Opdivo (240 mg, intravenous infusion; n=353) or placebo (n=356) once every 2 weeks for up to 1 year. Patients who had received cisplatin-based neoadjuvant (preoperative) chemotherapy prior to surgery were eligible for inclusion. The primary endpoint was all randomized patients (i.e., the intent-to-treat [ITT] population) andTumorDisease-free survival (DFS) in patients with PD-L1 expression ≥1%. A secondary endpoint of the trial is non-urothelial recurrence-free survival (NUTRFS), defined as the survival time without disease recurrence outside the bladder, ureter, or renal pelvis.

Results showed,The study met the primary endpoint:（1）In all randomized patients (ITT), median PFS was nearly doubled with Opdivo compared with placebo (20.8 months [95% CI: 16.5–27.6] vs 10.8 months [95% CI: 8.3–13.9])., the proportions of patients alive and recurrence-free at 6 months in the two groups were 74.9% and 60.3%, respectively (HR = 0.70; 98.22% CI: 0.55–0.90, p < 0.001). (2)Among patients with tumor PD-L1 expression ≥1%, the proportions of patients who were alive and recurrence-free at 6 months in the two groups were 74.5% and 55.7%, respectively.（HR=0.55，98.72%CI:0.35-0.85，p＜0.001）。

CheckMate 274 Study: DFS Results (Click image to enlarge)

The study also met the secondary endpoint.：Among all randomized patients (ITT), the median NUTRFS was 22.9 months (95% CI: 19.2-33.4) in the Opdivo treatment group and 13.7 months (95% CI: 8.4-20.3) in the placebo group., the proportions of patients in the two groups who were alive and free of extra-urinary recurrence at 6 months were 77.0% and 62.7%, respectively (HR=0.72; 95% CI: 0.59-0.89).InTumorIn patients with PD-L1 expression ≥1%, the proportions of patients alive and free of extraurinary recurrence at 6 months in the two groups were 75.3% and 56.7%, respectively (HR=0.55, 95% CI: 0.39-0.79).

In both trial populations, distant metastasis-free survival (DMFS) was also longer in the Opdivo treatment group compared with the placebo group.。Among all randomized patients (ITT), the median DMFS in the Opdivo treatment group was 40.5 months (95% CI: 22.4 to NE [not estimable]), versus 29.5 months (95% CI: 16.7 to NE) in the placebo group., the proportions of patients alive and free of distant metastasis at 6 months in the two groups were 82.5% and 69.8%, respectively (hazard ratio [HR] for distant metastasis or death = 0.75; 95% CI: 0.59–0.94).InTumorIn patients with PD-L1 expression ≥ 1%, the proportions of patients alive and free of distant metastasis at 6 months in the two groups were 78.7% and 65.7%, respectively (HR = 0.61, 95% CI: 0.42–0.90).

In this study, 17.9% of patients in the Opdivo treatment group and 7.2% of patients in the placebo group experienced treatment-related adverse events (TRAEs) of grade 3 or higher. Two patients in the Opdivo treatment group experienced treatment-related deaths due to pneumonia.

CheckMate 274 Study: NUTRFS Results (Click image to view full size)

Bladder cancer is the tenth most common cancer worldwide, with approximately 550,000 new cases diagnosed and about 200,000 deaths annually. Urothelial carcinoma (UC) is the most common type of bladder cancer, accounting for approximately 90–95% of all cases. Muscle-invasive urothelial carcinoma (MIUC) is a type of UC that has invaded the muscle of the bladder, ureter, or renal pelvis. Approximately 25% of newly diagnosed bladder cancer cases areDiagnosisIt is a muscle-invasive disease with a poorer prognosis compared to non-muscle-invasive urothelial carcinoma (non-MIUC).

Most UC cases are diagnosed at an early stage. The objective of early treatment for MIUC is to reduce the risk of disease recurrence or metastasis to other parts of the body. However, recurrence and disease progression rates remain high; over 50% of MIUC patients experience disease recurrence following radical surgery, necessitating additional postoperative treatment options. The prognosis for patients who relapse with metastatic UC is poor, with a median overall survival of approximately 12–14 months following systemic therapy.

It is worth noting that,CheckMate-274 is the first Phase 3 trial demonstrating that adjuvant (postoperative) immunotherapy reduces the risk of disease recurrence in patients with MIUC at high risk of recurrence following radical surgery.By shifting immunotherapy to the early stages of cancer, there is an opportunity to interrupt disease progression, reduce recurrence, and improve patient prognosis.

To date, Opdivo-based treatment regimens have already been evaluated in 4 Phase III clinical trials for early-stage cancerClinical Trialdemonstrated efficacy in, including adjuvant (postoperative) treatment of bladder cancer (CheckMate-274),Melanoma(CheckMate-238), esophageal/gastroesophageal junction cancer (CheckMate-577), non-small cell lung cancer (CheckMate-816).

Opdivo is a PD-(L)1 cancer immunotherapy designed to harness the body's own immune system to fight cancer. By blocking the PD-1/PD-L1 signaling pathway, it induces cancer cell death and is indicated for the treatment of multiple types ofTumorpotential. Currently, Opdivo has become a foundational therapy for various types of cancer.

In China, Opdivo® received marketing approval in June 2018, becoming the first approved immuno-oncology (I-O) therapeutic in the Chinese market, with its currently approved threeTumorIndications include: (1) Non-small cell lung cancer (NSCLC); (2) Squamous cell carcinoma of the head and neck (SCCHN); (3) Gastric or gastroesophageal junction adenocarcinoma. (Bioon.com)