Regulatory Decision Summary for Opdivo

The purpose of this supplemental new drug submission (SNDS) was to obtain market authorization for a new indication of use for Opdivo (nivolumab), in combination with ipilimumab, for the treatment of adults with previously untreated unresectable or metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer. After review, Health Canada authorized the following indication: Opdivo, in combination with ipilimumab, for the first-line treatment of adult patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer.

The submission was classified as a Project Orbis Type B submission and Health Canada collaborated with the United States Food and Drug Administration (FDA), the National Health Surveillance Agency (ANVISA) of Brazil, and the Israel Ministry of Health (IMoH) for the review.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

Efficacy was evaluated in the CHECKMATE-8HW study, a randomized, Phase 3, active-controlled trial designed to evaluate the efficacy and safety of Opdivo (nivolumab) in combination with ipilimumab versus standard-of-care (SOC) chemotherapy in the first-line treatment of patients with MSI-H/dMMR unresectable or metastatic colorectal cancer (CRC). The dosing regimen evaluated in the study was intravenously administered nivolumab (240 mg) in combination with ipilimumab (1 mg/kg) every 3 weeks for a maximum of 4 doses, followed by nivolumab alone (480 mg) every 4 weeks. A total of 303 previously untreated patients, in the metastatic setting, were randomized (2:1), 202 patients to the nivolumab plus ipilimumab (nivo+ipi) arm and 101 patients to the chemotherapy (chemo) arm. Among these, 255 had centrally confirmed MSI-H/dMMR status, 171 in the nivo+ipi arm and 84 in the chemo arm. Patients with confirmed MSI-H/dMMR status comprised the primary efficacy population for the interim analysis (IA) assessed.

At the time of the planned IA, the study met the primary efficacy endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for patients with centrally confirmed dMMR/MSI-H status treated with nivo+ipi over chemo in the first-line setting. The estimated hazard ratio (HR) was 0.21 (95% confidence interval [CI]: 0.14, 0.32; p<0.0001), representing a 79% reduction in the risk of progression or death with the combination. The median PFS was not reached (95% CI: 38.44, not estimable) for patients in the nivo+ipi arm and was 5.85 months (95% CI: 4.37, 7.79) for patients in the chemo arm. The CHECKMATE-8HW study also included the secondary endpoint of overall survival (OS); however, at the time of IA, OS had not been tested. Therefore, a survival benefit has not yet been demonstrated. However, the magnitude of the PFS benefit over SOC chemotherapy is considered clinically meaningful and substantial evidence of benefit for the target patient population.

The overall frequency and type of adverse events reported in the CHECKMATE-8HW study were generally consistent with the established safety profile when nivolumab is used in combination with ipilimumab. No new safety signals were identified. The most common (≥20%) adverse events (AEs) reported in the nivo+ipi arm were diarrhoea, pruritus, asthenia, and nausea. The immune-mediated AEs (imAEs) observed with nivolumab treatment in the trial were consistent with the established nivo+ipi safety profile. These included endocrine-related imAEs (hypothyroidism, adrenal insufficiency, hyperthyroidism, and hypophysitis) and non-endocrine related imAEs (colitis/diarrhoea, rash, hepatitis, and pneumonitis). The majority of imAEs reported were low Grade (Grades 1-2), and manageable. Overall, the safety of the combination regimen is well characterized and clinically manageable by standard practices and risk mitigation strategies outlined in the Product Monograph.

Overall, the benefit-risk profile was favourable for Opdivo (nivolumab) 10 mg/mL for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

For further details about Opdivo, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.