Regulatory Decision Summary for Opdivo

The efficacy and safety of nivolumab in combination with ipilimumab or nivolumab in combination with cisplatin and fluorouracil (‘chemotherapy’) was assessed in Checkmate 648, which enrolled 630 patients with previously untreated advanced or metastatic ESCC and were positive for PD-L1. Patients were randomized to either Arm A (nivolumab 3 mg/kg once every 2 weeks [Q2W] + ipilimumab 1 mg/kg once every 6 weeks [Q6W]), Arm B (nivolumab 240 mg Q2W + chemotherapy every 4 weeks [Q4W], or Arm C [chemotherapy alone]). The primary endpoints were overall survival (OS) and progression free survival (PFS). Of the enrolled patients, 82% were male, 46% were older than 65 years of age, 70% were based in Asia. Patients had histological confirmation of squamous cell carcinoma (98.0%) or adenosquamous cell carcinoma (1.9%) in the oesophagus.

The study for Nivolumab in combination with ipilimumab met its primary endpoints: Among the 315 patients with a positive tumor PD-L1 status, the hazard ratio (HR) for OS was 0.64 (95% Confidence Interval [CI]: 0.49, 0.84) with median OS of 13.7 and 9.0 months for nivolumab plus ipilimumab and chemotherapy alone, respectively. This means that the risk of death was reduced by 37% in treatment arm A (nivolumab plus ipilimumabi) when compared to chemo alone (treatment arm C). This translated into an estimated survival benefit of an extra 4 months. There was no apparent survival benefit in tumors that did not express PD-L1.

The study for Nivolumab in combination with chemotherapy (cisplatin and fluorouracil) met its primary endpoints: Among the 315 patients with a positive tumor PD-L1 status, the HR for OS was 0.54 (95% CI: 0.41, 0.71) with median OS of 15.4 months and 9.1 months for nivolumab plus chemo and chemo alone, respectively. This means that the risk of death was reduced by 44% in treatment arm B (nivolumab plus schemotherapy) when compared to chemotherapy along (treatment arm C). This translated into an estimated survival benefit of an extra 6 months. There was no apparent survival benefit in tumors that did not express PD-L1.

The safety of the combination immunotherapy (nivolumab plus ipilimumab) or immunotherapy plus chemotherapy (nivolumab plus cisplating and fluorouracil) in previously untreated patients with advanced or metastatic ESCC was acceptable in the context of the observed clinical benefit and consistent with the established safety profile of each individual component. Although there were no new safety signals or toxicities identified, combining two immunotherapies or an immunotherapy with chemotherapy is associated with significant toxicity: Important risks associated with nivolumab plus chemotherapy or nivolumab plus ipilimumab combinations include immune-mediated adverse reactions such as pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, endocrinopathies, and severe infusion reactions or events of special interests (myasthenic syndrome, pancreatitis, uveitis, encephalitis, myocarditis, myositis, rhabdomyolysis). The specific risks are included in the product monograph and prescribers have access to appropriate management guidelines, which from part of the strategy to mitigate those risks.

In terms of risks and benefits, the efficacy results for either combination treatment regimen did not support its use in tumors not expressing PD-L1 (negative), whereas tumors expressing PD-L1 (positive) had a substantial benefit when compared with chemotherapy alone and when considering safety aspects. Therefore, the benefit/risk profile was considered positive for patients with unresectable or metastatic ESCC tumors expressing PD-L1 ≥ 1%.

An updated Risk Management Plan (RMP) for Opdivo was reviewed by Health Canada and considered acceptable.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

The overall, the benefit-harm-uncertainty profile is favourable for Opdivo for the recommended indication. A Notice of Compliance (NOC) was issued.

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