Regulatory Decision Summary for Opdivo

The decision was based on a phase 3 trial that evaluated the efficacy and safety of neoadjuvant nivolumab in combination with platinum-doublet chemotherapy for patients with resectable NSCLC (tumors ≥4 cm or node positive). Patients were enrolled regardless of their tumor PD-L1 status. Patients with unresectable or metastatic non-small cell lung cancer (NSCLC), known epidermal growth factor receptor (EGFR) mutations or anaplastic large-cell lymphoma kinase (ALK) translocations, Grade 2 or greater peripheral neuropathy, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study.

358 patients were randomized to Arm A or B:

1. Opdivo 360 mg administered intravenously over 30 minutes and platinum-doublet chemotherapy administered intravenously every 3 weeks for up to 3 cycles (n = 170) OR
2. Platinum-doublet chemotherapy administered every 3 weeks for up to 3 cycles (n = 170).

Efficacy results

The study met its primary endpoints; treatment with nivolumab and platinum-doublet chemotherapy prior to curative surgery demonstrated a clinically significant improvement in event-free survival and pathologic complete response rate (EFS and pCR) when compared to platinum-doublet chemotherapy alone. The EFS hazard ratio was 0.63 (95% confidence interval 0.45, 0.87), which means that Arm A (nivo+chemo) experienced a risk reduction of 37% when compared with Arm B (chemo). The EFS median months were 31.6 for Arm A, and 20.8 for Arm B. In terms of pCR, the difference in favour of Arm A was 21.6% when compared to Arm B. In other words, Arm A (nivo+chemo) had a pCR of 24% compared to 2.2% in Arm B (chemo).

In an exploratory analysis, positive associations were observed between the level of PD-L1 expression and advanced disease stage, and the magnitude of the treatment benefit, therefore a qualifying statement was added to the indication, and EFS by stage and PD-L1 expression was labelled in the product monograph. 

Safety

The most common (>10%) adverse events were nausea, constipation, vomiting, neutropenia, anemia, thrombocytopenia, fatigue, malaise, decreased appetite, rash, alopecia, hiccups and neuropathy peripheral. Serious adverse events occurred in 30% of patients who were treated with nivolumab in combination with platinum-doublet chemotherapy. The most frequent serious adverse events were pneumonia and vomiting. Study therapy with nivolumab in combination with platinum-doublet chemotherapy was permanently discontinued for adverse events in 10% of patients and 30% had at least one treatment withheld for an adverse event. The most common adverse events (≥1%) resulting in permanent discontinuation of nivolumab in combination with platinum doublet chemotherapy were anaphylactic reaction (1.7%), decreased neutrophil count (1.1%) and fatigue (1.1%).

No deaths due to study drug toxicity were reported in patients treated with Opdivo in combination with platinum-doublet chemotherapy. Overall, the safety of neoadjuvant nivolumab 360 mg administered IV every 3 week in combination with platinum-doublet chemotherapy for resectable NSCLC was consistent with the known safety profile of nivolumab.

In terms of risks and benefits, the efficacy results for the neoadjuvant combination treatment of nivolumab and platinum-doublet chemotherapy demonstrated a substantial benefit when compared with chemotherapy alone and when considering safety aspects.

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

The overall benefit/risk profile was considered positive for adult patients with resectable NSCLC for Opdivo (10 mg nivolumab/mL) 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.