Regulatory Decision Summary for OPDIVO

Expression of PD-L1 and PD-L2 by tumours such as melanoma or on other cells in the tumour microenvironment allows tumours to evade immune-mediated destruction. Programmed death-1 is expressed at high levels by tumour infiltrating lymphocytes in melanoma and other tumours. Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Nivolumab is a fully human monoclonal immunoglobulin G4 (IgG4) antibody (HuMAb) that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

The pivotal trial submitted in support of the proposed indications demonstrated improved progression free survival and overall response rate in the treatment of unresectable or metastatic melanoma when treated with a combination of nivolumab and ipilimumab compared to nivolumab monotherapy. This appeared to be better demonstrated when the analysis was stratified based on PD-L1 expression less than 5%. Though the adverse event reporting rate was higher in the combination arm compared to monotherapy, no new, unexpected adverse events were reported. The reported adverse reactions were stated to be responsive to standard medical management. Immune mediated adverse events that are associated with PD-1 blocking antibodies including endocrinopathies, colitis, hepatitis, pneumonitis, nephrotoxicity and rash are labeled in the PM with appropriate instructions for medication discontinuation, dose holding and corticosteroid treatment.

Overall the benefit/risk analysis is considered favourable under the Notice of Compliance with conditions (NOC/c) pathway for the following two indications: "Opdivo is indicated for the treatment of patients with unresectable or metastatic BRAF V600 mutation-positive melanoma in previously untreated adults. An improvement in survival has not yet been established," and "Opdivo is indicated for the treatment of patients with unresectable or metastatic melanoma in previously untreated adults when used in combination with ipilimumab. Relative to OPDIVO monotherapy, an increase in progression-free survival (PFS) for the combination of OPDIVO with ipilimumab is established only in patients with low tumour PD-L1 expression (based on the predefined expression level of < 5%). An improvement in survival has not yet been established."