Regulatory Decision Summary for Opdivo SC

The purpose of the current supplement to a new drug submission (SNDS) was to seek authorization pursuant to section C.08.004 of the Food and Drugs Regulations, for Opdivo SC, filed by Bristol-Myers Squibb Canada for a new subcutaneous (SC) formulation. Opdivo SC is to be used: (1) as a monotherapy treatment; (2) as a monotherapy following combination treatment with nivolumab and ipilimumab; or (3) in combination with chemotherapy or cabozantinib, in the authorised indications for Opdivo (nivolumab which is intravenously administered), other than classic Hodgkin’s lymphoma. The use of Opdivo SC in combination treatment with ipilimumab was not sought.

Authorisation was supported by the results of Study CA20967T, which was a pharmacokinetic (PK) bridging study aimed to demonstrate non-inferior systemic drug exposure levels of subcutaneously administered nivolumab (i.e., Opdivo SC) to intravenous (IV) administered nivolumab (i.e., Opdivo). In Study CA20967T, 495 patients with advanced or metastatic renal cell carcinoma were randomized in a 1:1 ratio to receive Opdivo SC 1,200 mg every 4 weeks (n = 249) or intravenous Opdivo 3 mg/kg every 2 weeks (n = 247). Treatment was continued until progression, unacceptable toxicity, withdrawal of consent, or completion of a total of 2 years (104 weeks) of treatment or death. The primary objective of the study was to demonstrate PK non-inferiority of Opdivo SC versus Opdivo based on the co-primary endpoints of the time-averaged serum concentration over 28 days (Cavgd28) and trough serum nivolumab concentration at steady state (C_minss). Study CA20967T also included a secondary efficacy objective to demonstrate noninferiority of the overall response rate (ORR) of Opdivo SC compared to Opdivo, as assessed by blinded independent central review (BICR). The efficacy results are only considered exploratory in nature.

Study CA20967T demonstrated non-inferior nivolumab exposures resulting from the SC formulation. The Cavgd28 of Opdivo SC was 77.4 mcg/mL and of Opdivo was 36.9 μg/mL, with a geometric mean ratio (GMR) of 2.098. The C_minss of Opdivo SC was 122.2 mcg/mL compared to 68.9 μg/mL for Opdivo, with a GMR of 1.774. Non-inferiority of BICR-assessed ORR was also demonstrated (24% in the Opdivo SC arm and, 18% in the Opdivo arm [intravenous formulation]). Given that non-inferior exposures to nivolumab were demonstrated following administration of Opdivo SC, along with supportive evidence of non-inferior BICR-assessed ORR in patients with advanced or metastatic renal cell carcinoma, it is reasonable to assume that efficacy will be maintained for the proposed indications.

Safety profiles including serious adverse events (AEs) and Grade 3 AEs were comparable between the SC and IV arms in Study CA20967T. Drug-related injection site reactions were reported in 8% (20/247) of patients in the Opdivo SC arm, all of which were mild (Grade 1-2 in severity) and mostly resolved without any treatment. No injection site reactions were reported among patients with Opdivo SC injected in the thigh.

Based on Study CA20967T demonstrating non-inferior exposures to nivolumab resulting from Opdivo SC administration as compared to the standard Opdivo (intravenous) dose, along with supportive evidence of a non-inferior efficacy based on an exploratory endpoint of BICR-assessed ORR and a safety profile that is not appreciably worse for Opdivo SC, the benefit-risk profile of Opdivo SC is considered to be comparable to Opdivo for the indications proposed.

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

The chemistry and manufacturing information submitted for Opdivo SC has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

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

Overall, the benefit-harm-uncertainty profile was favourable for Opdivo SC 120 mg/mL for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance is recommended.

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