Regulatory Decision Summary for Opdivo

This Supplemental New Drug Submission (SNDS) was filed to obtain market authorization for a new Opdivo (nivolumab) indication, in combination with ipilimumab, to treat adult patients with unresectable hepatocellular carcinoma. After review, the indication recommended for authorization was: Opdivo (nivolumab) in combination with ipilimumab for the first-line treatment of adult patients with unresectable or advanced hepatocellular carcinoma.

The submission was classified as a Project Orbis Type B submission and Health Canada collaborated with the United States Food and Drug Administration (FDA), Health Science Authority (HSA), SwissMedic (SMC), Brazilian Health Regulatory Agency (ANVISA) and Israeli 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. The sponsor’s request for Priority Review was denied.

The authorization of Opdivo was based on the safety and efficacy results of a Phase 3 global, multi-centre, randomized, open-label, controlled clinical trial, CheckMate-9DW. Systemic treatment-naïve adult patients with unresectable or advanced hepatocellular carcinoma received either Opdivo in combination with ipilimumab (Opdivo 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks intravenously for up to 4 cycles followed by Opdivo 480 mg (flat dose) every 4 weeks; n = 332) or investigator’s choice of sorafenib (400 mg orally twice daily; n = 50) or lenvatinib (8 mg orally daily (if body weight < 60 kg) or 12 mg orally daily (if body weight ≥ 60 kg); n = 275).

The primary efficacy endpoint was overall survival (OS) in all randomized patients. The key secondary efficacy endpoints included blinded independent central review (BICR)-assessed overall response rate (ORR) and duration of response (DOR) based on RECIST 1.1 criteria. Study CheckMate-9DW met its primary endpoint with a statistically significant improvement in OS at the pre-specified analysis (Hazard Ratio of 0.79, 95% confidence interval [CI]: 0.65, 0.96, representing an estimated 21% reduction in the risk of death). The median OS was 23.66 months in the Opdivo in combination with ipilimumab arm compared to 20.63 months in the sorafenib/lenvatinib arm.

The risks associated with Opdivo plus ipilimumab treatment differ from those of tyrosinase kinase inhibitors such as sorafenib and lenvatinib-based systemic therapy due to the different targets and mechanisms of actions of these agents (i.e. kinases and the immune system, respectively).

The most common adverse events reported in patients treated with Opdivo in combination with ipilimumab were transaminases increased, rash, pruritus, fatigue, and diarrhea. Colitis was identified as a non-liver related serious adverse reaction. The most commonly reported all grade liver-related serious adverse events included hepatitis, increased transaminases, hepatic failure, ascites and hepatoxicity.

There were more fatal treatment-related adverse reactions in the combination therapy arm than in the sorafenib/lenvatinib arm. Also, in the pivotal study, CheckMate-9DW, more deaths within the first 6 months were observed with Opdivo in combination with ipilimumab compared to lenvatinib or sorafenib. This higher risk of death may be associated with poor prognostic features. A warning to this effect has been included in the Product Monograph advising prescribing health professionals to consider these risks before treatment initiation.

Overall, the risk is manageable for the target population through close monitoring and the use of treatment modifications and/or reductions as described in the product monograph. The overall risk/benefit is considered positive for this target population given the improvements noted in OS over the systemic targeted therapy regimen.

Overall, the benefit-risk profile was favourable for Opdivo (at 1 mg/kg during the combination phase and either 240 mg every two weeks or 480 mg every 4 weeks during the monotherapy phase) 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.