Regulatory Decision Summary for Imjudo

The purpose of this new drug submission was to seek market authorization for Imjudo (tremelimumab) for the treatment of patients with unresectable hepatocellular carcinoma, when used in combination with durvalumab. After evaluation of the submitted data package, Health Canada authorized the use of Imjudo (tremelimumab for injection) in combination with durvalumab is indicated as a first-line treatment of adult patients with unresectable hepatocellular carcinoma (uHCC) who require systemic therapy.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

Market authorization for the use of Imjudo (tremelimumab) in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma (uHCC), was based on results of a pivotal randomized, open-label, multicenter Phase III Study and a supportive uncontrolled Phase I/II Study. In the pivotal trial, patients (n = 1171) with uHCC who are ineligible for locoregional therapy and who have not received prior systemic therapy were randomized in 1:1:1 to receive Imjudo plus durvalumab combination therapy (T300+D; n = 393), durvalumab monotherapy (D; n = 389), or sorafenib (S; n = 389).

The primary efficacy endpoint was overall survival (OS) comparing T300+D and S for superiority in the intention-to-treat (ITT) population and the key secondary efficacy endpoint was OS comparing D and S for superiority. Results from the final analysis demonstrated that the median OS as 16.4, 16.6 and 13.8 months for T300+D, D, and S, respectively. Compared to S, both T300+D and D showed a statistically significant improvement in OS, with the estimated hazard ratios (HRs) of 0.76 and 0.83 representing a 24% and 17% reduction in the risk of death, respectively, based on the adjusted analysis accounting for the observed baseline imbalances. Of note, uncertainty remains regarding the treatment effect of tremelimumab, given the small difference in the OS treatment benefit between the T300+D (HR: 0.76) and the D (HR: 0.83) relative to the S.

The most common adverse reactions reported in at least 10% of the patients who received Imjudo in combination with durvalumab were pruritus, diarrhoea, rash, fatigue, decreased appetite, pyrexia, aspartate aminotransferase (AST) increased, hypothyroidism, nausea, abdominal pain, insomnia, and asthenia. The predominant risks associated with Imjudo in combination with durvalumab were immune-mediated adverse reactions (imARs), including enterocolitis, intestinal perforation, hepatitis, dermatitis, Stevens-Johnson syndrome, endocrinopathy, pneumonitis, interstitial lung disease, myocarditis, neuropathy, encephalitis, myasthenia gravis, as well as toxicities in other organ systems. Increased toxicity was seen with the combination therapy as compared to the durvalumab monotherapy. The safety findings observed with T300+D were generally consistent with the known safety profile for each of Imjudo and durvalumab. The risks associated with Imjudo are adequately captured in the Product Monograph (PM), including a Serious Warnings and Precautions box, monitoring, treatment modifications, and management recommendation for imARs. A Risk Management Plan (RMP) was submitted and considered acceptable by the Marketed Health Products Directorate (MHPD).

A Notice of Non-Compliance (NON) was issued by Health Canada due to unresolved concerns identified during the review. In response to the NON issuance, the sponsor submitted additional information which addressed the concerns identified.

In view of the OS improvement observed with Imjudo in combination with durvalumab, and the manageable safety profile, the benefits outweigh the risks for the target patient population.

The recommended dose of Imjudo is 300 mg as a single dose, followed by durvalumab 1500 mg at Day 1 of Cycle 1. Continue durvalumab 1,500 mg as a single agent every 4 weeks until disease progression or unacceptable toxicity.

The chemistry and manufacturing information submitted for Imjudo 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.

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

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