Regulatory Decision Summary for Imfinzi

The approval was based on a randomized, double-blind, placebo-controlled, multi-regional, Phase III study D933AC00001 (TOPAZ-1) to assess the efficacy and safety of durvalumab in combination with the current standard of care (Gemcitabine/Cisplatin = gem/cis) for the first line treatment of adult patients with locally advanced or metastatic biliary tract tumours (BTCs).

Six hundred and eighty five patients were randomised to either placebo + gem/cis or durvalumab 1,500mg (D) plus gem/cis; 345 patients were male, 340 patients were female, the mean age was 62 years (range: 20 to 84 years). During the statistical review of the study design and the analyses results, no major issues were identified.

TOPAZ-1 met its primary endpoint and confirmed that the addition of durvalumab (D) to gemcitabine-based chemotherapy (gem/cis) provided a small, but statistically significant survival benefit for adult patients with advanced or malignant BTCs. The enrolled study population was representative of the target population. The overall survival (OS) hazard ratio (HR) was 0.80 for D + gem/cis compared to placebo + gem/cis; the 95% confidence interval (CI) was between 0.66 and 0.97 (p = 0.021). The HR for the secondary endpoint, progression free survival (PFS), was 0.75 (95% CI: 0.63, 0.89, p = 0.001). In other words, when it comes to the risk of dying, the durvalumab treatment group had a 20% risk reduction compared to the placebo group, and a 25% risk reduction when it comes to disease progression. The median OS was 12.8 months in the durvalumab group, and 11.5 months in the placebo group. The Kaplan Meier curve separated at 6 months in favour of the durvalumab group. Prior to that, the curves crossed at 2 to 4 months, which is a commonly observed phenomena in immunotherapy, and is likely associated with a delay in treatment effect.

Treatment with D + gem/cis in patients with BTC demonstrated a tolerable and manageable safety profile, consistent with the known safety profiles of the individual components. The most commonly reported adverse events (AEs) causally-related to any study treatment in both treatment groups were anemia, nausea, neutropenia and neutrophil count decreased which were generally balanced between both groups and reflective of the known toxicities of gem/cis. A higher exposure adjusted rate (per 100 patient years) of cholangitis, pyrexia, sepsis, anaemia, acute kidney injury, pulmonary embolism, urinary tract infection, upper gastrointestinal haemorrhage, biliary sepsis, COVID 19, and ischaemic stroke were reported for the D + gem/cis group when compared to the placebo + gem/cis group. Adverse events leading to death that were considered causally-related occurred in 2 (0.6%) patients in the D + gem/cis group (due to ischemic stroke and hepatic failure) and 1 (0.3%) patient in the placebo + gem/cis group (due to polymyositis). AEs leading to discontinuation of study treatment were reported in 13% of patients treated with D + gem/cis versus 15.2 of patients treated with placebo + gem/cis. Immune-mediated AEs were reported in 12.7% of patients in D +gem/cis and 4.7% of patients in the placebo + gem/cis group, the most common reactions were hypothyroidism, rash, and adrenal insufficiency. All of this was labelled accordingly in the Product Monograph. Overall, the addition of durvalumab to gem/cis did not increase the incidence or severity of the known toxicities of durvalumab or gem/cis. No new safety concern has been identified by adding durvalumab to gem/cis.

Overall, the safety and tolerability profile of durvalumab was considered acceptable in the target patient population; and in combination with gemcitabine-based chemotherapy demonstrates a favourable benefit-risk profile in the proposed indication. As such, a Notice of Compliance was recommended.

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

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