Regulatory Decision Summary for Imfinzi

The purpose of this Supplemental to a New Drug Submission (SNDS), filed by AstraZeneca Canada Inc., which was accepted and reviewed under Priority Review status, was to seek a new indication for Imfinzi for the treatment of patients with muscle invasive bladder cancer (MIBC) in combination with cisplatin-based chemotherapy as neoadjuvant treatment, followed by Imfinzi as monotherapy adjuvant treatment after radical cystectomy. After a review of the data submitted in the SNDS, the indication was revised to Imfinzi is indicated for the treatment of patients with resectable muscle invasive bladder cancer (MIBC) in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by adjuvant Imfinzi monotherapy treatment after radical cystectomy.

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

The NIAGARA study is an ongoing 1:1 randomized, open-label, multicentre Phase III clinical trial designed to evaluate the safety and efficacy of neoadjuvant Imfinzi in combination with gemcitabine and cisplatin followed by adjuvant Imfinzi monotherapy (n = 533) after radical cystectomy compared to neoadjuvant gemcitabine and cisplatin treatment alone (n = 530) in adult patients (≥ 18 years of age) with resectable muscle-invasive bladder cancer (MIBC). Randomized patients had no prior systemic chemotherapies or immune-mediated therapies for the treatment of their MIBC and had to be candidates for radical cystectomy at enrolment and weigh > 30 kg and have creatinine clearance (CrCL) ≥40 mg/mL. The primary efficacy outcome was event-free survival (EFS) with the key secondary outcome being overall survival (OS). EFS was defined on study as the time from randomization to the first recurrence of disease post radical cystectomy, time of first documented progression in patients who were medically precluded for radical cystectomy, or time of expected surgery in patients who refuse to undergo a radical cystectomy or failure to undergo a radical cystectomy in participants with residual disease, or the time of death due to any cause, whichever occurs first.

Patients randomized to the Imfinzi treatment arm had a statistically significant and clinically meaningful improvement in EFS and OS compared to patients randomized to the gemcitabine and cisplatin chemotherapy control arm. The EFS hazard ratio (HR) was 0.68 with a 95% confidence interval (CI) between 0.56 and 0.82. The OS HR was 0.75 with a 95% CI between 0.59 to 0.93. The OS benefit represents a 25% reduction in the risk of death for patients randomized to the Imfinzi arm compared to patients receiving only neoadjuvant chemotherapy.

The recommended dose for Imfinzi treatment is for 12 cycles - four 3-week cycles at 1,500 mg in combination with gemcitabine and cisplatin as neoadjuvant therapy and eight 4-week cycles at 1,500 mg as adjuvant monotherapy treatment following radical cystectomy. Treatment should be discontinued for disease progression that precludes definitive surgery, disease recurrence, unacceptable toxicity or upon completion of a total of 12 cycles of Imfinzi.

The safety of Imfinzi was generally consistent with the known adverse event profiles of anti-PD-L1 and anti-PD-1 monoclonal antibody therapies. Notably, however, there were twenty-five serious embolic adverse events (4.7% of patients) in patients treated with Imfinzi compared to only five serious embolic adverse events (1% of patients) in patients treated in the chemotherapy control arm. This was a statistically meaningful difference between two arms that were well balanced for demographics and baseline disease characteristics. Following review and the implementation of revisions requested by Health Canada, the Product Monograph has been updated with a warning documenting higher incidences of serious embolic events associated with the Imfinzi treatment arm compared to the chemotherapy control arm in the Phase III NIAGARA pivotal study.

A Risk Management Plan (RMP) for Imfinzi was submitted and, following review, the sponsor has agreed to provide an updated Canadian addendum to the RMP to identify thromboembolic events as an important potential risk for Imfinzi to align with the warning reported in the Product Monograph.

The benefit-risk profile for Imfinzi is considered positive, as assessed in this Priority Review SNDS filing, for the treatment of patients with resectable muscle-invasive bladder cancer as neoadjuvant therapy in combination with gemcitabine and cisplatin followed by adjuvant Imfinzi monotherapy after radical cystectomy, when the product is used as according to the instructions in the updated Product Monograph, including careful consideration if Imfinzi should be administered to patients who have pre-existing risk factors for developing thromboembolic events.

A Notice of Compliance was recommended.

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