Regulatory Decision Summary for Zynlonta

The purpose of the submission is to seek a marketing authorization with conditions for Zynlonta as monotherapy the treatment of adult patients with relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma, who have received two or more lines of systemic therapy and cannot receive chimeric antigen receptor T-cell (CAR-T cell) therapy or have previously received CAR-T cell therapy.

This submission was filed under the Notice of Compliance with Conditions (NOC/c) Guidance.

After evaluation of the submitted data package, Health Canada authorized, with conditions, Zynlonta as monotherapy for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, or high-grade B-cell lymphoma, who have received two or more lines of systemic therapy and have previously received or are unable to receive CAR-T cell therapy.

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

Authorization was primarily based on the results from an open-label, single-arm, multi-centre Phase 2 study ADCT-402-201 in 145 adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least two prior lines of systemic therapy. Patients received Zynlonta 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles.

The efficacy of Zynlonta was evaluated on the basis of the overall response rate (ORR) determined by an Independent Review Committee (IRC). The ORR of was 48.3% with 24.8% of patients achieving a complete response (CR). After a median follow-up of 7.8 months, the median duration of response (DOR) based on the IRC assessment was 13.4 months in all responders. These efficacy results are considered promising evidence of clinical benefit for Zynlonta. The survival benefit has not been established and is to be confirmed in an ongoing Phase 3 clinical trial.

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

The most frequently reported adverse reactions (≥20%) associated with Zynlonta were increased gamma-glutamyltransferase (GGT), neutropenia, thrombocytopenia, fatigue, anemia, nausea, cough, increased blood alkaline phosphatase, and peripheral edema. The most frequent serious adverse reactions (≥2%) included febrile neutropenia, pyrexia, abdominal pain, and pleural effusion. Fatal infections were reported in 2.1% of patients. Adverse reactions led to dose interruptions in 51% of patients and treatment discontinuation in 24.8% patients. These safety findings and the applicable risk mitigation measures are adequately described in the final Zynlonta Product Monograph (PM).

Overall, based on the evidence reviewed, the anticipated benefits outweigh the potential risks and remaining uncertainties of Zynlonta for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, DLBCL arising from low grade lymphoma, or high-grade B-cell lymphoma, who have received at least two prior lines of systemic therapy and have previously received or are unable to receive chimeric antigen receptor T-cell (CAR-T cell) therapy.

The benefit-harm-uncertainty profile was favourable for Zynlonta 10 mg/vial 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.

The recommended dose is 0.15 mg/kg every 3 weeks for 2 cycles, followed by 0.075 mg/kg every 3 weeks for subsequent cycles.

Health Canada granted this submission advanced consideration under the NOC/c policy.

For more information on the conditions issued, please refer to the Notice of Compliance with conditions (NOC/c) Website.

The chemistry and manufacturing information submitted for Zynlonta 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.

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