Regulatory Decision Summary for Amtagvi

The purpose of the New Drug Submission (NDS) is to seek authorisation under the Notice of Compliance with conditions (NOC/c) pathway for Amtagvi (Lifileucel) for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.

After review, the indication recommended for authorisation under the NOC/c pathway is:

Amtagvi (lifileucel) is a tumour-derived autologous T-cell immunotherapy indicated for the treatment of adult patients with unresectable or metastatic melanoma that has progressed on or after at least one prior systemic therapy including a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor, and who have no satisfactory alternative treatment options.

The marketing authorisation with conditions is primarily based on tumour objective response rate and durability of response. An improvement in survival has not yet been established.

Patients with unresectable or metastatic melanoma that has progressed on or after at least one prior systemic therapy including an anti-PD-1 therapy, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor, and who have no satisfactory alternative options represent a population with a substantial unmet medical need. Study C-144-01 is a phase 2, single-arm study that evaluated the Amtagvi (lifileucel) treatment in this heavily pretreated population. Enrolled patients underwent tumor harvest for lifileucel manufacturing; subsequently, patients received a preparative nonmyeloablative lymphodepletion (NMA-LD) chemotherapy, followed by a single dose of Amtagvi infusion and post-infusion administration of interleukin-2 (IL-2).

There were 111 patients who underwent tumor harvest of whom, 22 (19.8%) did not receive an Amtagvi infusion due to manufacturing failure, early deaths and other reasons. Another 2 patients who received Amtagvi that did not meet the product specification were excluded from the efficacy analysis set. In the efficacy analysis set of 87 patients, the objective response rate was 28.7% (95% confidence interval [CI]: 19.5%, 39.4%). Of the 25 responders, 3 achieved complete responses (3.4%) and 22 with partial responses (25.3%). The minimum and maximum Duration of Response (DOR) at the time of the data cutoff was 1.4+ and 26.3+ months, respectively. The median DOR was 10.4 months (95% CI: 4.1, not reached). Significant toxicity, however, was observed with the Amtagvi treatment. In the safety analysis set (N = 156), all patients experienced at least a treatment-emergent adverse event (TEAE); 94.9% were reported with at least a Grade 3 or 4 TEAE; and 6.4% with a fatal treatment-related AE. The most common TEAEs (≥ 30%) were thrombocytopenia, anemia, neutropenia, leukopenia, lymphopenia, febrile neutropenia, chills, pyrexia, fatigue, electrolyte imbalance, cardiac arrhythmia, edema, rash, hypotension, dyspnea, hepatic enzyme abnormal and diarrhea. Ten treatment-related deaths occurred, including infections (sepsis, pneumonia, encephalitis), internal organ hemorrhage (intra-abdominal hemorrhage, intracranial hemorrhage), acute respiratory failure, renal failure, cardiac arrhythmia, ascites and liver injury, and bone marrow failure. The identified risks and the overall safety profile of Amtagvi are sufficiently labelled in the Product Monograph (PM), including the Serious Warnings and Precautions box, Warnings and Precautions and Adverse Reactions sections. Warnings and Precautions include information regarding the significant risks, such as prolonged severe cytopenia, severe infection, cardiac disorders, impaired respiratory or renal function, and others. The risk mitigation strategies for the Amtagvi treatment are considered adequate.

Overall, the durable responses observed with the Amtagvi treatment support it as a therapeutic option in the target population, in which very few treatment options exist. Toxicities are managed / mitigated primarily through labelling, which enhances patient selection, toxicities monitoring and management. Taken together, the benefit-risk profile of the Amtagvi treatment is considered favourable under the NOC/c Policy for the treatment of adult patients with unresectable or metastatic melanoma that has progressed on or after at least one prior systemic therapy including a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor, and who have no satisfactory alternative treatment options. Given the single-arm design of the pivotal study, residual uncertainty remains in terms of the treatment efficacy over the long term, such as survival benefit. Therefore, verification of the clinical benefit in a well-controlled, randomized study is necessary to confirm the benefit – risk balance for the Amtagvi treatment. Data from phase III confirmatory study are included as conditions of authorization 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 Risk Management Plan (RMP) for Amtagvi was reviewed by Health Canada and considered acceptable.

The chemistry and manufacturing information submitted for Amtagvi 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 Amtagvi, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.