Summary Basis of Decision for Amtagvi

Clinical Pharmacology

Amtagvi (lifileucel) is a preparation of tumour-infiltrating lymphocytes isolated from an individual patient’s tumour and expanded ex vivo without genetic modification. Lifileucel products are highly polyclonal and patient specific.

The pharmacodynamic activity of lifileucel was explored by measuring longitudinal changes of cytokine and chemokine levels in the peripheral blood from baseline (prior to lymphodepletion) up to 84 days post infusion of lifileucel. Cytokines and chemokines measured included interleukin (IL)-15, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 10 (CXCL10), interferon gamma (IFN-γ), and tumour necrosis factor alpha (TNF-α). Both IL-15 and CXCL10 levels peaked around Day 1 to Day 4 after lifileucel administration, decreased thereafter, and returned to baseline levels within 1 to 3 months. The mean IFN-γ level was below baseline values on Day 1 to Day 4 after lifileucel infusion and returned to baseline levels on and after Day 14 post infusion. No noticeable changes were observed in the levels of the other measured cytokines and chemokines.

Due to the cellular nature of lifileucel, conventional pharmacokinetic studies of absorption, distribution, metabolism, and excretion cannot be conducted. Hence, the pharmacokinetic activity of lifileucel was evaluated by monitoring the in vivo persistence of unique T-cell receptor (TCR) clonotypes from lifileucel lots in the peripheral blood over time (up to one year post infusion). The proportion of unique TCR clonotypes from the lifileucel lots contributing to the peripheral blood TCR repertoire in infused patients was analyzed using a semi-quantitative polymerase chain reaction followed by next-generation sequencing.

The proportion of TCR clonotypes in the peripheral blood mononuclear cells also identified in lifileucel increased from a mean of 14% at enrollment (number of samples [n] = 95) and 20% at 7 days before infusion (n = 32) to 83% on Day 4 following the lifileucel infusion (n = 45). The proportion of TCR clonotypes declined to 51% on Day 14 (n = 96) and remained between 37% and 41% from Day 42 (n = 120) to Month 12 (n = 22) following the lifileucel infusion. There was high interindividual variability. No significant correlation was found between lifileucel persistence and efficacy.

The impact of intrinsic and extrinsic factors on lifileucel persistence was retrospectively explored using the in vivo persistence data obtained on Day 42. No associations were observed other than a trend relating to the patients’ sex: male patients showed higher lifileucel persistence compared to female patients. The clinical implication of the different lifileucel persistence in male and female patients is not known. The best overall response in treated patients appeared comparable between males and females. No clear association was observed between Day 42 lifileucel persistence and the number of IL-2 doses administered. However, considering the high variability of lifileucel persistence and the small sample size of patients who received fewer than six infusions of IL-2, this result was viewed as exploratory.

The recommended dosing of Amtagvi is aligned with the dose range that was associated with objective responses observed in the primary efficacy cohort (Cohort 4) of Study C-144-01, namely, 7.5 x 10⁹ to 72 x 10⁹ viable cells.

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

Clinical Efficacy

The efficacy of Amtagvi was evaluated in a Phase II, multicentre, open-label, single-arm study (C-144-01) in adult patients with unresectable or metastatic melanoma (Stage IIIc or Stage IV per the American Joint Committee on Cancer Staging Manual, Seventh Edition) whose disease had progressed following treatment with at least one systemic therapy, including a programmed cell death protein 1 (PD-1) blocking antibody, and if BRAF V600 mutation positive, following treatment with a BRAF inhibitor with or without a MEK inhibitor. Enrolled patients underwent tumour resection for Amtagvi manufacturing. Subsequently, these patients received the Amtagvi regimen, consisting of a preparative nonmyeloablative lymphodepletion (NMA-LD) chemotherapy, followed by a single infusion of Amtagvi and post-infusion administration of interleukin (IL)-2 (a T-cell growth factor). The preparative NMA-LD chemotherapy consisted of cyclophosphamide 60 mg/kg daily with mesna (sodium 2-mercapto ethane sulfonate) for 2 days, followed by fludarabine 25 mg/m² daily for 5 days. Three to 24 hours after Amtagvi infusion, IL-2 600,000 IU/kg was administered every 8 to 12 hours for up to 6 doses.

In total, 111 patients underwent tumour resection in the primary efficacy cohort, Cohort 4 of the study. Of the 111 patients, 22 (19.8%) did not receive Amtagvi due to the following: failure to manufacture Amtagvi (6 patients [5.4%]), disease progression (5 patients [4.5%]), death due to disease progression (3 patients [2.7%]), initiation of a new anticancer therapy (2 patients [1.8%]), fatal adverse event related to the lymphodepleting regimen (1 patient [0.9%]), adverse event (1 patient [0.9%]), withdrawal of consent and physician’s decision (2 patients [1.8%]), and meeting the exclusion criteria (2 patients [1.8%]).

Eighty-seven patients received Amtagvi that met the protocol-prespecified product specifications and were included in the efficacy analysis set. The patients were heavily pretreated, with a median of three prior lines of systemic therapy (min, max: 1, 8). All 87 patients had received anti-PD-1 or anti-programmed death ligand-1 (anti-PD-L1) therapy, 72 (82.8%) had received anti-cytotoxic T lymphocyte-associated protein-4 (anti-CTLA-4) therapy, 48 (55.2%) had received anti-PD-1 and anti-CTLA-4 combination therapy, and 24 (27.6%) had received a BRAF inhibitor or a combination of BRAF and MEK inhibitors. The median age of patients was 58 years (min, max: 25, 74 years), 25.3% of patients were 65 years of age or older, and 50.6% of patients were male. The majority of patients (95.4%) were White, 2.3% were Black, and 1.1% were Asian. Most patients (98.9%) had Stage IV melanoma, 27.6% had BRAF V600 mutation-positive tumours, 23.0% had tumours with PD-L1 tumour proportion score greater than or equal to 5%, 64.4% of patients had elevated lactate dehydrogenase, and 50.6% had brain and/or liver metastases. The median administered dose of Amtagvi was 20.5 x 10⁹ viable cells (min, max: 1.3 x 10⁹, 72.0 x 10⁹).

The primary endpoint of the study was objective response rate as assessed by the Independent Review Committee using the Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1). In the efficacy analysis set, the objective response rate was estimated to be 28.7% (95% confidence interval [CI]: 19.5%, 39.4%). Of the 25 responders, 3 achieved complete responses (3.4%) and 22 achieved partial responses (25.3%).

Duration of response was the key secondary endpoint. With a median follow-up for responses of 18.6 months, the median duration of response was 10.4 months (95% CI: 4.1, not reached). The minimum and maximum durations of response were 1.4+ and 26.3+ months, respectively.

Overall, the submitted efficacy results are considered promising for the target patient population. In order to confirm the clinical benefit of Amtagvi, the sponsor will provide the final results from an ongoing, randomized, open-label, Phase III study (IOV-MEL-301) assessing the efficacy and safety of the Amtagvi regimen in combination with pembrolizumab compared with pembrolizumab monotherapy in patients with untreated, unresectable or metastatic melanoma.

Indication

The New Drug Submission for Amtagvi was filed by the sponsor with the following proposed indication:

Amtagvi (lifileucel) is an autologous T-cell immunotherapy indicated 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.

Considering the current treatment landscape, the patient population, and the efficacy and safety results from Study C-144-01, Health Canada revised the proposed indication to specify that Amtagvi is for use in patients who have no satisfactory alternative treatment options. In addition, a caveat statement was included to provide clarity on the evidence of the treatment benefit. Accordingly, Health Canada approved the following indication:

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

For more information, refer to the Product Monograph for Amtagvi, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of the Amtagvi regimen was evaluated in Study C-144-01, an open-label, multicentre, multicohort, single-arm study (described in the Clinical Efficacy section). The Amtagvi regimen consists of a preparative NMA-LD chemotherapy, a single infusion of Amtagvi, and post-infusion administration of IL-2.

Significant toxicity was observed in patients treated with the Amtagvi regimen. In the safety analysis set (comprising 156 patients who received any lifileucel infusion), all patients experienced at least one treatment-emergent adverse event that occurred within 30 days of the lifileucel infusion, 96.8% had at least one Grade 3 or 4 treatment-emergent adverse event, and 6.4% had a treatment-related fatal adverse event. The Grade 3 or 4 treatment-emergent adverse events reported in at least 30% of patients were thrombocytopenia (78.8%), anemia (51.3%), and febrile neutropenia (41.7%).

Ten treatment-related deaths were reported, including six deaths that occurred within 30 days of Amtagvi administration and four deaths that occurred between 35 days and 150 days after Amtagvi administration. The causes of death were infections (sepsis, pneumonia, and encephalitis; 3 patients), internal hemorrhage (intra-abdominal hemorrhage and intracranial hemorrhage; 2 patients), acute respiratory failure (1 patient), renal failure (1 patient), cardiac arrhythmia (1 patient), ascites and liver injury (1 patient), and bone marrow failure (1 patient). In addition, two deaths that occurred during the NMA-LD period were considered related to the chemotherapy, and were due to septic shock and acute kidney injury.

Hypersensitivity reactions are an identified risk of Amtagvi. In the safety analysis set, 7.7% of patients experienced hypersensitivity reactions. Grade 3 or 4 hypersensitivity reactions occurred in 3.8% of patients.

In addition, central nervous system toxicities were reported in the study, including encephalopathy in 20.5% of patients (Grade 3: 6.4%, Grade 4: 0.6%) and delirium in 14.1% of patients (Grade 3: 3.8%).

The identified risks and the overall safety profile of the Amtagvi regimen, along with the risk mitigation strategies, are appropriately presented in the Product Monograph for Amtagvi. A Serious Warnings and Precautions box highlights that severe and fatal adverse reactions have occurred in patients treated with the Amtagvi regimen, including prolonged severe cytopenia and severe infections, internal organ hemorrhage, cardiopulmonary impairment, and renal impairment. It also emphasizes that Amtagvi is to be administered as a one-time treatment at a qualified treatment center under the supervision of a physician experienced in the use of anticancer agents.

Further safety evaluation will take place upon submission of the final results from an ongoing, randomized, open-label, Phase III study (IOV-MEL-301) assessing the efficacy and safety of the Amtagvi regimen in combination with pembrolizumab compared with pembrolizumab monotherapy in patients with untreated, unresectable or metastatic melanoma.

For more information, refer to the Product Monograph for Amtagvi, approved by Health Canada and available through the Drug Product Database.

Amtagvi (lifileucel) is a preparation of autologous, non-genetically modified tumour-infiltrating lymphocytes (TILs), which include both cytotoxic and helper T cells that infiltrate tumours as a component of the immunological response to a patient’s cancer. These T cells may recognize tumour-specific neoantigens and mediate tumour cell lysis via the interaction of the T-cell receptor (TCR) with the peptide-human leukocyte antigen (pHLA) complex on the tumour cells. The specific mechanism of action of Amtagvi is unknown.

The sponsor submitted a review of relevant published literature and a single non-clinical research report. The dosing regimen, mechanism of action, and safety of adoptive cell therapy (i.e., cellular immunotherapy) with TILs in the treatment of advanced solid tumours are supported by the peer-reviewed publications that present data obtained with TILs products in academic laboratories and at clinical sites over more than three decades. Based on these publications, the administration of lifileucel is preceded by a preparative nonmyeloablative lymphodepletion (NMA-LD) chemotherapy and followed by a short course of high-dose interleukin (IL)-2 to support the engraftment, expansion, and activation of the transferred TILs. The infused TILs are expected to traffic to tumour sites to carry out their cell-killing function in a tumour antigen-specific manner and to persist in the periphery; no side effects other than those normally transiently associated with NMA-LD and IL-2 are anticipated.

Amtagvi has been extensively characterized in vitro. It contains primarily T cells of the cluster of differentiation (CD) 4 (CD4+) and CD8+ lineages, which belong predominantly to the effector memory and central memory subtypes. Lymphocytes within the product were highly functional, as demonstrated by their notable ability to release interferon gamma (IFN-γ) in response to stimulation of CD3/CD28/CD137. Regulatory T cells (Tregs) were mostly eliminated during the ex vivo expansion process (the elimination of Tregs contributes to the activity of adoptive cell therapy). In addition, the TILs did not undergo terminal differentiation upon the 22-day expansion process. Instead, they acquired a differentiation state fully compatible with further activation and long-term persistence, as shown by the detection of TILs-derived T cells for up to one year post infusion in a melanoma patient.

Conventional non-clinical studies of Amtagvi cannot be conducted, given that Amtagvi is a patient-specific product and does not function across species. Early studies of mouse TILs in syngeneic tumour models demonstrated no associated toxicity. Classic genotoxicity assays and carcinogenicity assessment in rodent models were not performed. No non-clinical reproductive toxicity studies have been conducted with Amtagvi to assess whether it can cause fetal harm. Clinical trials of Amtagvi excluded women who were pregnant, whereas women of childbearing potential were advised to use contraception for up to 12 months after receiving Amtagvi. These recommendations have been included in the Amtagvi Product Monograph.

In view of the intended use of Amtagvi, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Product Monograph for Amtagvi, approved by Health Canada and available through the Drug Product Database.

Characterization of Amtagvi

Amtagvi (lifileucel) is a cell suspension composed of viable tumour-infiltrating lymphocytes (TILs) derived from a patient’s own resected tumour tissue and expanded ex vivo in the presence of anti-CD3 antibody (OKT3), interleukin (IL)-2, and feeder cells.

Amtagvi lots were assessed for cellular composition and phenotype by flow cytometry using markers for cell lineage, memory, differentiation, and activation.

Amtagvi may contain very low levels of product-related impurities such as B cells, natural killer (NK) cells, monocytes, and melanoma-associated chondroitin sulfate proteoglycan-positive (MCSP+) cells from the tumour starting material resected from the patient. Rigorous risk assessments conducted by the sponsor indicate that the potential presence of MCSP+ cells in the final drug product, in a low quantity, does not pose a significant risk to the safety of patients with advanced melanoma.

All process-related impurities were identified and their clearance by the proposed manufacturing process was adequately assessed. The determined theoretical residual amounts of each process-related impurity (i.e., the potential worst-case residual amounts per dose of drug product) are expected to be reduced by the manufacturing process to a negligible level that poses no significant risk to the patient. A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risk of the formation or introduction of nitrosamines during the manufacturing process is considered negligible or low; therefore, no confirmatory testing is required.

Manufacturing Process of Amtagvi and Process Controls

The manufacturing of Amtagvi is a continuous process conducted over a period of approximately 22 days.

The process begins with fragmentation of the patient’s tumour tissue and transfer of the fragments into cell culture media containing IL-2, which allows for the migration of TILs from the tumour matrix into the cell culture media. Subsequently, the TILs are transferred into cell culture media containing OKT3, IL-2, and feeder cells, which are required for the rapid expansion of TILs. The feeder cells are prepared from apheresis material that has tested negative for the presence of human viruses. After a second step of rapid cell expansion, the T cells are harvested, washed, formulated in cryopreservation buffer, filled into cryobags, cryopreserved under controlled conditions, and stored in the vapour phase of liquid nitrogen at or below -150 °C.

One manufactured dose of Amtagvi consists of 7.5 x 10⁹ to 72 x 10⁹ total viable cells in a total volume of 100 mL to 400 mL filled into 1 to 4 cryogenic bags. Amtagvi is cryopreserved in 5% dimethyl sulphoxide, 0.5% human albumin, and 300 IU/mL IL-2 (aldesleukin). None of the non-medicinal ingredients (excipients) in Amtagvi are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of lifileucel with the excipients is supported by the stability data provided.

The overall manufacturing process is controlled via raw material controls, procedural and environmental controls, established process parameter ranges, in-process controls, and final product quality control testing. Process validation studies performed at the proposed manufacturing sites demonstrated that Amtagvi could be reliably and consistently manufactured supporting readiness for commercial manufacture. A continued process verification is in place to provide ongoing assurance that the process remains in a state of control.

Control of Amtagvi

The control strategy for Amtagvi was based on a risk assessment that identified critical quality attributes to inform release specifications that ensured all critical attributes were within acceptably safe ranges. Adequate evidence of safety was provided regarding the chain of identity and the chain of custody procedures to mitigate the risk of a mix-up of patient batches.

Analytical methods utilized for release testing were demonstrated to be fit for purpose, allowing an accurate, precise, and suitably sensitive determination of critical quality attributes, including impurities. Impurities were appropriately controlled within acceptably safe limits.

The specifications for Amtagvi were narrowed with respect to cell dose (total number of viable cells) in the final product to ensure patients receive a product within quality attribute ranges supported by strong evidence of clinical efficacy.

Amtagvi is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of Amtagvi

The stability data submitted support the proposed shelf life of 12 months for Amtagvi, when stored at or below -150 °C. Each bag of Amtagvi is contained within a protective metal cassette. Amtagvi is stored in the vapour phase of liquid nitrogen and supplied in a liquid nitrogen cryoshipper. Once one bag of Amtagvi is thawed, the infusion must be completed within 3 hours at room temperature (18 °C to 25 °C).

Adequate information was provided to demonstrate the suitability and integrity of the container-closure system.

Facilities and Equipment

Results from recent inspections of the two Amtagvi manufacturing sites conducted by the United States Food and Drug Administration were leveraged by Health Canada in lieu of on-site evaluations. The design, operations, and controls of the facilities and equipment involved in the production are considered suitable. The manufacturing sites are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The manufacturing process of Amtagvi incorporates adequate control measures to prevent introduction of non-viral and viral adventitious agents.

All raw materials and excipients of animal, human or cellular origin, or those that had indirect contact with materials of animal or human origin are appropriately sourced and tested. Sufficient information is provided that the materials of biologic origin are derived from sources with no or negligible risk of transmissible spongiform encephalopathy agents or other human pathogens. Materials of recombinant origin are approved for therapeutic use or are produced using only non-animal-sourced reagents. Drug product release testing includes tests for bacterial endotoxins, mycoplasma, and sterility.

Aseptic controls and techniques are employed throughout the manufacturing process. Aseptic process validation runs are conducted at periodic intervals to provide assurance that the manufacturing process is continually executed under aseptic conditions.