AMTAGVI Suspension for intravenous infusion Ref.[108367] Active ingredients: Lifileucel

Pharmacodynamic activity was evaluated by measuring longitudinal changes of cytokines and chemokines (IL-15, IL-6, IL-7, IL-9, IL-10, IL-12(p40), CCL2, CXCL10, IFN-γ, and TNF-α) using plasma samples collected at baseline and post-infusion of AMTAGVI up to Month 3. The mean level of IL-15 and CXCL10 peaked following lymphodepletion and administration of AMTAGVI at Day 1-4, decreased over time, and returned to baseline levels within 1-3 months. The mean IFN-γ level was below baseline post lymphodepletion and AMTAGVI infusion at Day 1-4 and returned to baseline by Day 14. Other cytokines and chemokines listed above did not show any noticeable changes. No difference was observed in the cytokines and chemokines level between responding and non-responding patients.

The proportion of unique TCR clonotypes from the AMTAGVI lots contributing to the peripheral blood TCR repertoire among infused patients was analyzed using a semi-quantitative polymerase chain reaction followed by next generation sequencing. The proportion of TCR clones that are composed of clonotypes identified in the product increases from a mean of 16% (n=125) at pre-infusion to 83% at Day 4 after AMTAGVI infusion. The TCR clones declined to 51% at Day 14 (n=51) and remain 37% to 41% from Day 42 (n=120) to month 12 (n=37) post-infusion of AMTAGVI. No significant correlation was found between AMTAGVI persistence and efficacy.

No carcinogenicity or genotoxicity studies have been conducted with AMTAGVI. No studies have been conducted to evaluate the effects of AMTAGVI on fertility.

The efficacy of a single treatment with AMTAGVI was evaluated in a global, multicenter, multicohort, openlabel, single-arm clinical study. This study enrolled patients with unresectable or metastatic melanoma who had previously been treated with at least one systemic therapy, including a PD-1 blocking antibody, and if BRAF V600 mutation-positive, a BRAF inhibitor or BRAF inhibitor with MEK inhibitor. This study excluded patients with uncontrolled brain metastases, organ allograft or prior cell transfer, melanoma of uveal or ocular origin, systemic steroid therapy for any reason, Grade 2 or higher hemorrhage within 14 days prior to study enrollment (tumor resection), left ventricular ejection fraction (LVEF) less than 45% or New York Heart Association (NYHA) functional classification greater than Class 1, and patients with forced expiratory volume in one second (FEV1) of less than or equal to 60%.

There were 111 patients who underwent tumor resection of whom 22 (19.8%) patients did not receive AMTAGVI due to the following reasons: inability to manufacture AMTAGVI (n=6), disease related death (n=3), meeting exclusion criteria (n=5), disease progression (n=3), starting new anti-cancer therapy or consent withdrawal (n=3), or adverse events from lymphodepletion including one death (n=2). Among 89 patients who received AMTAGVI, two (2) patients were excluded because the product did not meet specification and five (5) patients were excluded due to product comparability.

The primary efficacy analysis set included 82 patients who received AMTAGVI. Among these, nine (9) patients received AMTAGVI at a dose less than 7.5 × 10⁹ viable cells and did not achieve an objective response. The recommended AMTAGVI dosing range was set at 7.5 × 10⁹ to 72 × 10⁹ viable cells (73 patients received this dosing range).

Median time from tumor tissue procurement to the end of the manufacturing process was 23 days and to infusion was 34 days. Lesion origin of AMTAGVI products included skin, lymph nodes, liver, lung, peritoneal, musculoskeletal, breast, and other anatomic sites including chest wall, abdominal wall, adrenal gland, abdominal-peritoneal, paraesophageal, axillary, thigh, back, supraclavicular, and soft tissue.

All 73 (100%) patients received prior anti-PD-(L)1 therapy, 63 (86.3%) received prior anti-CTLA-4 therapy, 42 (57.5%) received anti-PD1/anti-CTLA-4 combination therapy and 20 (27.4%) received a BRAF inhibitor or combination therapy with BRAF and MEK inhibitors. The median age was 58 years (min, max: 25, 74 years), with 26.0% age 65 or older, 52.1% were male, 94.5% were white, 2.7% were black, and 1.4% were Asian. Patients received a median of 3 prior lines of therapy and a median of 2 prior lines of anti-PD(L)1 containing therapies. Disease characteristics were: BRAF V600 mutation-positive: 27.4%; PD-L1 TPS greater than or equal 5%: 23.3%; elevated LDH: 63.0%; brain and/or liver metastases: 54.8%. The median target lesion sum of diameters was 108.7 mm (min, max: 15.7, 552.9). The performance status prior to tumor procurement was ECOG 0 (71.2%) and ECOG 1 (28.8%).

AMTAGVI was administered following a lymphodepleting regimen consisting of cyclophosphamide 60 mg/kg daily with mesna for 2 days followed by fludarabine 25 mg/m² daily for 5 days. Three (3) to 24 hours after infusion, patients received IL-2 (aldesleukin) at 600,000 IU/kg every 8 to 12 hours for up to 6 doses in order to support cell expansion in vivo. The median administered AMTAGVI dose was 21.1 × 10⁹ viable cells. The median number of administered IL-2 (aldesleukin) doses was 6.

Efficacy was established on the basis of objective response rate (ORR) and duration of response (DoR) (see Table 3). The median time to initial response to AMTAGVI was 1.5 months (min, max: 1.3, 4.2).

Table 3. Efficacy Results Among Patients Who Received AMTAGVI Dose Range of 7.5 × 10⁹ to 72 × 10⁹ Viable Cells:

CI, confidence interval; DoR, duration of response; NR, not reached; ORR, objective response rate.
^a Per RECIST v1.1 assessed by Independent Review Committee (IRC).
^b Number of responders was N=23.
^c Kaplan-Meier estimate of median potential follow-up for DoR was 18.6 months.
^d Kaplan-Meier estimate in months among all responders. DoR measured from the date of confirmed initial objective response to the date of progression or death from any cause.
^e + sign indicates a censored value
^f Observed proportion of patients with duration of response beyond landmark time

Supporting pooled efficacy analysis included 189 patients who underwent tumor resection of whom 33 did not receive AMTAGVI due to the following reasons: inability to manufacture AMTAGVI (n=8), disease related death within 40 days after tumor harvest (n=5), meeting exclusion criteria (n=6), disease progression (n=6), starting new anti-cancer therapy or consent withdrawal (n=4), or adverse events from lymphodepletion including two deaths (n=4). Among the 156 patients who received AMTAGVI, 2 patients who received AMTAGVI that did not meet the product specification and 1 patient who received AMTAGVI below the protocol specified dosing range due to anaphylactic reaction were excluded.

The supporting pooled efficacy set included 153 patients. The median administered AMTAGVI dose was 21.1 × 10⁹ viable cells and the median number of administered IL-2 (aldesleukin) doses was 6. The ORR was 31.4% (95% CI: 24.1%, 39.4%) with a CR of 5.2% (n=8) and PR of 26.1% (n=40). The median time to initial response to AMTAGVI was 1.5 months (min, max: 1.3, 4.2). The median DoR was not reached (range: 1.4+, 45.0+). Among responders, 62.5%, 56.3% and 54.2% maintained durable responses at 6, 9 and 12 months, respectively, following the initial response.