Real World Data of Novel Talicabtagene Autoleucel (humanized CD19 CAR-T) from India; Ensuring Equitable Access with Excellent Safety and Efficacy Profile

Background: Talicabtagene autoleucel (Tali-cel), (formerly Actalycabtagene autoleucel) is a humanized anti-CD19 CAR-T cell therapy, approved by the CDSCO (Indian regulatory agency) in October 2023 based on its efficacy and safety data (ASH 2022, 2023). Since its approval, several centers across India have delivered this commercialized CAR T-cell therapy. In this study, we report the real-world feasibility, access, efficacy, and safety evidence of Tali-cel following commercial approval for relapsed / refractory (r/r) B-cell malignancies.

Methods: Patients with r/r B-cell malignancies (r/r B-cell lymphomas (BCL) and acute lymphoblastic leukemia (ALL)) aged ≥ 15 years received Tali-cel from 15^th November 2023 till 30^th June 2024 as standard-of-care were studied. Patients received a single infusion of Tali-cel at target dose of ≥ 5x10⁶/kg, after conditioning with Flu-Cy or bendamustine. Post CAR-T maintenance was allowed. Tertiary cancer centers across India with expertise to treat hematological malignancies were enrolled for administration after getting trained on the algorithms and clinical management of Tali-cel. Monthly manufacturing slots scheduling, and allocation was done by the central production coordinating unit comprised of production managers and medical advisors. The slot allocation was based on multiple parameters including request initiation time, patient’s fitness, disease status, and availability of funds. The feasibility and access were evaluated by manufacturing success rate (MSR), out of specifications (OOS) rate and vein-to-vein time. Efficacy assessments included objective response rate (ORR). Hematological toxicities and adverse events of special interests including Grade 3-4 CRS, ICANS and IEC-HS (Immune-effector cell associated- Hemophagocytic lymphohistiocytosis) (defined as per ASTCT criteria) were analyzed.

Results: Nine centres across India participated in the real-world analysis, with 79 patients enrolled. 68 patients have received infusion, 2 patients had manufacturing failure, 5 died before infusion and 4 awaited infusions at cut-off date. Utilization between r/r ALL 56% (44/79) and r/r BCL 44% (35/79) was similar. The median age was 22 (12-64) years for r/r ALL and 53 (17-71) years for r/r BCL patients. The male population was 72% (57/79) and median prior lines of therapy was 3 (1-7) for all patients. The median % blasts in r/r B-ALL at the time of infusion was 2 (0-92), and 31% (11/35) had bulky disease (disease site >7cm) in r/r BCL.

Centralized manufacturing model ensured that suitable patients received the manufacturing slots within 30 days. The overall MSR was 97% (77/79) with the OOS rate of 3% (2/77) due to sterility failure, however, the product was successfully delivered upon remanufacturing to both patients. The median vein to vein time was 25 days (16-72). The vein-to-vein time was independent of the proximity of the cancer care centers from the manufacturing site.

As of cut-off date, the day 28 response assessment post infusion was done for 48 patients (28 r/r ALL, 20 r/r BCL), with an ORR of 85% (41/48). The remaining 20 patients were yet to be evaluated for response. In r/r ALL cohort, the best ORR was 93% (26/28) with 92% (24/26) MRD negative CR Until the last follow-up, 100% (26/26) of r/r ALL and 80% (12/15) of r/r BCL patients continue to remain in The ORR in the real-world settings were comparable to the pivotal Phase I/II trial (r/r ALL: 73% (11/15) and r/r BCL: 68% (26/38)).

Grade 3-4 cytopenia were noted in 64% (18/28) and 80% (16/20) in r/r ALL and r/r BCL cohort respectively. Grade 3-4 CRS developed in 4% (1/28) of r/r ALL and 5% (1/20) of r/r BCL patients. Grade 3-4 ICANS developed in 10% (2/20) of r/r BCL and none in r/r ALL patients. IEC-HS developed in 14% (4/28) of r/r ALL and 15% (3/20) of r/r BCL cohorts. The incidence of hypogammaglobulinemia was 29% (8/28) and 65% (13/20) in r/r ALL and r/r BCL cohorts, respectively.

Conclusion: The real-world evidence further confirms the efficacy and safety of Tali-cel in B-cell malignancies. The manufacturing success and safe and effective clinical delivery allow the deployment of CAR-T cell therapy outside the clinical trial settings in India.