P1409: PHASE-2 STUDY OF VARNIMCABTAGENE AUTOLEUCEL (IMN-003A) FIRST-IN-INDIA INDUSTRY CD19-DIRECTED CAR-T WITH FRACTIONATED INFUSIONS FOR PATIENTS WITH RELAPSED REFRACTORY B CELL MALIGNANCIES: IMAGINE STUDY

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Varnimcabtagene autoleucel (IMN-003A) is an autologous second-generation CAR-T cell product with a 4-1BB domain and A3B1 binder, non-FMC63 based murine single chain variable fragment targeting CD19, manufactured in India. Pre-clinical studies and phase 1 clinical trial in Spain has demonstrated potent in vitro, in vivo and clinical activity. Safety and efficacy results of IMAGINE phase 2 clinical trial for patients in India with relapsed/refractory B cell malignancies (CTRI/2022/03/041162) are presented here. Aims: Evaluate safety and efficacy of IMN-003A in patients with relapsed refractory B cell malignancies (B-ALL and B-NHL). Methods: Patients (pts) 3 to 45 years (B-ALL) and ≥ 18 years (B-NHL) with relapsed refractory B cell malignancies (RR BCM) were eligible if they had measurable disease, assessed by lymphoid blasts (B-ALL) or metabolic tumour bulk (B-NHL), received ≥1 prior regimen, refractory to last line of treatment with ECOG 0 to 1. Bridging therapy was allowed after apheresis. Flu-Cy lymphodepletion was used on days -5 to -3. Target dose was 1x106/kg CAR+ cells (B-ALL) and 5x106/kg CAR+ cells (B-NHL) (overall range 0.1x106 to 5x106), with fractionated infusions (10%/30%/60%). Primary objectives were overall response rate (ORR: CR + CRi in B-ALL and CR + PR in B-NHL) at day +90 after first infusion, and occurrence of adverse events including cytokine release syndrome (CRS) and/or Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS). Response was assessed by NCCN (B-ALL) and IWG (B-NHL) criteria; minimal residual disease (MRD) for B-ALL was analyzed by flow cytometry at 10-4 sensitivity and PET-CT for B-NHL. Adverse events (AEs) were graded using CTCAE v5.0. Results: At data cut-off, 22 pts (median age 31 yrs, range 3 - 66) with RR BCM (n=11 B-ALL; n=11 B-NHL) were enrolled. 18 pts received IMN-003A cells; 6 (33.3%) needed bridging therapy. Patient characteristics are described in Figure 1A. Median CAR-T cell manufacturing time was 14 days (range 10-27) with 100% manufacturing success. Median follow-up after IMN-003A administration was 97 days (range 3 - 284). Overall response rate (ORR) was 88.2% at D+28 (B-ALL 85.7%; B-NHL 88.8%) and 72.7% at D+90 (B-ALL 71.4%; B-NHL 75%). Two pts relapsed by D+90. Of MRD-evaluable pts, response was 100% at day+28 (n=7) and 83.3% at D+90 (n=6). Median time to first response was 28 days. Median progression-free survival (PFS, range 90-NR, Figure 1B) and overall survival (OS) were not reached (range 99-NR). AESIs reported were CRS (Grade [G] 1 70.5%; G3 + 5.9%; overall 76.4%); ICANS (G1 5.9%; G3 + 0%; overall 5.9%); neutropenia (G3 + 94.1%; overall 100%); anemia (G3 + 35.3%; overall 100%); and thrombocytopenia (G3 + 23.5%; overall 94.1%). CRS median onset was D+6 and duration 3 days. No G3+ ICANS was reported. Tocilizumab usage was in 41.2% (n=7/17) (majority for persistent G1 CRS). Treatment related mortality was 5.9% (n=1/17); 2 pts died of disease progression. IMN-003A cells demonstrated peak expansion on D+10 (range 7 – 21 days). 94% at D+28 and 36% at D+90 (range D+21 - NR) had measurable CAR+ T cells in peripheral blood. Updated results will be presented in the meeting. Summary/Conclusion: Varnimcabtagene autoleucel (IMN-003A) is a First-In-India Industry CD19-directed CAR-T Cell Therapy for RR BCM and has demonstrated excellent safety and efficacy outcomes with deep and durable responses including absence of severe neurotoxicity. This offers a significant benefit over standard treatment options for patients in India for RR BCM.Keywords: B cell acute lymphoblastic leukemia, Non-Hodgkin’s lymphoma, Clinical trial, CAR-T