Primary Analysis of Varnimcabtagene Autoleucel (IMN-003A) in Phase 2 Study (IMAGINE), a First-in-India Industry CD19-Directed CAR-T Cell Therapy for Patients with Relapsed Refractory B Cell Malignancies

Background: Varnimcabtagene autoleucel (IMN-003A) is an autologous second-generation CAR-T cell product with a 4-1BB co-stimulatory domain and a non-FMC63 based murine single chain variable fragment targeting CD19 (A3B1 binder), manufactured in India. Preclinical and Phase 1 study was conducted at HCB / IDIBAPS Spain. Here, we present the primary analysis of IMAGINE, a Phase 2, multicenter, single-arm study of var-cel for patients in India with relapsed/refractory B cell malignancies (RR BCM) (CTRI/2022/03/041162).

Methods: Patients (pts) aged 3 to 45 years (B-ALL) and ≥ 18 years (B-NHL) with RR BCM were eligible if they had measurable disease, as assessed by lymphoid blasts (B-ALL) or metabolic tumour bulk (B-NHL), received ≥1 prior regimen, refractory to the last line of treatment with good performance status (ECOG 0 to 1). Bridging therapy was allowed after apheresis. Cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) on days -5 to -3 were used as preparative lymphodepletion regimen. The target dose was 1x10⁶/kg CAR+ cells (B-ALL) and 5x10⁶/kg CAR+ cells (B-NHL) (overall range 0.1x10⁶ to 5x10⁶) and was administered in a fractionated manner (10%/30%/60%) over 3 days with at least 24h between infusions. 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 safety. Response was assessed as per NCCN (B-ALL) and IWG (B-NHL) criteria; bone marrow 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. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria.

Results: At data cut-off, of 25 pts enrolled (median age 31 yrs, range 3 - 66) with RR BCM [n=13 B-ALL, median blasts 0.34% (range 0.01 - 27.2); n=12 B-NHL, median TMTV 67.9 ml (range 27.1 - 1177), median SPD 3846 mm² (range 1001 to 35849], 24 pts received var-cel (1 withdrawal) with majority of infusions on Days 0, +3, +7 and 12 pts (50%) needed bridging therapy. Median CAR-T cell manufacturing time was 14 days (range 10 - 27) with 100% manufacturing success.

Median follow-up after IMN-003A administration was 205 days (range 12 – 434). Overall response rate (ORR) was 91.7% (22/24) at D+28 (B-ALL 91.7%, MRD neg 83.3% (n=10/12); B-NHL 91.7%, CR 66.7%) and 80.9% (17/21) at D+90 [B-ALL 80%, MRD neg 80% (n=8/10); B-NHL 81.8% (9/11), CR 63.6%]. One B-NHL pt in PR at D+28 achieved CR at D+90. Three pts relapsed by D+90. Of MRD evaluable pts, response was 100% at day+28 (n=11/11) and 88.9% at D+90 (n=8/9). Median time to first response was 28 days.

Median progression free survival (PFS, range 12-NR), duration of response (DOR, range 0-NR) and overall survival (OS) were not reached (range 12-NR).

AESIs reported were CRS (Grade [G] 1 62.5%; G3+ 4.2%; overall 66.7%); ICANS (G1 4.2%; G3+ 0%; overall 4.2%); neutropenia (G3+ 91.7%; overall 100%); anemia (G3+ 29.2%; overall 95.8%); and thrombocytopenia (G3+ 20.8%; overall 91.7%). CRS median onset was D+5 and duration 3 days. No G3+ ICANS was reported. Tocilizumab, steroids and anakinra usage was in 37.5% (n=9/24, majority for persistent G1 CRS), 8.3% and 4.2% respectively. Treatment related mortality was 4.2% (n=1/24); 3 pts died of disease progression.

IMN-003A cells demonstrated peak expansion on D+10 (range 7 – 28 days). 79.2% at D+28 and 29.2% at D+90 had measurable CAR+ T cells in peripheral blood; median D+28 (range D+10 - NR). Updated results will be presented in the meeting.

Conclusions: Varnimcabtagene autoleucel (IMN-003A), a First-In-India Industry CD19-directed CAR-T Cell Therapy for RR BCM, has demonstrated manageable safety profile and durable efficacy outcomes with deep responses including absence of severe neurotoxicity. This offers a significant benefit over standard treatment options for patients with RR BCM.