Safety, tolerability, and preliminary efficacy results of a phase 1 study of LB2102, a dnTGFβRII armored DLL3-targeted autologous CAR-T cell therapy, in patients with relapsed or refractory small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC).

Abstract

8104 Background : Delta-like- ligand 3 (DLL3) is a promising therapeutic target for SCLC and other neuroendocrine tumors. Here, we present preliminary results from the ongoing dose-escalation study of LB2102, an autologous CAR-T cell therapy engineered to target DLL3 and armored with a TGF-β receptor blockade to overcome the immunosuppressive tumor microenvironment. Methods : This ongoing, open-label, multicenter, phase 1 study evaluates LB2102 in patients with SCLC/LCNEC who are relapsed/refractory to ≥1 prior line of therapy. Dose escalation follows a modified 3+3 design, with planned dose levels of 0.3, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 x 10 6 CAR+ T cells/kg. All subjects undergo 3-day lymphodepletion (LD) with fludarabine (30 mg/m 2 ), and cyclophosphamide (300 mg/m 2 ). The primary objective is to assess safety, tolerability and determine the recommended phase 2 dose (RP2D). Results : As of December 13, 2024, 9 patients were treated with LB2102 across dose-level (DL) 1 at 0.3x10 6 (n=3), DL2 at 1x10 6 (n=3), and DL3 at 2x10 6 CAR+ T cells/kg (n=3). Eight subjects had SCLC and one subject on DL2 had LCNEC. The median age was 54 (range 20-61), and the median prior lines of therapy was 2 (range 1-7). Bridging therapy was administered in all patients. No Dose-limiting toxicities (DLT) and no neurotoxicity was observed. One subject in DL3 experienced grade 1 CRS. Grade >3 treatment-emergent adverse events (TEAEs) attributed to LB2102 included anemia (n=2), leukopenia (n=2) and neutropenia (n=2); none were classified as serious, and all were deemed related to lymphodepletion. At DL3, best observed response per RECIST1.1 was 1 partial response (with deepening of response over time) and 2 stable disease (SD). The best overall response for subjects at DL1 was progressive disease (n=3) and at DL2 was SD (n=3) (with increased tumor shrinkage in 1 subject). Significant CAR-T expansion in peripheral blood was observed as measured by qPCR at DL3 (n=3) with a median C max of 694.4 copies/µg genomic DNA (range, 45.6-2256.7) and a median T max of 15 days (range, 10-29). Conclusions : LB2102 has been well tolerated with no DLT observed up to DL3 (2 x 10 6 CAR+ T cells/kg). There appears to be a dose-dependent efficacy signal observed at higher doses with responses correlating to CAR-T expansion, although the data is limited. Given no DLTs and preliminary efficacy signal up to DL3, further exploration of higher dose levels is warranted. Clinical trial information: NCT05680922 . Dose levels (CAR+ T cells/kg) Subject No. Best Overall Change in Sum of Tumor Size (%) DL1: 0.3 x 10 6 1 +22.8% 2 Non-evaluable* 3 +57.1% DL2: 1 x 10 6 4 -31.6% 5 -22.6% 6 -4.8% DL3: 2 x 10 6 7 -14.3% 8 -69.8% 9 -20.6% *Subject had non-measurable disease at baseline and progressed during study period.