A novel DLL3-targeted CAR-T cell therapy has demonstrated encouraging preliminary efficacy and manageable safety in patients with relapsed or refractory small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), according to phase 1 trial results presented at the 2025 American Society of Clinical Oncology Annual Meeting.
Clinical Activity Observed Across Dose Levels
LB2102, a DLL3-directed autologous CAR-T cell therapy, achieved partial responses in 2 of 12 patients (16.7% objective response rate) and disease control in 8 patients (66.7% disease control rate) across the first four dose levels evaluated. The best overall responses included partial responses in one patient each at dose level 3 (DL3) and dose level 4 (DL4), while stable disease was observed in 3 patients at dose level 2 (DL2), 2 patients at DL3, and 1 patient at DL4.
"Preliminary antitumor activity has been observed...with responses deepening at higher dose levels," wrote lead study author Jacob Sands, MD, and colleagues. "Continued dose escalation of LB2101 in SCLC and LCNEC is warranted."
Sands serves as associate chief of the Lowe Center for Thoracic Oncology and oncology medical director of the International Patient Center at Dana-Farber Cancer Institute, as well as an assistant professor at Harvard Medical School.
Safety Profile Supports Continued Development
The open-label, multicenter, dose-escalation study (NCT05680922) found no dose-limiting toxicities up to dose level 4, which delivered 4.0 x 10⁶ CAR T-cells/kg. Treatment-emergent adverse events occurred in all 12 patients across the four dose levels, but the severity distribution was manageable: one patient experienced maximum grade 1 events, four patients had maximum grade 2 events, three patients experienced maximum grade 3 events, and four patients had maximum grade 4 events. Importantly, no deaths due to adverse events were observed.
Grade 1 cytokine release syndrome (CRS) was observed in only 2 patients—one each from the DL3 and DL4 cohorts—with fever as the only symptom. The CRS events occurred 6 days and 16 days following infusion, respectively, and lasted 1-2 days. Treatment-emergent adverse events related to LB2102 included anemia (25.0% any grade, 16.7% grade ≥3), decreased neutrophil count (16.7%), decreased white blood cell count (16.7%), CRS (16.7%), hypotension (16.7%), and nausea (16.7%).
Study Design and Patient Population
The phase 1 trial enrolled patients 18 years or older with histologically or cytologically confirmed SCLC or LCNEC who had relapsed after or were refractory to at least one prior line of therapy. Patients required at least one radiologically measurable lesion per RECIST 1.1 criteria, adequate organ function, and an ECOG performance status of 0 or 1.
Patients received intravenous LB2102 following 3-day lymphodepleting chemotherapy consisting of fludarabine at 30 mg/m² and cyclophosphamide at 300 mg/m². The dose escalation followed a modified 3+3 design across four initial dose levels: DL1 (0.3 x 10⁶ CAR T-cells/kg), DL2 (1.0 x 10⁶ CAR T-cells/kg), DL3 (2.0 x 10⁶ CAR T-cells/kg), and DL4 (4.0 x 10⁶ CAR T-cells/kg), with three patients enrolled at each level.
The study population had a mean age of 53.3 years, with 58.3% female and 91.7% White patients. Primary tumor types included SCLC (83.3%) and LCNEC (16.7%). Most patients had extensive-stage disease at initial diagnosis (58.3%) and a history of brain metastases (66.7%). The median number of prior lines of therapy was 1 (range, 1-5), with 91.7% having received prior platinum-based therapies and 75.0% prior radiotherapy.
Pharmacokinetic Profile
In pharmacokinetic-evaluable patients (n = 8), LB2102 demonstrated a median Cmax of 671 copies/μg genomic DNA (range, 45.6-2510), median Tmax of 15 days (range, 5-29), and median AUC of 6,860 copies/μg genomic DNA (range, 137-44000).
Continued Dose Escalation Planned
The ongoing study will continue evaluating three additional dose levels: dose level 5 (8.0 x 10⁶ CAR T-cells/kg), dose level 6 (12.0 x 10⁶ CAR T-cells/kg), and dose level 7 (16.0 x 10⁶ CAR T-cells/kg). The primary endpoints are safety and determining the recommended phase 2 dose of LB2102, while secondary endpoints include efficacy, pharmacokinetics, and immunogenicity.
