Novel CAR T-cell Therapy Shows Best Overall PR in R/R SCLC and LCNEC

Safety and efficacy were noted with LB2102 for patients with small cell lung cancer and large cell neuroendocrine carcinoma.

Results from a phase 1 trial (NCT05680922) of LB2102, a DLL3-directed autologous CAR T-cell therapy, assessing patients with relapsed/refractory small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), found no dose-limiting toxicities up to dose level 4 (DL4), as well as preliminary antitumor activity, according to a presentation from the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

The best overall responses included partial responses (PRs) in 1 patient at dose level 3 (DL3) and 1 patient at DL4, and stable disease (SD) in 3 patients at dose level 2 (DL2), 2 patients at DL3, and 1 patient at DL4. In the overall population (n = 12), the objective response rate (ORR) was 16.7% with a disease control rate of 66.7%.

Of note, treatment-emergent adverse effects (TEAEs) occurred in all 3 patients enrolled at each of the 4 dose levels (n = 12). One patient in the DL4 cohort had a maximum grade TEAE of grade 1; 4 patients in the dose level 1 (DL1) and DL4 cohorts had a maximum of grade 2; 3 patients from the DL2 and DL3 cohorts had a maximum of grade 3; and 4 patients enrolled in the DL2, DL3, and DL4 cohorts had a maximum TEAE of grade 4. No deaths due to AEs were observed in the study.

“Preliminary antitumor activity has been observed…with responses deepening at higher dose levels,” lead study author Jacob Sands, MD, and colleagues wrote in a poster presentation of the data. “Continued dose escalation of LB2101 in SCLC and LCNEC is warranted.”

Sands is a physician, 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 in Boston, Massachusetts.

Phase 1 Study Design

The open-label, multicenter, dose-escalation study evaluated one-time treatment with LB2102 in patients 18 years of age or older with histologically/cytologically confirmed SCLC or LCNEC who relapsed after or were refractory to at least 1 prior line of therapy, defined as disease progression or insufficient response. Patients on the study had a presence of at least 1 radiologically measurable lesion per RECIST 1.1 criteria, adequate organ function, and an ECOG performance status of 0 or 1.

Study investigators excluded patients who received prior treatment with a DLL3-targeted therapy; had a history of checkpoint inhibitor–associated pneumonitis; had ascites or pleural/peritoneal effusions; had leptomeningeal or active/symptomatic brain metastases; or had active autoimmune disease being treated with immunomodulators. Notably, patients with treated brain metastases were allowed to enroll if they were stable after definitive therapy.

Patients were treated with intravenous LB2102 after undergoing 3-day lymphodepleting chemotherapy, which consisted of fludarabine at 30 mg/m² and cyclophosphamide at 300 mg/m². Dose escalation followed a modified 3+3 design, which included DL1 (0.3 x 10⁶ CAR T-cells/kg; n = 3), DL2 (1.0 x 10⁶ CAR T-cells/kg; n = 3), DL3 (2.0 x 10⁶ CAR T-cells/kg; n = 3), and DL4 (4.0 x 10⁶ CAR T-cells/kg; n = 3). The ongoing study will continue evaluating 3 additional dose levels, including 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 (16.0 x 10⁶ CAR T-cells/kg).

The primary end points are safety and determining the recommended phase 2 dose of LB2102. Secondary end points included efficacy, pharmacokinetics (PK), and immunogenicity of LB2102.

Baseline Patient Characteristics

In the overall population across the first 4 dose levels, the mean age was 53.3 years (standard deviation, 12.0), and 25.0% of patients were 60 years of age or older. The majority of patients were female (58.3%) and White (91.7%). Primary tumor types included SCLC (83.3%) and LCNEC (16.7%). Additionally, most patients had extensive-stage disease at initial diagnosis (58.3%), poorly differentiated histologic grade 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). The majority of patients had received prior radiotherapy (75.0%) and prior platinum-based therapies (91.7%). The median number of lines of bridging therapies was 1 (range, 0-2).

Additional Safety and PK Data With LB2102

TEAEs related to LB2102 occurred in 7 patients; Grade 3 or greater TEAEs attributed to the CAR T-cell therapy included anemia (n = 2), leukopenia (n = 2), and neutropenia (n = 2), although none were classified as serious TEAEs, and all were attributed to lymphodepletion. Grade 1 cytokine release syndrome (CRS) was observed in 2 patients—1 each from the DL3 and DL4 cohorts—and fever was the only symptom. The CRS events occurred 6 days following infusion in the patient from the DL3 cohort and 16 days after infusion the 1 patient from the DL4 cohort; these CRS events lasted 1 day and 2 days, respectively. In the overall population, 5 patients experienced serious TEAEs, of which 1 serious TEAE was CRS associated with LB2102. Notably, no AEs of special interest, DLTs, neurotoxicity, or TEAEs that led to discontinuation were reported.

TEAEs related to LB2102 in the overall population included anemia (any grade, 25.0%; grade ≥3, 16.7%), CRS (16.7%; 0%), hypotension (16.7%; 0%), nausea (16.7%; 0%), decreased neutrophil count (16.7%; 16.7%), decreased white blood cell count (16.7%; 16.7%), arthralgia (8.3%; 0%), and muscular weakness (8.3%; 0%).

In PK-evaluable patients in the overall population (n = 8), the median C_max was 671 copies/µg genomic DNA (range, 45.6-2510), the median T_max was 15 days (range, 5-29), and the median AUC was 6,860 copies/µg genomic DNA (range, 137-44000).

Reference

Sands J, Chiappori A, Creelan BC, et al. 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). J Clin Oncol. 2025;43(suppl 16):8104. doi:10.1200/JCO.2025.43.16_suppl.8104