Phase I study of BL-M14D1, a novel DLL3-directed antibody-drug conjugate (ADC), in patients with locally advanced or metastatic small-cell lung cancer (SCLC), neuroendocrine carcinoma (NEC), and other solid tumors.

Abstract

3001 Background: BL-M14D1 is a novel DLL3-directed ADC with a potent topoisomerase I inhibitor Ed-04. Results for safety and efficacy from a phase I study on BL-M14D1 in patients with locally advanced or metastatic (LA/M) SCLC and NEC are presented. Methods: Patients who had LA/M solid tumors were enrolled in dose escalation and dose expansion phase and treated with BL-M14D1 at 0.66, 2.0, 3.5, 4.0, 4.5, 5.0, and 6.0mg/kg on Day 1 every 3 weeks (D1 Q3W). SCLC and NEC patients enrolled in dose expansion phase were treated at 4.0 and 4.5mg/kg D1 Q3W. Results: As of Nov 30, 2025, a total of 127 patients were enrolled, including 87 SCLC and 40 NEC. Median prior line of therapy was 2 (range 1-5). Treatment-related AEs (TRAEs) rate was 98.4% and grade≥3 TRAEs rate was 74.0%. The most frequent grade≥3 TRAEs were hematologic, including thrombocytopenia (54.3%), neutropenia (53.5%), leukopenia (46.5%) and anemia (32.3%), which were able to be effectively managed with standard supportive measures including dose reductions, as demonstrated by a low rate (1.6%) of TRAEs leading to discontinuation. One grade 3 ILD and one treatment-related death was reported. Efficacy data at 4.0 and 4.5mg/kg was presented below. BL-M14D1 has demonstrated a promising efficacy with an ORR/cORR of 71.1%/57.8% and mPFS of 7.2 months in heavily pre-treated SCLC. Furthermore, BL-M14D1 has shown encouraging activity in other gastrointestinal and gynecological NECs. Conclusions: BL-M14D1 has demonstrated promising antitumor activity with a tolerable safety profile at dose levels of 4.0mg/kg and 4.5mg/kg D1 Q3W in heavily pretreated patients with SCLC and NEC, supporting further clinical development of BL-M14D1 in SCLC and other less common NECs. Phase III studies assessing BL-M14D1 in SCLC and NEC are in preparation. Clinical trial information: NCT06505824 . SCLC Total * (N=83) SCLC 4.0mg/kg (N=34) SCLC 4.5mg/kg (N=37) NEC † Total * (N=22) NEC † 4.0mg/kg (N=3) NEC † 4.5mg/kg (N=19) Median prior LoT (range) 2 (1-5) 2 (1-3) 2 (1-5) 2 (1-3) 2 (1-2) 2 (1-3) ORR, % (95% CI) 71.1 (60.1, 80.5) 73.5 (55.6, 87.1) 70.3 (53.0, 84.1) 40.9 (20.7, 63.6) 33.3 (0.8, 90.6) 42.1 (20.3, 66.5) cORR, % (95% CI) 57.8 (46.5, 68.6) 61.8 (43.6, 77.8) 56.8 (39.5, 72.9) 27.3 (10.7, 50.2) 33.3 (0.8, 90.6) 26.3 (9.1, 51.2) DCR, % (95% CI) 94.0 (86.5, 98.0) 97.1 (84.7, 99.9) 91.9 (78.1, 98.3) 90.9 (70.8, 98.9) 100 (29.2, 100) 89.5 (66.9, 98.7) mFU for PFS (mo) (95% CI) 6.8 (5.5, 7.2) 7.7 (5.6, 8.2) 4.4 (4.1, 5.5) 3.0 (1.6, 4.3) NR (1.8, NR) 3.0 (1.4, 3.9) mPFS (mo) (95% CI) 7.2 (5.6, 12.7) 7.2 (5.6, NR) 6.9 (4.2, NR) 5.3 (3.9, NR) 4.6 (3.9, 5.3) NR (2.6, NR) † Sites of NEC included cervix, esophagus, stomach and others. * Efficacy analysis included pts at 4.0 and 4.5 mg/kg who received BL-M14D1 and had at least one post-baseline scan.