Abstract Background: Patients with neuroendocrine carcinomas (NECs) have limited treatment options after front-line therapy, and have a high unmet clinical need for new effective therapies. Delta-like ligand 3 (DLL3) is broadly expressed in NECs. ZL-1310 is a novel antibody-drug conjugate (ADC) that employs the TMALIN® (Tumor Microenvironment Activable LINker-payload) platform, an anti-DLL3 monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable protease-cleavable linker. We report initial safety and efficacy data from Phase 1b of the ZL-1310-002 (NCT06885281) trial assessing ZL-1310 monotherapy in patients (pts) with NECs. Methods: Patients had advanced/metastatic de novo NECs (excluding small cell lung cancer) and had progressed on or after platinum-based chemotherapy. ZL-1310 was given via IV at a starting dose of 1. 6 mg/kg every 3 weeks until disease progression or unacceptable toxicity. Antitumor activity was assessed by RECIST v1. 1 (investigator-assessed). Results: As of 11 Nov 2025, 28 pts with NECs were treated (GastroEnteroPancreatic (GEP) -NEC: 50%, cervical/uterine: 14%, unknown primary 14%, neuroendocrine prostate carcinoma (NEPC) 7%, bladder 7%, large cell neuroendocrine carcinoma of the lung (LCNEC-L) 4%, mediastinal 4%) ; median age was 53 years (range: 27, 76), ECOG PS: 0/1 (32%/68%) ; male: 18 (64%) ; Asian: 64%; 5 (18%) of the pts had 2 lines of prior therapy. DLL3 expression by immunohistochemistry was performed retrospectively in central laboratory and was available for 26 pts and 80% (21/26) patients were positive (cutoff: H-score ≥ 1). The median H-score was 123 (range: 0-288). Median follow-up was 2. 9 months (range: 0. 2-6. 0) ; pts received a median of 3. 2 treatment cycles (range: 1, 9). Seventeen (61%) of pts remain on treatment; disease progression was the most common reason for treatment discontinuation. A total of 25 pts (89%) had treatment-emergent adverse events (TEAEs), and 4 (14. 3%) had Grade 3+ TEAEs. Most common TEAEs (20%, all grade) include anemia (39%), nausea (36%) and vomiting (29%). One pt (3. 6%) decreased the dose of ZL-1310 due to AE (G3 neutrophil count decreased) ; one pt (3. 6%) experienced G2 interstitial lung disease leading to treatment discontinuation. No Grade 5 AE was reported. Objective response rate (ORR) was 48% with 8 confirmed and 2 unconfirmed responses in 21 evaluable pts, including one pt with prior DLL3-targeted bispecific antibody treatment who achieved confirmed PR. Conclusions: ZL-1310 dosed at 1. 6mg/kg Q3W is well tolerated. The AE profile observed in pts with NEC is generally consistent with that of SCLC from a larger study. The preliminary efficacy results are encouraging in this patient population with a high unmet need following platinum-based chemotherapy. Phase 2 expansion in NEC is ongoing to further evaluate the safety and efficacy of ZL-1310 and updated data will be presented. Citation Format: Rohit Thummalapalli, Ming Lu, Alexander Spira, Amr Mohamed, Rahul Aggarwal, Yu Wang, Namrata Vijayvergia, Jordi Rodon, Andrew Scott Paulson, Pingkuan Zhang, Hui Yang, Yuan Xin, Jingmin Wen, Jie Chen. Preliminary results from the phase 1b/2, open-label, multi-center study of ZL-1310, a DLL3-targeted ADC, in patients with neuroendocrine carcinomas and other selected solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT189.
Thummalapalli et al. (Fri,) studied this question.