Abstract CT193: Intracranial activity of ZL-1310, a DLL3-targeted ADC, in patients with previously treated extensive-stage small cell lung cancer and baseline brain metastasis: Analysis of a phase 1 trial

Abstract Background: Brain metastasis (BM) is prevalent in extensive-stage small-cell lung cancer (ES-SCLC) and also a common cause for treatment failure. BM remains as an unmet need with limited treatment options available such as palliative radiotherapy. 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 protease-cleavable linker. ZL-1310 has demonstrated encouraging systemic efficacy in heavily pre-treated ES-SCLC. We report the initial intracranial efficacy of ZL-1310 from a phase 1 study. Methods: This multi-country Phase 1 study (NCT06179069) enrolled adults with ES-SCLC who have progressed following ≥1 platinum-based chemotherapy. Those with stable or asymptomatic BM are eligible (including those with no prior brain radiotherapy). ZL-1310 is given intravenously every 3 weeks until disease progression or unacceptable toxicity. Systemic efficacy was assessed by investigators using Response Evaluation Criteria in Solid Tumors (RECIST) v1. 1. Intracranial efficacy was assessed by blinded independent radiologists using Modified Criteria for Radiographic Response Assessment in NeuroOncology (mRANO). Results: As of 1 Aug 2025, 104 pts received ZL-1310 across 6 dose levels (0. 8-2. 8 mg/kg). The median age was 65 years (range: 36, 80) ; 42. 3% of pts were female, and 28. 8% were Asian. Fifty-four (51. 9%) had 1 prior line and the remaining 50 (48. 1%) had 2 or more lines of prior therapies. A total of 94 (90. 4%) received a prior anti-PDL1, 13 (12. 5%) had prior lurbinectedin, and 10 (9. 6%) had prior DLL3-targeted therapy. Brain metastases were present in 33 (31. 7%) pts (including 11 pts with untreated BM) at baseline. Independently reviewed intracranial efficacy results were available for 24 pts, including 15 pretreated with radiation and 9 untreated. Confirmed intracranial response was 58. 3% (14/24, 95% CI: 36. 6, 77. 9%), including 5 CR and 9 PR. The intracranial response rate in pts without prior brain radiation was 66. 7% (6/9) and 53. 3% (8/15) in pts with prior brain radiation. Intracranial disease control rate was 95. 8% (23/24). The median time to onset of intracranial response was 5. 6 weeks (min 5. 1, max 8. 7 weeks). Of the 33 pts with BM and systemic efficacy evaluable, confirmed ORR was 61%, including 1 confirmed CR. Grade ≥3 treatment-related adverse events were reported for 22/104 (21. 2%) pts overall and 5/39 (12. 8%) pts in the 1. 6 mg/kg dose level; those reported in ≥2 pts at the 1. 6 mg/kg dose level included anemia and neutropenia (2 pts each). Independent mRANO evaluation is ongoing and updated data will be provided. Conclusions: ZL-1310 is well tolerated and demonstrated encouraging systemic efficacy in heavily pretreated ES-SCLC with BM. The preliminary independent assessment also showed ZL-1310 has high intracranial efficacy including in patients with untreated BM. Citation Format: Pedro Rocha, Manish Patel, Yi-Long Wu, Jun Zhao, Grace Dy, María Eugenia Olmedo García, Qiming Wang, Valentina Gambardella, Oscar Juan-Vidal, Afshin Dowlati, David Vicente Baz, Alexander Spira, Anne C. Chiang, Yingying Du, Martin Gutierrez, Xiaorong Dong, Jie Hu, Mariam Alexander, Haiyong Wang, Wenxiu Yao, Liza Villaruz, Zhen Wang, Pingkuan Zhang, Renke Zhou, Xiao Wang, Luis Paz-Ares. Intracranial activity of ZL-1310, a DLL3-targeted ADC, in patients with previously treated extensive-stage small cell lung cancer and baseline brain metastasis: Analysis of a phase 1 trial 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 CT193.