1456 A phase I study of hSTC810 (Nelmastobart), an anti-BTN1A1 antibody, in patients with advanced solid tumors

<h3>Background</h3> Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint predominantly expressed on activated tumor cells mutually exclusively with PD-L1. BTN1A1 is a potential target for novel immunotherapy options for patients refractory to anti-PD-L1 therapy. This Phase I study evaluates the safety and clinical activity of hSTC810 (Nelmastobart), a humanized monoclonal antibody targeting BTN1A1, in patients with advanced solid tumors. <h3>Methods</h3> This was a first-in-human, Phase I, multicenter, open-label, dose escalation study of hSTC810 in patients with advanced solid tumors. Using a 3 + 3 dose escalation design, including accelerated titration, hSTC810 was administered intravenously every two weeks at six dose levels to determine the safety profile, maximum tolerated dose (MTD), and recommended Phase II dose (RP2D). The dose escalation cohort was evaluated for dose-limiting toxicities (DLTs) during the first 2 cycles (28 days). Once the dose was deemed safe, a backfill cohort was allowed. Tumor response was assessed every 4 cycles (8 weeks) using RECIST 1.1. Patients were treated until disease progression or unacceptable toxicity. <h3>Results</h3> From April 2022 to February 2024, a total of 47 patients were enrolled in the dose-escalation and backfill cohorts in several tumor types, including colorectal, lung, urothelial, breast, cholangiocarcinoma, melanoma, ovarian, and etc. The median treatment duration for all patients was 16.6 weeks (maximum 69 weeks). There were no DLTs reported and the MTD was not reached. The most common study drug-related TEAEs were CTCAE Grade 1-2 fatigue (21.3%), headache (10.6%), somnolence, nausea, and rash (6.4% each). One study drug-related CTCAE Grade 3/4/5 TEAE was reported. In evaluable patients, a best response of partial response (PR) was observed in one patient with MSI-H colorectal cancer (3 mg/kg), and a best response of stable disease (SD) was observed in 15 patients at multiple dose levels. Notably, 1 patient (SCLC, 10 mg/kg) is continuing treatment with hSTC810 through an expanded access program. To date, the patient has been receiving treatment for 22 months and has maintained disease stabilization. Pharmacokinetic (PK) analysis showed a linear PK and consistent exposure. Positive anti-drug antibodies (ADA) were observed in 1 patient at Cycle 1 Day 1. <h3>Conclusions</h3> hSTC810 has demonstrated preliminary anti-tumor activity and durable disease stabilization in patients with advanced solid tumors. hSTC810 is well tolerated with no DLT up to the final dose of 15 mg/kg. Further clinical development in a phase 1b/2 study is currently underway, which aims characterize therapeutic doses and efficacy in selected solid tumors. <h3>Ethics Approval</h3> 1 Independent Ethics Committee or Institutional Review Board The Protocol and informed consent form (ICF) were submitted to and approved by the duly constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC) for each center prior to initiation of the study. A copy of the letter of approval and the IRB/IEC membership roster were received by the Sponsor prior to any drug shipment. 2 Ethical Conduct of the Study The study was conducted in accordance with the Declaration of Helsinki and with all applicable laws and regulations of the locale and country where the study was conducted, and in compliance with Good Clinical Practice Guidelines.