Abstract CT250: Trofuse-023: A phase 3, randomized, open-label study of pembrolizumab with or without maintenance sacituzumab tirumotecan (sac-TMT) as first-line treatment for metastatic squamous non-small-cell lung cancer (NSCLC)

Abstract Background: The anti-PD-1 antibody pembrolizumab plus platinum-based chemotherapy is a standard of care treatment option for metastatic squamous NSCLC without targetable genetic aberrations and regardless of PD-L1 status. Despite treatment advancements, there remains an unmet need for patients with metastatic squamous NSCLC. Trophoblast cell-surface antigen 2 (TROP2), a transmembrane glycoprotein involved in cancer growth and invasion, has emerged as a promising therapeutic target for NSCLC. Sac-TMT (also known as MK-2870/SKB264) is an antibody-drug conjugate composed of an anti-TROP2 antibody coupled to a belotecan-derivative topoisomerase I inhibitor KL610023 (drug-to-antibody ratio, 7.4) via a novel linker. Sac-TMT monotherapy has demonstrated encouraging antitumor activity in patients with previously treated advanced NSCLC. The TroFuse-023 study will evaluate the addition of sac-TMT to pembrolizumab vs pembrolizumab alone as first-line treatment in patients with metastatic squamous NSCLC. Methods: Enrolled patients will be aged ≥18 years with histologically or cytologically confirmed stage IV squamous NSCLC, measurable disease per RECIST version 1.1, ECOG PS of 0 or 1, and provision of a tumor sample for determination of PD-L1 and TROP2 status. Patients will receive induction of pembrolizumab (200 mg IV Q3W) plus chemotherapy (carboplatin AUC 6 mg/mL/min IV Q3W and paclitaxel 200 mg/m2 IV Q3W or nab-paclitaxel 100 mg/m2 IV weekly) for 4 cycles. For randomization to the maintenance phase, patients must be without disease progression (per RECIST version 1.1 by BICR) with an evaluable tumor scan at week 12, have ECOG PS 0 or 1, adequate organ function, and all adverse events (AEs) resolved to grade ≤1. Approximately 592 eligible patients will be randomized 1:1 to receive pembrolizumab 400 mg IV Q6W with or without sac-TMT 4 mg/kg IV Q2W for up to 16 6-week cycles. If there is clinical benefit, patients may continue to receive sac-TMT alone until disease progression, unacceptable AEs, or patient withdrawal. Randomization is stratified by ECOG PS (0 vs 1), PD-L1 tumor proportion score (<50% vs ≥50%), TROP2 expression (low vs medium vs high), and response at randomization (complete response/partial response vs stable disease). The primary endpoint is OS and the key secondary endpoint is PFS per RECIST version 1.1 by BICR. Other secondary endpoints include safety and patient-reported outcomes. Enrollment began on June 10, 2024, and the study is ongoing globally with 210 planned sites. Citation Format: Marina Chiara Garassino, James Chih-Hsin Yang, Delvys Rodríguez-Abreu, Nikolaj Frost, Sung Yong Lee, Gilberto de Castro Jr, Nir Peled, Ignacio Casarini, Dariusz Kowalski, Takayasu Kurata, Yoshitaka Zenke, Bin Zhao, Niyati Bhagwati, Zachary Zimmer, Caicun Zhou. Trofuse-023: A phase 3, randomized, open-label study of pembrolizumab with or without maintenance sacituzumab tirumotecan (sac-TMT) as first-line treatment for metastatic squamous non-small-cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT250.