Phase 1/2 study of the trophoblast cell surface antigen 2 (TROP2) antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) as monotherapy or combination therapy in gastrointestinal cancers: LIGHTBEAM-02A.

TPS846 Background: There is a significant need for new tolerable and effective therapeutic options for colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and biliary tract cancer (BTC) that can provide survival benefit. TROP2 is expressed broadly in several cancers, including CRC, PDAC, and BTC. Sac-TMT (formerly MK-2870/SKB264) is an ADC consisting of a humanized antihuman TROP2 monoclonal antibody, a linker, and a cytotoxic belotecan–derivative topoisomerase I inhibitor. The nonrandomized, open-label, phase 1/2 LIGHTBEAM-02A study (NCT06428409) is being conducted to examine the safety and efficacy of sac-TMT in gastrointestinal cancers. Methods: Approximately 130 patients will be assigned to 1 of 3 cohorts based on their disease. Patients in cohort 1 (CRC; n ≤ 50) must have previously treated locally advanced or metastatic colorectal adenocarcinoma; patients in cohort 2 (PDAC; n ≅ 40) must have previously treated locally advanced or metastatic PDAC; patients in cohort 3 (BTC; n ≅ 40) must have previously treated locally advanced or metastatic BTC. Cohort 1 is included in a dose-escalation phase to determine the recommended phase 2 dose of sac-TMT when used in combination with fluorouracil and leucovorin and an efficacy phase. In the dose-escalation phase, patients will receive sac-TMT 3 mg/kg or 4 mg/kg intravenously (IV) every 2 weeks (Q2W) on days 1 and 15 of each 4-week cycle plus 2400 mg/m 2 fluorouracil IV infused over 46-48 hours Q2W and 400 mg/m 2 leucovorin IV Q2W; in the efficacy phase, patients will receive the recommended phase 2 dose of sac-TMT with the same chemotherapy regimen as the dose-escalation phase. Patients in cohorts 2 and 3 will receive sac-TMT 4 mg/kg IV monotherapy Q2W on days 1 and 15 of each 4-week cycle. The primary objectives are to evaluate safety and tolerability and objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary objectives are to evaluate duration of response and progression-free survival per RECIST v1.1 by BICR and overall survival. Enrollment is ongoing. Clinical trial information: NCT06428409 .