KEYMAKER-U06: Phase 1/2 umbrella platform study of TROP2 antibody-drug conjugate sacituzumab tirumotecan plus pembrolizumab plus chemotherapy (substudy 06C) and sacituzumab tirumotecan plus paclitaxel (substudy 06D) in gastroesophageal adenocarcinoma

TPS511 Background: Treatment options for patients with gastroesophageal adenocarcinoma (GEA) are limited and prognosis is poor. KEYMAKER-U06 is a multicenter, open-label, phase 1/2, umbrella platform study designed to evaluate investigational agents with or without pembrolizumab and/or chemotherapy for GEA. Substudy 06C (NCT06469944) will be conducted to evaluate sacituzumab tirumotecan(TROP2 antibody-drug conjugate; formerly MK-2870/SKB264) plus pembrolizumab plus investigator’s choice of chemotherapy as first-line therapy for patients with advanced or metastatic GEA. Substudy 06D (NCT06445972) will be conducted to evaluate sacituzumab tirumotecan plus paclitaxel as second-line therapy for patients with advanced or metastatic GEA. Methods: In both substudies, patients aged ≥18 years with confirmed advanced or metastatic HER2-negative GEA (gastric, gastroesophageal junction, or esophageal adenocarcinoma), measurable disease per RECIST v1.1 by investigator review and verified by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status score of 0 or 1 are eligible; patients in substudy 06C should be treatment naive and patients in substudy 06D should have disease progression on or after 1 prior therapy. Both substudies will have a safety lead-in phase of ≤10 patients to determine the recommended phase 2 dose of sacituzumab tirumotecan when used in combination with pembrolizumab plus chemotherapy (substudy 06C) or paclitaxel (substudy 06D). In the safety lead-in phase, patients will receive sacituzumab tirumotecan 3 mg/kg or 4 mg/kg IV per a Bayesian optimal interval design. In the efficacy phase of substudy 06C, ≅120 patients (including 10 patients in safety lead-in) will be allocated or randomly assigned to receive pembrolizumab 400 mg IV every 6 weeks plus investigator’s choice of chemotherapy (arm 1) or sacituzumab tirumotecan IV on days 1, 15, and 29 of each 6-week cycle plus pembrolizumab plus investigator’s choice of chemotherapy (arm 2). In the efficacy phase of substudy 06D, ≅80 patients (including 10 patients in safety lead-in) will be allocated or randomly assigned to receive ramucirumab 8 mg/kg IV on days 1 and 15 of each 4-week cycle plus paclitaxel 80 mg/m 2 IV on days 1, 8, and 15 of each 4-week cycle (arm 1) or sacituzumab tirumotecan IV on days 1, 15, and 29 of each 6-week cycle plus paclitaxel (arm 2). Primary outcomes for both substudies are safety and tolerability for the safety lead-in and ORR per RECIST v1.1. by BICR for the efficacy phase (calculated based on pooled data from safety lead-in and efficacy phase); secondary outcomes include DOR and PFS per RECIST v1.1 by BICR, OS, safety, and tolerability. Enrollment is ongoing in both substudies. Clinical trial information: NCT06469944 ; NCT06445972 .