A multicohort, biomarker-driven phase 2 trial of personalized total neoadjuvant therapy with targeted agents for high-risk rectal cancer (The TRAINER study)

This multicohort, single-center, phase II trial explored the efficacy and safety of a biomarker-driven total neoadjuvant therapy (TNT) regimen in high-risk locally advanced rectal cancer (LARC) patients. The regimen included induction chemotherapy (4 cycles of mFOLFOX6) with targeted agents (bevacizumab for cohort B and cetuximab for cohort C), followed by short-course radiotherapy (25 Gy/5Fx) and consolidation chemotherapy (2 cycles of mFOLFOX6, with cetuximab in cohort C). The primary endpoint was complete response (CR; sustained clinical CR [cCR] + pathological CR [pCR]). Secondary endpoints included compliance, safety, pathological outcomes, and survival. Between April 2021 and October 2024, 90 of 96 patients completed the prescribed treatment. CR was achieved in 36 (18 in cohort B and 18 in cohort C) patients (40%). No grade IV-V toxicity was observed, although three and 41 patients experienced targeted agent-related adverse effects in cohort B and C, respectively. In the two cohorts, 43 and 38 patients underwent curative surgery with sphincter preservation in 39 (90.7%) and 34 (89.5%) patients, respectively. Postoperative complications occurred in seven (16.3%) and five (13.2%) patients, of whom one (2.6%) patient in cohort C received reoperation. This intensified TNT regimen with targeted agents for high-risk LARC patients achieved a satisfactory CR rate with acceptable toxicities and complications.