CIRCULATE-Japan: Circulating tumor DNA-guided adaptive platform trials to refine adjuvant therapy for colorectal cancer.

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA at pre- and post-surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of circulating tumor DNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively-conducted large-scale registry designed to monitor circulating tumor DNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test if postoperative surgery alone is non-inferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if circulating tumor DNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a, double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for circulating tumor DNA-negative and positive patients, respectively, and helps to answer whether measuring circulating tumor DNA postoperatively has prognostic and/or predictive value. Our circulating tumor DNA -guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy.