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

Taniguchi, Hiroya; Nakamura, Yoshiaki; Kotani, Daisuke; Yukami, Hiroki; Mishima, Saori; Sawada, Kentaro; Shirasu, Hiromichi; Ebi, Hiromichi; Yamanaka, Takeharu; Aleshin, Alexey; Billings, Paul R.; Rabinowitz, Matthew; Oki, Eiji; Takemasa, Ichiro; Kato, Takeshi; Mori, Masaki; Yoshino, Takayuki

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to 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 ctDNA 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 ctDNA 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 whether postoperative surgery alone is noninferior 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 ctDNA 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 the GALAXY study. Therefore, CIRCULATE‐Japan encompasses both “de‐escalation” and “escalation” trials for ctDNA‐negative and ‐positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA‐guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.