553P - Association of ctDNA-based MRD detection and MRD clearance with short-term overall survival in patients with resectable colorectal cancer: Updated analysis of CIRCULATE-Japan GALAXY

Background

ctDNA-based molecular residual disease (MRD) detection is significantly associated with a high risk of recurrence in colorectal cancer (CRC). However, the impact of ctDNA status on overall survival (OS) remains unclear.

Methods

GALAXY, a prospective observational study, monitored ctDNA in patients (pts) with clinical stage II-IV CRC following curative intent surgery (UMIN000039205). ctDNA was detected using a personalized, tumor-informed assay (Signatera™) in serial plasma samples collected postoperatively. MRD status was defined with testing 2 to 10 weeks post-surgery, before adjuvant therapy.

Results

Of 5996 pts with CRC enrolled between May 2020 and February 2024, 2168 with stage I-IV pts with ctDNA available after surgery were included (median follow-up: 22.5 months). Post-surgical ctDNA positivity in the MRD window (MRD-positive)correlated with higher recurrence risk (HR 10.3, 95% CI 8.5-12.5, P<0.0001). Moreover, MRD-positive pts had significantly shorter OS than those with MRD-negativity (24-month OS, 80.1% vs. 98.1%; HR 10.3, 95% CI, 6.6-16.1, P<0.0001). In addition, among pts who recurred, those with MRD-positivity had a higher risk of death than MRD-negative pts (24-month OS, 73.7% vs. 91.3%; HR 3.1, 95% CI, 1.8-5.3, P<0.0001). Of 157 pts who were MRD-positive and had ctDNA results available at 3 months post-surgery, 96 pts experienced ctDNA clearance and showed significantly longer disease-free survival (DFS) and OS (24-month DFS, 50.5% vs. 8.7%; HR 0.19, 95% CI, 0.13-0.29; P<0.0001; 24-month OS, 88.6% vs. 71.2%; HR 0.28, 95% CI, 0.11- 0.68; P=0.005). The survival difference was more pronounced when analyzing ctDNA clearance at 6 months post-surgery (DFS: HR 0.10, 95% CI, 0.06-0.19; P<0.0001; OS: HR 0.17, 95% CI, 0.04-0.69; P=0.013).

Conclusions

MRD positivity is significantly associated with poorer short-term OS, even among pts with recurrence, suggesting the need for escalated interventions for MRD-positive pts. In addition, ctDNA clearance is significantly correlated with superior DFS and OS, which warrants the need to evaluate ctDNA clearance as a surrogate endpoint in future clinical studies.

Clinical trial identification

000039205.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Japan Agency for Medical Research and Development.

Disclosure

J. Watanabe: Financial Interests, Personal, Invited Speaker: Medtronic, Johnson and Johnson, Eli Lilly, Takeda Pharmaceutical Company Limited; Financial Interests, Institutional, Funding: Medtronic, TERUMO, AMCO, Stryker Japan. M. Kotaka: Financial Interests, Personal, Invited Speaker: Chugai, Takeda. K. Yamazaki: Financial Interests, Personal, Invited Speaker: Chugai Pharma, Daiichi Sankyo, Yakult Honsha, Takeda, Bayer, Merck Serono, Taiho Pharmaceutical, Lilly, Sanofi, Ono Pharmaceutical, MSD, Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical. Y. Kagawa: Financial Interests, Personal, Invited Speaker: Bayer, Chugai, Ono, Lilly, Merck, Takeda, MSD; Financial Interests, Personal and Institutional, Coordinating PI: Ono. K. Yeh: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, PhytoHealth, Novartis, ONO, Merck, AstraZeneca, Pierre Fabre, MSD, Bayer; Non-Financial Interests, Member: American Society of Clinical Oncology, American Association for Cancer Research. G. Laliotis: Financial Interests, Personal, Full or part-time Employment: Natera, Inc.; Financial Interests, Personal, Stocks/Shares: Natera, Inc.; Non-Financial Interests, Advisory Role: Docus, ai. A. Jurdi: Financial Interests, Institutional, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera. D. Kotani: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eli lilly, MSD, MerckBiopharma, Ono pharma, Pfizer, Taiho pharma, Takeda, Sysmex, Nihonkayaku, Novartis, Guardant Health; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Institutional, Local PI: Ono pharma, MSD, Servier, Novartis, Janssen pharma, IQVIA, Syneos health, CIMIC shiftzero, CIMIC; Financial Interests, Institutional, Funding: Ono pharma. H. Bando: Financial Interests, Institutional, Research Grant: Ono pharmaceutical; Other, Lecture fee: Ono pharmaceutical, Taiho pharmaceutical, Eli Lilly Japan. H. Taniguchi: Financial Interests, Personal, Invited Speaker: Ono, Takeda, Eli Lilly, Chugai, Taiho, Merck Biopharma, Amgen, MSD K.K, Bristol-Myers Squibb Japan, Roche Diagnostics; Financial Interests, Institutional, Coordinating PI: Takeda, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Ono. T. Kato: Financial Interests, Personal, Invited Speaker: CHUGAI PHARMACEUTICAL CO., LTD, Eli Lilly and Company, ONO Pharmaceutical Co, Takeda Pharmaceutical Company Limited; Financial Interests, Institutional, Research Grant: CHUGAI PHARMACEUTICAL CO; Financial Interests, Personal, Coordinating PI: ASAHIKASEI. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd, Sanofi K.K., MSD K.K., Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Amgen K.K., Pfizer Japan Inc., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Eisai Co., Ltd., Roche Diagnostics K.K., FALCO Biosystems Ltd., Merus N.V., Bristol-Myers Squibb K.K., Medical & Biological Laboratories Co., LTD., Takeda Pharmaceutical Co., Ltd. E. Oki: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly, Bristol-myers squibb, MSD, Takeda Pham; Financial Interests, Institutional, Research Grant: Guardant Health. All other authors have declared no conflicts of interest.