Rapid Readout: ctDNA Dynamics and Clinical Outcomes in the Adjuvant Management of Colorectal Cancer (GALAXY Study)

Background

• Circulating tumor DNA (ctDNA)–based molecular residual disease has the potential to select patients who may benefit more from standard-of-care adjuvant chemotherapy by accurately assessing recurrence-risk post-surgery and by evaluating adjuvant colon cancer therapy (ACT) efficacy.
• CIRCULATE-Japan project is a large platform enrolling patients with clinical stage II–IV resectable colorectal cancer (CRC) to evaluate the clinical utility of ctDNA minimal residual disease analysis. The study comprises 1 observational (GALAXY study) and 2 randomized phase 3 trials (VEGA and ALTAIR trials).

Methods

• The GALAXY study utilizes a personalized, tumor-informed ctDNA assay (Signatera bespoke multiplex polymerase chain reaction next-generation sequencing) based on whole-exome sequencing of tumor tissue and matched normal sample.
• The blood samples are collected before surgery and 4, 12, 24, 36, 48, 72, and 96 weeks after surgery.
• Investigators can receive the results of the ctDNA assay in a timely manner and consider patients for enrollment in associated interventional phase 3 trials, such as VEGA and ALTAIR.
• Association of ctDNA dynamics with a short-term clinical outcome and ACT efficacy are being investigated.
• Patients enrolled in VEGA and ALTAIR trials were excluded from this analysis.

Results

• Even with an extended follow-up time, post-op 4-week positivity was significantly associated with inferior disease-free survival (DFS), consistent with previous results.
• 6- and 12-month DFS rates by ctDNA dynamics from post-op 4 to 12 weeks were significantly different between “positive to negative” and “positive to positive” groups with a hazard ratio of 15.8.
• Among post-op 4-week ctDNA-positive patients, ACT was able to clear ctDNA in 68% of ctDNA-positive patients by post-op 24 weeks, and a 6-month DFS rate was significantly higher in patients with ACT vs without ACT across all stages.
• 2 of 3 post-op 4-week ctDNA-positive patients even with stage I or low-risk stage II recurred.
• Patients who were post-op 4-week ctDNA-negative patients did not derive significant benefit from ACT, with an HR of 1.3 in high-risk stage II and III.

Conclusions

• This study shows that stratifying postsurgical treatment decisions using the assay can identify patients likely to benefit from ACT across all stages.
• ctDNA dynamics from post-op 4-week ctDNA-positive to 12 weeks could become a new surrogate end point beyond DFS.
• ctDNA-guided adjuvant strategy will further be established by ongoing randomized VEGA and ALTAIR studies and will be presented at future conferences.