The DYNAMIC-III trial, presented by Dr. Jeanne Tie at the ESMO Congress 2025, has provided new insights into personalizing adjuvant chemotherapy for stage III colon cancer patients using circulating tumor DNA (ctDNA) testing. While the study did not meet its primary non-inferiority endpoint, it demonstrated significant reductions in chemotherapy toxicity and identified a subgroup of patients who may safely receive de-escalated treatment.
Trial Design and Rationale
The multicenter, randomized phase II/III trial addressed a critical challenge in stage III colon cancer management: identifying which patients truly benefit from adjuvant chemotherapy while avoiding unnecessary toxicity in those already cured by surgery. The study enrolled 968 evaluable patients approximately 5-6 weeks post-surgery, with 702 (72.5%) testing ctDNA-negative.
Patients were randomized 1:1 to either ctDNA-guided management or standard care. In the ctDNA-guided arm, ctDNA-negative patients received de-escalated therapy, including shortened chemotherapy duration (6 to 3 months), reduced regimen intensity (from doublet to single-agent fluoropyrimidine), or observation alone.
Primary Results Fall Short of Non-Inferiority
After a median follow-up of 47 months, the trial's primary endpoint of 3-year recurrence-free survival (RFS) showed 85.3% in the ctDNA-guided arm versus 88.1% in the standard care arm. The difference of -2.8% exceeded the pre-specified non-inferiority margin of 7.5%, with the 97.5% lower confidence interval reaching -8.0%.
Despite missing the primary endpoint, the ctDNA-guided approach delivered substantial benefits in treatment burden and toxicity. Oxaliplatin use dropped dramatically from 88.6% in standard care to 34.8% in the ctDNA-guided arm (P < 0.001). Grade ≥3 adverse events occurred in 6.2% versus 10.6% of patients (P = 0.037), while treatment-related hospitalizations decreased from 13.2% to 8.5% (P = 0.048).
Promising Results in Low-Risk Subgroup
A pre-planned subgroup analysis revealed particularly encouraging results in clinically low-risk tumors (T1-3N1). In this population, ctDNA-guided de-escalation achieved comparable outcomes to standard therapy, with 3-year RFS of 91.0% versus 93.2% (difference -2.2%; 97.5% lower CI -7.2%).
Expert Perspectives on Clinical Implications
Prof Andrew Beggs from the University of Birmingham noted that while the study wasn't conclusively "better" in the overall population, it showed promise for earlier stage cancers. "This study adds evidence that it is likely we will be able to better select patients for chemotherapy after bowel cancer surgery, by only selecting those who really need it, removing the side effects for those who are found not to need chemotherapy in the end," he stated.
Prof Marco Gerlinger from Barts Cancer Institute emphasized the clinical significance despite the formal negative result. "Although the trial is not practice changing for all Stage 3 colon cancers, it is highly important and will likely influence clinical practice," he said. "For low-risk Stage 3 tumours, patients may make an informed decision to omit or reduce chemotherapy intensity if the test comes back negative as the trial showed that this reduces severe side effects."
Implications for Precision Oncology
The DYNAMIC-III findings reinforce ctDNA's role as a robust biomarker for molecular residual disease detection. Prof Gerlinger noted that the trial demonstrates "the circulating tumour DNA test alone is insufficient to determine in which patients chemotherapy can be omitted without risking under-treatment," suggesting that combination approaches with other risk stratification methods may be needed.
The study's results support the feasibility of ctDNA-based personalized adjuvant strategies in stage III colon cancer, particularly for patients with lower-risk disease characteristics. As Prof Beggs observed, the rapid development of liquid biopsy technology may lead to more sensitive tests that could better identify appropriate candidates for treatment de-escalation.
Future Directions
The trial investigators concluded that while overall non-inferiority was not established, the substantial reduction in treatment burden while maintaining favorable survival outcomes—especially in clinically low-risk patients—paves the way for further precision oncology trials. Additional research is needed to determine optimal combinations of ctDNA testing with other biomarkers and to identify which patients can safely omit chemotherapy entirely versus those requiring only reduced intensity treatment.
