ESMO 2025 No success for ctDNA-guided de-escalation of adjuvant treatment for colon cancer

MedNet.nl: In patients with stage III colon cancer and a negative postoperative ctDNA test, de-escalation of adjuvant treatment is not noninferior to standard adjuvant chemotherapy. However, the phase 2/3 AGITG DYNAMIC-III study showed that ctDNA-guided de-escalation is associated with significantly fewer side effects.

The AGITG DYNAMIC-III study investigated ctDNA-guided treatment. Treatment was escalated in participants with a positive ctDNA test and de-escalated in patients with a negative test. The results of the escalation arm were presented earlier this year at the ASCO conference and showed that escalating treatment in ctDNA-positive patients did not lead to improved recurrence-free survival (RFS; HR=1.11). At the ESMO conference, the researchers presented the results of de-escalating treatment in the ctDNA-negative group.

The researchers randomized 1002 patients with stage III colon cancer who were at least fit enough for treatment with fluoropyrimidine. The ctDNA-negative de-escalation cohort comprised 353 patients, and 349 ctDNA-negative patients received standard care. In the de-escalation cohort, the recommended treatment was made less intensive, for example by omitting oxaliplatin or shortening the treatment.

The researchers had previously stated that for noninferiority, the primary endpoint of 3-year RFS could differ by a maximum of 7.5%. The 3-year RFS was 85.3% in the de-escalation group versus 88.1% in the standard care arm, but the confidence interval showed that a difference of more than 8.0% was possible. This meant that there was no noninferiority. A subgroup analysis of patients with high and low clinical risk showed that the 3-year RFS differed little, particularly in the low clinical risk group (91.0 vs 93.2%).

On the other hand, ctDNA-guided treatment was significantly less intensive for patients. In this group, the majority were treated with fluoropyrimidine monotherapy (57.85 vs 9.2% in the standard care group) and a minority with an oxaliplatin doublet (34.8 vs 88.6%). ctDNA-guided treatment was therefore associated with fewer grade ≥3 adverse events (6.2 vs 10.6%) and fewer hospital admissions (8.5 vs 13.2%).

The researchers argue that ctDNA-guided de-escalation strategies should be further investigated.

Tie J, et al. ctDNA-guided adjuvant chemotherapy de-escalation in stage III colon cancer: primary analysis of the ctDNA-negative cohort from the randomized AGITG DYNAMIC-III trial (intergroup study of AGITG and CCTG). ESMO 2025, abstract LBA9.

This article was originally published in Dutch on MedNet.nl