ctDNA-Informed Treatment Doesn’t Impact RFS in Stage III Colon Cancer

Escalated adjuvant chemotherapy did not improve recurrence-free survival in patients with stage III colon cancerwhen using a ctDNA-informed approach.

When utilizing circulating tumor DNA (ctDNA) as a prognostic indicator, escalated adjuvant chemotherapy did not improve recurrence-free survival (RFS) in patients with stage III colon cancer, according to cohort results of the phase 2/3 AGITG DYNAMIC-III trial (ACTRN12617001566325) presented during the 2025 American Society of Clinical Oncology Annual Meeting.¹

At a median follow-up of 42.2 months (range, 0.78-63.0), results showed that the 2-year RFS rate for patients who received ctDNA-informed treatment escalation was 52% (90% CI, 44%-59%) compared with 61% (90% CI, 54%-68%) for patients who received standard adjuvant chemotherapy (HR, 1.11; 90% CI, 0.83-1.48; P = 0.57). The 3-year RFS rates were 48% (90% CI, 40%-55%) and 52% (90% CI, 44%-60%), respectively.

“Treatment escalation, including to FOLFOXIRI, did not impact ctDNA clearance or recurrence-free survival,” said lead study author Jeanne Tie, MD, MBChB, FRACP, medical oncology lead for the Lower Gastrointestinal Tumour Stream at the Peter MacCallum Cancer Centre and senior research fellow in the Division of Personalised Oncoogy at the Walter and Eliza Hall Institute of Medical Research, in Melbourne, Australia. “As such, future studies should explore novel adjuvant strategies in this high-risk population.”

For patients with stage III colon cancer and detectable ctDNA following surgery, recurrence risk remains high despite standard adjuvant chemotherapy. Furthermore, the risk of recurrence markedly increases with increasing ctDNA burden, and if a patient’s ctDNA cannot be cleared, it is associated with an elevated recurrence risk.

Approximately 30% of patients with stage III colon cancer will develop disease recurrence, even with standard adjuvant oxaliplatin-based chemotherapy. In patients with high-risk stage III colon cancer, 6 months of oxaliplatin-based chemotherapy is linked with more favorable recurrence compared with 3 months of treatment.² Postoperative ctDNA has also been considered a strong independent prognostic factor,^3-5 Tie added.

In the DYNAMIC-III trial, investigators explored the impact of adjuvant chemotherapy de-escalation or escalation as informed by ctDNA following surgery. The data presented during the meeting comprised the primary analysis in patients with ctDNA-positive disease, with Tie noting that data for those who were ctDNA negative were immature.

DYNAMIC-III is a multicenter, phase 2/3 trial assessing 1002 patients with resected stage III colon cancer who were eligible for adjuvant chemotherapy. Patients were randomly assigned 1:1 to ctDNA-informed management or standard-of-care (SOC) therapy, with physicians choosing the selected chemotherapy regimen prior to randomization; the latter was blinded to the ctDNA result.

To be eligible for enrollment, patients had to have had R0 resection, an ECOG performance status of 0 to 2, be fit to at least receive fluoropyrimidine, have a staging CT within 12 weeks, have provision of adequate tumor tissue less than 6 weeks post-surgery, and have no synchronous colorectal cancer.

For the study to have a ctDNA-informed management strategy, patients with a ctDNA-positive result 5 to 6 weeks following surgery with a tumor-informed assay were given an escalated adjuvant chemotherapy regimen.

The escalated options included:

• No chemotherapy to 5-fluorouracil (5-FU) and capecitabine;
• 5-FU/capecitabine to 6 months of oxaliplatin doublet;
• 3 months of oxaliplatin doublet to 6 months of oxaliplatin doublet or at least 3 months of FOLFOXIRI;
• and 6 months of oxaliplatin doublet to at least 3 months of FOLFOXIRI.

One cycle of pre-planned chemotherapy was permitted prior to the ctDNA-informed regimen. Those with ctDNA-negative disease had a de-escalated regimen.

The primary end point was 2-year RFS in the ctDNA-positive cohort. Secondary end points included safety and end-of-treatment (EOT) ctDNA clearance; exploratory end points included postoperative ctDNA levels.

Additionally, the boundaries for declaring superiority in the escalation arm were based on the target sample size of 250 (escalation arm, n = 125), and under the null where the expected number of recurrences was 126 (each arm, n = 63). Superiority of ctDNA-informed treatment escalation vs standard chemotherapy also needed to show an HR of 0.746.

A total of 1002 patients across 56 institutions were randomly assigned between October 2017 and April 2023, and 27% (n = 259) were ctDNA positive, of which 44% (n = 113) had clinical low-risk disease (non-N2 and non-T4).

Stratification factors included clinical risk (low vs high) and disease sites.

The ctDNA-informed cohort comprised 129 patients who were ctDNA–positive (27%) and 353 who were ctDNA–negative; in the standard management arm, 130 patients were ctDNA-positive (27%) compared with 349 who were ctDNA-negative.

Regarding baseline characteristics, the median age in the ctDNA-informed escalation group was 64 years (range, 30-87) and 61 years (range, 30-90) in the SOC group; 64% vs 62% of patients were male. Eighty-three percent and 76% of patients, respectively, had an ECOG performance status of 0; 49% and 41% of patients, respectively, had right-sided tumors. In the ctDNA-informed group, 60% of patients had high clinical-risk disease (T4 or N2), a median of 22 nodes examined (IQR, 17-29), 39% had extramural tumor deposits, 19% had obstructions or perforations, and 11% had mismatch repair-deficient (dMMR) tumors.

In the SOC cohort, 53% of patients had clinical high-risk disease, a median of 20 nodes examined (IQR, 15-26), 31% had extramural tumor deposits, 19% had obstructions or perforations, and 9% had dMMR tumors.

Of patients who were ctDNA-informed, 89% (n = 115) received escalated adjuvant chemotherapy, stratified as no chemotherapy (3%), single-agent fluoropyrimidine (2%), 3 months of oxaliplatin doublet (1%), 6 months of oxaliplatin doublet (44%), and at least 3 months of FOLFOXIRI (50%).

In the SOC arm (n = 130), patients received no chemotherapy (3%), single agent fluoropyrimidine (11%), 3 months of oxaliplatin doublet (45%), and 6 months of oxaliplatin doublet (41%). No patients received 3 months or more of FOLFOXIRI.

In the ctDNA-informed and SOC arms, treatment-related hospitalization rates were similar at 59 days (IQR, 52-68) and 53 days (49-61), respectively (OR, 1.21; P = .058), as well as the median days of treatment duration at 150 days (IQR, 126-161) and 147 days (IQR, 76-161). Seventy-four percent and 68% of patients completed their planned treatment, respectively.

Regarding safety, treatment-related hospitalization rates were 16% and 14% in the ctDNA-informed and SOC arms, respectively. Grade 3/4 treatment-related adverse effects occurred in 18.6% and 16.9% of patients respectively, including febrile neutropenia (2.3% vs 2.3%), diarrhea (10.9% vs 7.7%), oral mucositis (1.6% vs 0.8%), nausea (2.3% vs 3.8%), and vomiting (1.6% vs 2.3%). There were 2 treatment-related deaths in the ctDNA-informed arm and none in the SOC arm.

Additionally, results of a post hoc analysis exploring FOLFOXIRI vs FOLFOX/CAPOX showed that the 3-year RFS rates were 47% vs 51%, respectively (HR, 1.09; 90% CI, 0.78-1.53; P = .662), and the ctDNA clearance rates were 60% and 62%, respectively. Subgroup analysis data showed that patients with a T stage greater than 4 had higher RFS (HR, 0.86; 95% CI, 0.58-1.26) vs those with T4 stage (HR, 1.63; 95% CI, 1.05-2.54; P = .0627), favoring standard therapy.

Investigators noted that of all patients who were ctDNA-positive, the risk of recurrence correlated with ctDNA burden in a prespecified correlative analysis. Here, the 3-year RFS rates were 78% for those with tumor-derived mutant molecules/mL quartiles <0.06, 63% for 0.06-0.17, 36% for 0.18-1.31, and 22% for greater than 1.31 tumor-derived mutant molecules/ML quartiles.

RFS was also analyzed by EOT ctDNA. In patients who were ctDNA-positive, 2- and 3-year RFS rates were 23% and 86%, respectively; these rates were 12% and 84%, respectively (HR, 11.1; 95% CI, 6.7-20; P <.0001).

References

1. Tie J, Wang Y, Loree JM, et al. ctDNA-guided adjuvant chemotherapy escalation in stage III colon cancer: primary analysis of the ctDNA-positive cohort from the randomized AGITG dynamic-III trial (intergroup study of AGITG and CCTG). J Clin Oncol. 2025;43(suppl 17):3503. doi:10.1200/JCO.2025.43.16_suppl.3503
2. André T, Meyerhardt J, Iveson T, et al. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol. 2020;21(12):1620-1629. doi:10.1016/S1470-2045(20)30527-1
3. Tie J, Wang Y, Tomasetti C, et al. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016;8(346):346ra92. doi:10.1126/scitranslmed.aaf6219
4. Nakamura Y, Watanabe J, Akazawa N, et al. ctDNA-based molecular residual disease and survival in resectable colorectal cancer. Nat Med. 2024;30(11):3272-3283. doi:10.1038/s41591-024-03254-6
5. Taieb J, Souglakos J, Boukovinas I, et al. Combined analyses of circulating tumor DNA and Immunoscore in patients with stage III colon cancer: a post hoc analysis of the PRODIGE-GERCOR IDEA-France/HORG-IDEA-Greece Trials. J Clin Oncol. 2025;43(13):1564-1577. doi:10.1200/JCO.24.00648