ctDNA-Guided Adjuvant Therapy Misses Primary End Point in Colon Cancer Trial

A circulating tumor DNA (ctDNA)-guided approach to adjuvant treatment did not meet its primary end point in patients with high-risk stage II and III colon cancer, although the strategy was associated with less neurotoxicity than treatment in a matched historical cohort, according to findings from the phase 2 PEGASUS trial (NCT04259944) published in Nature Cancer.¹

Among 135 enrolled patients, 35 (26%) were classified as ctDNA-positive following postsurgery assessments. At 3 years, disease-free survival (DFS) was 58.4% in ctDNA-positive patients compared with 82.8% in ctDNA-negative patients (HR, 2.71; 95% CI, 1.35-5.45; P = .0036), underscoring the prognostic significance of postoperative ctDNA detection.

The multicenter, single-arm study evaluated whether serial ctDNA testing could guide chemotherapy de-escalation or escalation following surgery for microsatellite-stable, T4N0 or stage III colon cancer. The strategy aimed to limit unnecessary chemotherapy exposure in patients without detectable measurable residual disease (MRD) while intensifying treatment for those with evidence of persistent disease.

ctDNA-Guided Treatment Strategy

Standard adjuvant chemotherapy for high-risk stage II and III colon cancer typically involves oxaliplatin plus a fluoropyrimidine following surgery. Although this approach reduces recurrence risk, treatment-related toxicities, including potentially persistent peripheral neuropathy, remain important considerations.

In PEGASUS, patients with negative ctDNA result at 2 consecutive postsurgery assessments received 6 months of capecitabine monotherapy. Patients with detectable ctDNA initially received 3 months of capecitabine plus oxaliplatin (CAPOX). Those with persistent ctDNA positivity could escalate treatment to 6 months of folinic acid, fluorouracil, and irinotecan (FOLFIRI), while additional ctDNA assessments informed subsequent treatment decisions.

The primary end point was the 2-year relapse-free rate among patients who tested ctDNA-negative at both postsurgery assessments. Investigators initially planned to evaluate 134 patients in this group but included 100 in the final analysis. Twelve relapses occurred within 2 years, corresponding to a relapse-free rate of 88% (90% CI, 81%-93%). This fell below the prespecified target of at least 92%, and the primary end point was not met.

Clinical Implications and Future Directions

Investigators compared outcomes with those of a matched historical cohort from the TOSCA trial (NCT00646607).² Two-year DFS was 79.7% in PEGASUS vs 82.2% in the TOSCA cohort (HR, 0.89; 95% CI, 0.51-1.55; P = .669). Although efficacy appeared similar, the nonrandomized comparison cannot establish equivalence between the strategies.¹

The ctDNA-guided approach was associated with a 43.2% absolute reduction in neurotoxicity compared with the historical cohort. These findings suggest that tailoring chemotherapy according to ctDNA status may help reduce treatment-related adverse effects, although prospective randomized studies are needed to confirm this benefit.

Exploratory transcriptomic analyses also linked consensus molecular subtype 4, characterized by stroma-rich tumor biology, to poorer outcomes. The findings suggest that combining molecular residual disease assessment with tumor biology may help refine recurrence-risk stratification.

Overall, PEGASUS supports the feasibility of serial ctDNA testing to inform adaptive adjuvant treatment decisions in colon cancer. “By integrating longitudinal ctDNA monitoring with tumor molecular characterization, PEGASUS provides a framework for next-generation adjuvant trials that move beyond static risk stratification toward biologically informed treatment adaptation,” according to the authors of the study.However, the unmet primary end point and the poor outcomes observed among ctDNA-positive patients highlight the need for randomized validation of treatment de-escalation and escalation strategies, as well as more effective approaches for patients with persistent molecular residual disease.

REFERENCES

1. Marsoni S, Montagut C, Pietrantonio F, et al. Circulating tumor DNA-guided de-escalation or escalation of adjuvant therapy in high-risk stage II and stage III colon cancer: the phase 2 PEGASUS trial. Nat Cancer. 2026 Sep 14. doi: 10.1038/s43018-026-01237-9

2. Sobrero A, Lonardi S, Rosati G, et al. FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial. J Clin Oncol. 2018 May 20;36(15):1478-1485. doi: 10.1200/JCO.2017.76.2187