PEGASUS ctDNA Strategy Misses Colon Cancer Endpoint

A circulating tumor DNA (ctDNA)-guided strategy for postoperative chemotherapy did not meet its primary endpoint in patients with resected, high-risk stage II or stage III colon cancer, according to the phase 2 PEGASUS trial published in Nature Cancer. The strategy was associated with less neurotoxicity than treatment in a matched historical cohort.

The multicenter, open-label, nonrandomized trial included 135 evaluable patients with microsatellite-stable tumors at 11 centers in Italy and Spain. Treatment was assigned according to serial ctDNA testing. Patients with two consecutive negative postoperative tests were assigned 6 months of capecitabine. Patients testing positive received 3 months of CAPOX, with escalation to 6 months of FOLFIRI for persistent positivity. The primary endpoint was the 2-year relapse-free rate among patients with confirmed negative postoperative tests.

Of 135 patients, 100 were ctDNA negative and 35 were positive. The negative cohort was smaller than the planned 134 patients. Twelve recurrences occurred within 2 years in this group, yielding an 88% relapse-free rate (90% CI, 81%–93%), below the prespecified threshold of at least 92%. Postoperative ctDNA positivity was associated with worse 3-year disease-free survival: 58.4% versus 82.8% (hazard ratio, 2.71; 95% CI, 1.35–5.45).

In an exploratory comparison with matched patients from the TOSCA trial, 2-year disease-free survival was 79.7% with PEGASUS versus 82.2% with TOSCA. Grade 1–2 neurological toxicity occurred in 13.8% versus 41.5%, respectively; grade 3–4 toxicity occurred in 3.8% versus 19.3%. These historical comparisons cannot establish equivalent efficacy or a causal reduction in toxicity.

The investigators emphasized the need for randomized validation. Interpretation is limited by the small sample, historical controls, and use of an older ctDNA assay. ctDNA remained undetectable in all five patients with lung-only recurrence and all three with peritoneum-only recurrence, underscoring limitations of ctDNA surveillance.

Source: 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. Nature Cancer. 2026. doi:10.1038/s43018-026-01237-9