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.

Oxaliplatin-fluoropyrimidine combinations are standard adjuvant therapy after radical resection of high-risk stage II and stage III colon cancer but expose many patients to toxicity while failing to prevent relapse in others. PEGASUS was a multicenter, single-arm, phase 2 trial evaluating the feasibility of an adaptive circulating tumor DNA (ctDNA)-guided treatment strategy in patients with resected microsatellite-stable, T4N0 or stage III colon cancer. Postsurgery ctDNA-positive patients received 3 months of CAPOX, escalating to 6 months of FOLFIRI if persistently positive, whereas confirmed ctDNA-negative patients received 6 months of capecitabine. The primary endpoint was the 2-year relapse-free rate among ctDNA-negative patients at 2 subsequent postsurgery liquid biopsies. Among the 135 enrolled patients, 26% (n = 35) were ctDNA positive at the postsurgery landmark, with a 3-year disease-free survival rate of 58% for ctDNA positive versus 83% for ctDNA negative (hazard ratio = 2.71; 95% CI = 1.35-5.45; P = 0.0036). With 100 rather than 134 ctDNA-negative cases, the observed 2-year relapse-free rate (88%, 90% CI = 81-93%) was below the predefined threshold (≥92%); the primary endpoint was not met. Versus a matched TOSCA ( NCT00646607 ) control cohort, ctDNA-guided strategy showed similar disease-free survival and substantially less neurotoxicity. Transcriptomic profiling linked the relapse to consensus molecular subtype 4, stroma-rich biology. These findings suggest that dynamic ctDNA-guided management can be leveraged operationally in clinical practice, highlighting the needs for randomized trials and more effective strategies for ctDNA-positive disease. ClinicalTrials.gov identifier: NCT04259944 .