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

An international clinical trial evaluating circulating tumor DNA to guide postoperative chemotherapy in high-risk stage II and stage III colon cancer has missed its primary end point. Researchers published findings from the PEGASUS trial on September 14, 2026, revealing that while treatment neurotoxicity dropped significantly, relapse-free rates fell short of pre-specified study targets.

The PEGASUS Trial Design and Patient Cohort

Known formally as the phase 2 PEGASUS trial, the investigator-initiated, multicenter, prospective study enrolled patients across 11 medical centers in Italy and Spain.

Traditional adjuvant treatment relies heavily on static anatomical factors like bowel wall depth and involved lymph nodes. PEGASUS sought to replace that blunt approach with a dynamic, longitudinal liquid biopsy framework. At the initial postoperative landmark, individuals tested positive or negative for ctDNA, establishing a baseline for subsequent treatment decisions. Analyzing tumor-specific DNA in the bloodstream through a highly sensitive, minimally invasive method, circulating tumor DNA serves as a ground-breaking instrument for spotting and tracking cancer. Following cancer treatment, minuscule remnants known as minimal residual disease can linger in a significant subgroup of patients at levels imperceptible to physical exams or imaging scans, which can ultimately lead to cancer recurrence.

Increasing data shows that circulating tumor DNA as a marker of minimal residual disease after treatment for solid tumors can predict relapse. Determining their therapeutic reaction and identifying individuals who could gain advantages from adjuvant treatment might be facilitated by this approach. The qualitative aspects of circulating tumor DNA have been found useful in designing targeted cancer therapies for patients based on distinct mutations occurring on circulating tumor DNA.

Treatment Adaptation Protocol and Unmet Primary End Point

Therapies were assigned dynamically based on molecular findings. In PEGASUS, patients with a negative circulating tumor DNA result at two consecutive postsurgery assessments received six months of capecitabine monotherapy. Patients with detectable circulating tumor DNA initially received three months of capecitabine plus oxaliplatin, known as CAPOX. Those with persistent circulating tumor DNA positivity could escalate treatment to six months of folinic acid, fluorouracil, and irinotecan, referred to as FOLFIRI, while additional circulating tumor DNA assessments informed subsequent treatment decisions.

Photo: Targetedonc

The trial’s primary end point focused on the 2-year relapse-free rate among patients who tested circulating tumor-DNA-negative at both postsurgery assessments. Failing to reach the predetermined benchmark of 92% or higher, the trial did not achieve its primary goal. Across the study, 100 patients were circulating-tumor-DNA negative at the postoperative landmark. Of these, 97 remained persistently negative during subsequent testing, while three later converted to circulating-tumor-DNA positive. FOLFIRI is not confirmed as an effective adjuvant escalation method by these exploratory observations, yet they did highlight varying molecular paths among individuals who maintained postoperative minimal residual disease.

Comparative Survival and Toxicity Outcomes Against the TOSCA Cohort

To evaluate efficacy, researchers compared outcomes with those of a matched historical cohort from the TOSCA trial (NCT00646607). In the PEGASUS group, the 2-year disease-free survival rate stood at 79.7%, compared to 82.2% within the TOSCA participants (HR, 0.89; 95% CI, 0.51-1.55; P = .669). However, tailoring chemotherapy according to molecular status yielded a major drop in adverse physical side effects.

Photo: oncodaily.com

Surgery alone cures the majority of patients with early-stage colon cancer; specifically, the 5-year disease-free survival rate reaches 78% for low-risk stage III patients and spans 78-91% for stage II patients. However, because there are no trustworthy biomarkers for minimal residual disease, adjuvant chemotherapy is advised for all stage III patients. A study by Tarazona et al. evaluated 150 resected colon cancer patients using serial circulating-tumor-DNA testing, showing a strong correlation between postoperative circulating-tumor-DNA detection and relapse.

Plasma-Based Detection Limits and Future Trial Directions

Combining assessments of molecular residual disease with tumor biology may improve risk stratification for recurrence, according to these results. Overall, PEGASUS supports the feasibility of serial circulating-tumor-DNA testing to inform adaptive adjuvant treatment decisions in colon cancer. The continued development and integration of circulating-tumor-DNA testing into clinical practice will be essential in shaping the future of cancer management.

“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.”

Study authors, via Targeted Oncology

Nevertheless, the failure to meet the primary end point alongside the adverse results seen in ctDNA-positive participants emphasizes the necessity for randomized trials to validate escalation and de-escalation tactics, as well as the discovery of more potent solutions for individuals with ongoing molecular residual disease. Readers should consult qualified medical professionals regarding cancer treatment options, as these findings represent clinical trial data rather than direct medical advice.

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