The oral chemotherapy agent TAS-102 has demonstrated significant activity in clearing circulating tumor DNA (ctDNA) in colorectal cancer patients with minimal residual disease following standard adjuvant therapy, according to results from the phase 2 INTERCEPT-TT trial published in the Journal of Clinical Oncology.
The single-arm study enrolled 15 patients with colorectal cancer who had completed standard-of-care treatments including surgery and chemotherapy but remained ctDNA-positive, indicating the presence of minimal residual disease. At 3 months, 7 patients (47%) achieved ctDNA clearance, and at 6 months, 36% maintained negative ctDNA status. In comparison, a synthetic control cohort showed only 6.7% spontaneous ctDNA clearance at both time points.
"The challenge is that even if we detect it at an early stage, meaning stage II or stage III, we cut it out, and we even give chemotherapy. Up to a third of patients end up having their disease come back in a refractory setting," explained Nicholas James Hornstein, MD, PhD, assistant professor at the Donald and Barbara Zucker School of Medicine of Hofstra University and Northwell Health, and lead author of the study.
Clinical Outcomes and Disease Control
Treatment with TAS-102 was associated with statistically significant improvements in ctDNA clearance rates at both 3 months (P = .0034) and 6 months (P = .025) compared to the synthetic control arm. The median disease-free survival reached 9.41 months in the TAS-102 cohort versus 5.75 months in the synthetic control group (HR, 0.47; 95% CI, 0.23-0.85; P = .03).
Despite these encouraging results, disease recurrence remained a significant challenge. Nine patients (60%) in the TAS-102 group developed radiographic recurrence, while 5 patients (33%) had positive ctDNA without radiographic evidence of disease. In the synthetic control arm, 28 patients (93%) developed radiographic recurrence.
Study Design and Rationale
The trial utilized a synthetic control arm rather than a traditional randomized placebo-controlled design due to ethical considerations. "If there's more than a 90% likelihood that your cancer is going to come back, how would you feel if I told you, 'Hey, I want you to just wait. We'll see what happens. Don't worry about it,'" Hornstein noted, explaining the rationale for avoiding a placebo arm in this high-risk population.
The synthetic control was derived from extensive data at The University of Texas MD Anderson Cancer Center, matching key patient characteristics to ensure appropriate comparison while maintaining patient safety and ethical standards.
Safety Profile and Dose Management
TAS-102 demonstrated a manageable safety profile consistent with its known toxicity pattern, though dose reductions were frequently required. The study observed no new safety signals, and dose modifications followed established guidelines used in the metastatic setting.
"TAS-102 is one of these drugs that we know requires dose reduction. It happens in the metastatic setting. It happened here," Hornstein explained. The complex dosing schedule of TAS-102, which involves on-and-off cycles throughout the month, required careful monitoring and patient education to ensure proper administration.
Implications for Future Research
While the study provides proof-of-principle that intervention during the ctDNA-positive state is feasible, researchers emphasize that more effective therapies are needed. "We can intervene and we can affect ctDNA positivity, but frankly, I like TAS-102 as an agent, but we need better drugs than we have right now to clear ctDNA and cure patients, because that's the goal," Hornstein stated.
The findings align with results from the larger phase 3 ALTAIR study, which showed similar benefits in the subgroup of patients with previously metastatic disease who were rendered disease-free. This consistency across studies supports the potential role of TAS-102 in this specific patient population.
Clinical Context and Unmet Need
Circulating tumor DNA testing provides physicians with a 6-to-9-month lead time in predicting disease recurrence, creating a therapeutic window for intervention. The technology allows detection of microscopic disease burden when traditional imaging shows no evidence of cancer, potentially enabling treatment when the tumor burden consists of hundreds rather than hundreds of thousands of cancer cells.
The study addresses a critical unmet need in colorectal cancer management, where approximately one-third of patients with early-stage disease experience recurrence despite optimal standard-of-care treatment. Current options beyond conventional polychemotherapy remain limited in the refractory setting.
Researchers are now exploring whether earlier intervention during the ctDNA-positive state, when the disease burden is minimal, might improve the effectiveness of treatments that show limited benefit in the metastatic setting. Multiple studies are underway testing this hypothesis with various therapeutic combinations and timing strategies.
