Trifluridine/Tipiracil Enhances Disease-Free Survival in ctDNA+ CRC

In a significant advancement for colorectal cancer treatment, a recent study presented at the 2025 ESMO Gastrointestinal Cancers Congress indicates that the combination of trifluridine and tipiracil (Lonsurf) has shown a numerical improvement in disease-free survival (DFS) among patients with circulating tumor DNA (ctDNA)-positive colorectal cancer (CRC) following curative resection. The phase 3 ALTAIR trial, registered under NCT04457297, provided compelling evidence, although the results did not reach statistical significance.

The trial involved 243 participants who were randomized to receive either trifluridine/tipiracil or a placebo after curative surgery. The lead author, Dr. Masahito Kotaka, MD, PhD, from Sano Hospital in Hyogo, Japan, reported that patients receiving trifluridine/tipiracil achieved a median DFS of 9.30 months, compared to 5.55 months for those on placebo (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.60-1.05; P = .107). Notably, the 12- and 24-month DFS rates for the treatment group were 31.8% and 16.9%, respectively, versus 26.8% and 14.5% in the placebo group.

The study highlighted that patients with stage IV disease or microsatellite stable (MSS) status derived significant benefits from the treatment. Specifically, stage IV patients had a median DFS of 9.76 months with trifluridine/tipiracil compared to 3.96 months for the placebo group (HR, 0.53; 95% CI, 0.32-0.87; P = .012).

Despite these promising findings, the safety profile raised concerns. Adverse effects were reported in 98.4% of patients taking trifluridine/tipiracil, with severe events (grade 3 or higher) occurring in 73.0% of this group, compared to only 3.3% in the placebo cohort. The most common side effects included decreased neutrophil (74.6%) and white blood cell counts (63.9%), prompting dose adjustments in 95.1% of patients on trifluridine/tipiracil.

The ALTAIR trial forms part of a broader CIRCULATE Japan initiative, which illustrates the importance of ctDNA monitoring in guiding post-surgical treatment strategies. Patients were required to be at least 20 years old, with no radiographic evidence of disease, and underwent standard perioperative therapy while being closely monitored for ctDNA levels using the Signatera assay.

The findings from the ALTAIR trial, while not statistically significant for the overall population, suggest potential for targeted treatment strategies, especially for specific subgroups of patients with advanced disease. The implications for clinical practice could be profound, as healthcare providers may consider incorporating ctDNA status into treatment planning for colorectal cancer patients.

As cancer treatment continues to evolve, the exploration of biomarkers like ctDNA is crucial in tailoring therapies to individual patient needs. Further research is warranted to establish the long-term benefits and risks associated with trifluridine/tipiracil in various patient demographics and disease stages. The ongoing dialogue among oncologists regarding treatment protocols will likely shape the future landscape of colorectal cancer management.