Trifluridine/Tipiracil Demonstrates DFS Benefit Over Placebo in Resected Stage IV CRC

Although trifluridine/tipiracil (Lonsurf) did not lead to a significant improvement in disease-free survival (DFS) over placebo in the full population of patients with colorectal cancer (CRC) who had molecular residual disease after curative resection who were enrolled to the phase 3 ALTAIR study (NCT04457297), trifluridine/tipiracil did provide clinically meaningful benefit to the subset of patients with stage IV disease.1

Findings, which were shared during the 2025 Gastrointestinal Cancers Symposium, showed that in all patients, the median DFS with trifluridine/tipiracil (n = 122) was 9.30 months (7.92-10.84) vs 5.55 months (4.17-7.33) with placebo (n = 121), which translated to a numerical but not statistically significant improvement with trifluridine/tipiracil (HR, 0.79; 95% CI, 0.60-1.05; P = .107). Moreover, in the trifluridine/tipiracil arm, the DFS rates at 6, 12, 18, and 24 months were 70.5% (61.5%-77.7%), 31.8% (23.6%-40.2%), 20.8% (13.9%-28.7%), and 16.9% (10.4%-24.8%), respectively; in the placebo arm, these respective rates were 45.5% (36.42%-54%), 26.8% (19.16%-35%), 21.5% (14.43%-29.6%), and 14.5% (7.85%-23.1%).

In the subgroup of patients with stage IV disease, the benefit of trifluridine/tipiracil (n = 34) was reported to be highly pronounced vs placebo (n = 32), with a median DFS of 9.76 months (7.62-11.76) and 3.96 months (3.71-7.98), respectively (HR, 0.53; 95% CI, 0.32-0.87; P = .012). In the trifluridine/tipiracil arm, the 6-, 12-, 18-, and 14-month DFS rates were 70.47% (52.05%-82.9%), 27.57% (13.79%-43.3%), 9.19% (.236%-21.9%), and 4.60% (0.43%-17.5%), respectively; in the placebo arm, these respective rates were 31.25% (16.38%-47.3%), 12.5% (3.95%-26.2%), 3.12% (0.24%-13.7%), and not reached.

“Overall survival data were immature, with only 24 events observed across both arms,” lead study author Hideaki Bando, MD, PhD, of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, and colleagues, wrote in a late-breaking poster spotlighting the data.

ALTAIR Background and Design

Testing circulating tumor DNA (ctDNA) for molecular residual disease has proven to serve as a strong predictor for CRC recurrence, although the effectiveness of starting systemic treatment to prevent or delay recurrence in patients with molecular disease after curative surgery remains an open question. With ALTAIR, investigators sought to determine the clinical relevance of leveraging trifluridine/tipiracil as a pre-emptive therapy for patients who were enrolled to the CIRCULATE-Japan study (UMIN000039205) and who had positive ctDNA following curative resection.

ALTAIR enrolled patients with CRC who received curative resection of primary and/or metastatic sites with or without standard adjuvant treatment and who prospectively tested ctNDA positive per the Signatera assay within 3 months before enrollment and did not experience recurrence per CT imaging.

Patients were then randomly assigned to receive either trifluridine/tipiracil or placebo for the duration of 6 months. Investigators performed CT and ctDNA analyses every 2 months for the first year and every 3 months for the second year, followed by additional CT analyses every 6 months for the third year. DFS served as the primary end point of the study, which assumed a median DFS of 8 months in the placebo arm, an HR of 0.667 for the trifluridine/tipiracil arm, a 0.05 significance level, and 0.80 power. It also assumed 2-year enrollment and 1-year follow-up, which required a total of 240 patients and 190 events.

Of the 243 patients who were registered in the trial, 122 were included in the trifluridine/tipiracil arm, and 121 were included in the placebo arm; 72 and 59 patients, respectively, discontinued. In the trifluridine/tipiracil arm, the most common reason for discontinuation was primary disease relapse (n = 34), followed by adverse effect (AE; n = 8), and the planned start date of the second course being set as the first day of treatment and the start of the next course being delayed beyond the same day of the week, 4 weeks later (n = 8).

Additional Findings

“Baseline characteristics were balanced between the 2 groups, and 96.3% of patients received standard-of-care treatment before enrollment,” the study authors wrote. In all patients, 64% were younger than 70 years, 58% were male, 71% had left-sided colon as their primary tumor site, and 45% had stage III disease. Thirty-six percent received neoadjuvant treatment, and 46% received adjuvant treatment. At 1 month post-operation, 53% tested positive for ctDNA. Most patients had BRAF wild-type disease (96%), and 61% had RAS wild-type disease (61%). Ninety-eight percent of patients had microsatellite-stable disease.

Additional efficacy findings were reported for patients with non-stage IV disease. In this group, the median DFS with trifluridine/tipiracil was 9.26 months vs 6.05 months with placebo (HR, 0.86; P = .378).

Moreover, the baseline MTM/mL levels proved to be significantly higher in patients with stage IV disease vs non-stage IV disease (0.68 vs 0.32; P = .024). “The trifluridine/tipiracil benefit was significantly pronounced with higher MTM/mL, with linear benefit observed with increasing MTM/mL values at the enrollment time point,” the study authors underscored in the abstract.

Regarding safety, any-grade AEs occurred in 98.4% of patients in the trifluridine/tipiracil arm vs 57% of those in the placebo arm; these effects were grade 3 or higher for 73.0% and 3.3% of patients, respectively. Serious AEs were experienced by 4.9% of those in the trifluridine/tipiracil arm; none occurred in the placebo arm. AEs led to discontinuation for 6.6% of patients in the trifluridine/tipiracil arm. No AEs proved to be fatal in either arm.

Any-grade AEs related to trifluridine/tipiracil or placebo occurred in 98.4% and 33.1% of patients, respectively; they were grade 3 or higher for 71.3% and 0.8% of patients, respectively. Only 1 serious treatment-related AE (TRAEs) was reported in the trifluridine/tipiracil arm, and 5 TRAEs led to discontinuation in this arm.

“No new safety signals were identified,” the study authors concluded.

Disclosures: Dr Bando disclosed receipt of honoraria from Chugai Pharma, Lilly, and Takeda.

Reference

Bando H, Watanabe J, Kotaka M, et al. A randomized, double-blind, phase III study comparing trifluridine/tipiracil (FTD/TPI) versus placebo in patients with molecular residual disease following curative resection of colorectal cancer (CRC): the ALTAIR study. J Clin Oncol. 2025;43(suppl 4):LBA22. doi:10.1200/JCO.2025.43.4_suppl.LBA22