Adjuvant Trifluridine/Tipiracil Benefit is Limited to Select Subgroups in MRD+ CRC

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Treatment with adjuvant trifluridine/tipiracil (Lonsurf) generated a numerical but not statistically significant disease-free survival (DFS) improvement in patients with colorectal cancer (CRC) who were positive for molecular residual disease (MRD) following curative-intent resection, according to findings from the phase 3 ALTAIR trial (NCT04457297) presented at the 2025 AACR Annual Meeting.

Findings showed that among the overall population, trifluridine/tipiracil (n = 122) generated a median DFS of 9.30 months (95% CI, 7.92-10.84) vs 5.5 months (95% CI, 4.17-7.33) for placebo (n = 121; HR, 0.79; 95% CI, 0.60-1.05; P = .107).

However, a statistically significant DFS benefit was observed in the subgroup of patients with oligometastatic stage IV disease with a median DFS of 9.76 months (95% CI, 7.62-11.76) for trifluridine/tipiracil (n = 34) vs 3.96 months (95% CI, 3.71-7.98) for placebo (n = 32; HR, 0.53; 95% CI, 0.32-0.87; P = .012). In an exploratory analysis, a statistically significant benefit was also seen in patients with a baseline mean tumor molecules per mL (MTM/mL) of at least 0.179, where the median DFS was 8.03 months (95% CI, 7.16-10.84) for trifluridine/tipiracil (n = 84) vs 3.93 months (95% CI, 3.71-5.55) for placebo (n = 74; HR, 0.58; 95% CI, 0.42-0.81; P = .0002).

“Heterogeneity of registration timepoint to the trial and heterogeneity of pre-enrollment systemic therapy may have confounded the results,” lead study author Hideaki Bando, MD, PhD, said in a presentation of the data. "This is the first randomized phase 3 trial of treat on molecular recurrence to successfully complete enrollment.”

Bando is a medical oncologist in the Department of Gastroenterology and Gastrointestinal Oncology at the National Cancer Center Hospital in Chūō, Japan.

ALTAIR Study Design

ALTAIR was a randomized, double-blind, phase 3 trial designed to assess the efficacy of trifluridine/tipiracil compared with placebo in patients with CRC with MRD positivity following curative surgical resection.

Eligible patients included those at least 20 years of age with detectable circulating tumor DNA (ctDNA) after definitive surgery for CRC and prior standard perioperative therapy. Patients could not have radiographic evidence of disease.

Patients were randomly assigned to receive either trifluridine/tipiracil or placebo for 6 cycles.

The primary end point was DFS. Secondary end points included ctDNA clearance rate, overall survival, safety, treatment completion rate, and quality of life.

The study was powered to detect a hazard ratio (HR) of 0.667, assuming a median DFS of 8 months in the placebo arm, with a two-sided alpha of 0.05 and 80% power. A total of 240 patients were required, with 190 DFS effects anticipated over a 2-year enrollment period and 1 year of follow-up.

Baseline Patient Characteristics

Patients enrolled in the ALTAIR study were generally well balanced between the trifluridine/tipiracil (n = 122) and placebo (n = 121) arms. In the pooled group between both arms (n = 243), the majority of patients were under 70 years of age (64%), were male (58%) and had left-sided colon cancer (71%). Stage III disease was the most common at initial diagnosis (45%), followed by stage IV (27%), stage II (24%), and stage 1 (4.1%).

Additionally, 36% received neoadjuvant therapy, and 46% received adjuvant treatment prior to enrollment. Surveillance enrollment was the most frequent entry point (63%), along with 24% of patients enrolling during MRD and 14% enrolling during adjuvant chemotherapy.

Baseline ctDNA positivity at 1 month postoperatively was observed in 53% of patients. BRAF V600E mutations were identified in 3.7% of the population, and 39% had RAS mutations. Most patients had microsatellite stable disease (98%). The median follow-up duration for this analysis was 23.9 months (range, 18.4-23.5).

Additional Subgroup Data

Patients with stage I to III disease achieved a median DFS of 9.27 months (95% CI, 7.62-10.97) in the trifluridine/tipiracil arm (n = 88) compared with 6.05 months (95% CI, 4.63-9.23) in the placebo arm (n = 89; HR, 0.86; 95% CI, 0.61-1.2; P = .375).

The exploratory analysis evaluated the distribution of ctDNA clearance patterns according to baseline ctDNA burden, using a threshold of 0.179 MTM/mL to stratify patients. In those with a MTM/mL of less than 0.179 MTM/mL, the median DFS was 10.2 months (95% CI, 9.30-15.9) in the trifluridine/tipiracil arm (n = 38) vs 10.3 months (95% CI, 6.05-not reached) in the placebo arm (n = 47; HR, 1.11; 95% CI, 0.65-1.87; P = .71).

In the trifluridine/tipiracil arm, no ctDNA clearance (HR, 19.32; 95% CI, 4.67-79.96; P < .0001) and transient clearance (HR, 7.74; 95% CI, 1.84-32.59; P = .0053) were negatively associated with worse DFS outcomes compared with sustained DFS clearance. This trend was also observed in the placebo arm for patients with no ctDNA clearance (HR, 14.33; 95% CI, 4.36-47.05; P < .0001) and transient clearance (HR, 3.89; 95% CI, 1.07-14.23; P = .0398).

Reference

Bando H, Watanabe J, Kotaka M, et al. A randomized, double-blind, phase III study comparing trifluridine/tipiracil versus placebo in patients with molecular residual disease following curative resection of colorectal cancer: The ALTAIR study. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT131.