New data from the phase 3 ALTAIR study demonstrates that trifluridine/tipiracil significantly improves disease-free survival (DFS) in patients with stage IV colorectal cancer (CRC) who show molecular residual disease after curative resection, despite not meeting its primary endpoint in the overall study population.
The findings, presented at the 2025 Gastrointestinal Cancers Symposium, revealed that stage IV CRC patients treated with trifluridine/tipiracil achieved a median DFS of 9.76 months compared to 3.96 months with placebo (HR, 0.53; 95% CI, 0.32-0.87; P = .012).
Stage IV Subgroup Shows Marked Improvement
In the stage IV disease subgroup, trifluridine/tipiracil demonstrated notably higher DFS rates across multiple timepoints:
- 6-month DFS: 70.47% vs 31.25% for placebo
- 12-month DFS: 27.57% vs 12.5% for placebo
- 18-month DFS: 9.19% vs 3.12% for placebo
Study Design and Overall Results
The ALTAIR trial, part of the larger CIRCULATE-Japan study, enrolled 243 patients who tested positive for circulating tumor DNA (ctDNA) following curative resection. Patients were randomized to receive either trifluridine/tipiracil or placebo for six months, with regular CT and ctDNA analyses throughout the study period.
In the overall study population, trifluridine/tipiracil showed a numerical but not statistically significant improvement in DFS:
- Median DFS: 9.30 months vs 5.55 months with placebo
- Hazard Ratio: 0.79 (95% CI, 0.60-1.05; P = .107)
Patient Characteristics and Biomarker Analysis
The study population was well-balanced between treatment arms, with:
- 64% of patients under 70 years
- 58% male participants
- 71% left-sided primary tumors
- 96% BRAF wild-type disease
- 98% microsatellite-stable disease
Notably, baseline MTM/mL levels were significantly higher in stage IV disease patients compared to non-stage IV patients (0.68 vs 0.32; P = .024), with treatment benefit showing a linear correlation with increasing MTM/mL values.
Safety Profile
The safety analysis revealed manageable toxicity:
- Grade 3 or higher adverse events: 73.0% in the treatment arm vs 3.3% with placebo
- Serious adverse events: 4.9% in the treatment arm
- Treatment discontinuation due to adverse events: 6.6%
- No treatment-related fatalities were reported
Lead study author Dr. Hideaki Bando from the National Cancer Center Hospital East in Kashiwa, Japan, and colleagues noted that no new safety signals were identified during the trial.
Clinical Implications
These findings suggest that trifluridine/tipiracil could represent a valuable treatment option for stage IV CRC patients with molecular residual disease after curative resection, particularly given the significant improvement in DFS for this high-risk population. Overall survival data remains immature, with only 24 events observed across both study arms at the time of analysis.
