Among 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, Lonsurf (trifluridine/tipiracil) did not result in significant improvement in disease-free survival (DFS) over treatment with a placebo, but showed benefit in patients with stage 4 disease.
Findings, which were shared during the 2025 Gastrointestinal Cancers Symposium, showed that in all patients, the median DFS with Lonsurf (122 patients) was 9.3 months versus 5.55 months with placebo (121 patients), which translated to a numerical but not statistically significant improvement with Lonsurf. Moreover, in the Lonsurf arm, the DFS rates at six, 12, 18 and 24 months were 70.5%, 31.8%, 20.8% and 16.9%, respectively; in the placebo arm, these respective rates were 45.5%, 26.8%, 21.5% and 14.5%.
In the subgroup of patients with stage 4 disease, the benefit of Lonsurf (34 patients) was reported to be highly pronounced versus placebo (32 patients), with a median DFS of 9.76 months and 3.96 months, respectively. In the Lonsurf arm, the six-, 12-, 18- and 14-month DFS rates were 70.47%, 27.57%, 9.19% and 4.6%, respectively; in the placebo arm, these respective rates were 31.25%, 12.5%, 3.12% and not reached.
“Overall survival data were immature, with only 24 events observed across both arms,” lead study author Dr. Hideaki Bando 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.
Additional Findings
“Baseline characteristics were balanced between the two 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 3 disease. Thirty-six percent received neoadjuvant treatment, and 46% received adjuvant treatment. At one-month post-operation, 53% tested positive for circulating tumor DNA (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 4 disease. In this group, the median DFS with Lonsurf was 9.26 months versus 6.05 months with placebo.
Moreover, the baseline MTM/mL levels proved to be significantly higher in patients with stage 4 disease versus non-stage 4 disease (0.68 versus 0.32). “The [Lonsurf] 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 side effects occurred in 98.4% of patients in the Lonsurf arm versus 57% of those in the placebo arm; these effects were grade 3 (severe) or worse for 73% and 3.3% of patients, respectively. Serious side effects were experienced by 4.9% of those in the Lonsurf arm; none occurred in the placebo arm. Side effects led to discontinuation for 6.6% of patients in the Lonsurf arm. No side effects proved to be fatal in either arm.
Any-grade side effects related to Lonsurf or placebo occurred in 98.4% and 33.1% of patients, respectively; they were grade 3 or worse for 71.3% and 0.8% of patients, respectively. Only one serious treatment-related side effect was reported in the Lonsurf arm, and five treatment-related side effects led to discontinuation in this arm.
“No new safety signals were identified,” the study authors wrote.
ALTAIR Background and Design
Testing 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 Lonsurf as a pre-emptive therapy for patients who were enrolled to the CIRCULATE-Japan study 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 three months before enrollment and did not experience recurrence per CT imaging.
Patients were then randomly assigned to receive either Lonsurf or placebo for the duration of six months. Investigators performed CT and ctDNA analyses every two months for the first year and every three months for the second year, followed by additional CT analyses every six months for the third year. DFS served as the primary end point of the study.
Of the 243 patients who were registered in the trial, 122 were included in the Lonsurf arm, and 121 were included in the placebo arm; 72 and 59 patients, respectively, discontinued. In the Lonsurf arm, the most common reason for discontinuation was primary disease relapse (34 patients), followed by side effect (eight patients) 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, four weeks later (eight patients).
Reference:
“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.” By Dr. Dr. Hideaki Bando, et al. J Clin Oncol.
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