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.
Authors: Bando Hideaki , Watanabe Jun , Kotaka Masahito , Matsuhashi Nobuhisa , Oki Eiji , Komatsu Yoshito , Shiozawa Manabu , Hirata Keiji , Miyamoto Yuji , Yeh Kun-Huei , Aleshin Alexey , Takemasa Ichiro , Kotani Daisuke , Sato Akihiro , Misumi Toshihiro , Nakamura Yoshiaki , Shi Qian , Taniguchi Hiroya , Kato Takeshi , Yoshino Takayuki 
Published: January 2025

LBA22

Background:
Tumor-informed circulating tumor (ct) DNA testing is recognized as a powerful predictor of CRC recurrence. However, the benefit of systemic therapy to prevent or delay clinical recurrence in patients (pts) with molecular recurrence after curative surgery remains uncertain.
Methods:
Pts with CRC who had undergone curative resection of primary and/or metastatic sites + standard of care (SoC) adjuvant treatment if applicable, were enrolled in ALTAIR study if they (1) prospectively tested positive for ctDNA using a clinically validated, personalized assay (Signatera™, Natera, Inc.) within 3 months before enrollment and (2) had no recurrence on radiological (CT) imaging. Pts were randomized to receive FTD/TPI or placebo for 6 months. CT and ctDNA analyses were conducted every 2 months in the first year, every 3 months in the second year, and every 6 months in the third year. The primary endpoint was disease-free survival (DFS), with secondary endpoints including ctDNA clearance, overall survival (OS), and adverse events. The study assumed a median DFS of 8 months in the placebo group, an HR of 0.667 for the FTD/TPI group, 0.05 significance level, 0.80 power, 2-year enrollment, and 1-year follow-up, requiring 240 pts and 190 DFS events. Baseline ctDNA levels were evaluated by mean tumor molecules (MTM)/ml.
Results:
Between July 2020 and June 2023, 243 pts were enrolled and randomized to FTD/TPI (n=122) or placebo (n=121). Baseline characteristics were balanced, and 96.3% of pts received SoC treatment postoperatively. FTD/TPI group had a median DFS of 9.30 months vs. 5.55 months in the placebo group, but this difference did not reach statistical significance in the primary population (HR, 0.79; 95% CI, 0.60-1.05;
P
= 0.107). The FTD/TPI benefit was highly significant in resected oligometastatic stage IV pts as shown in Table. The baseline MTM/ml levels were significantly higher in resected oligometastatic Stage IV pts vs non-Stage IV (0.68 vs 0.32,
P
= 0.024). Overall, FTD/TPI benefit was significantly pronounced with higher MTM/mL, with linear benefit observed with increasing MTM/mL values at the enrollment time point. OS data remain immature, with 24 events reported across both arms. Grade ≥3 adverse events occurred in 73.0% of the FTD/TPI arm versus 3.3% in the placebo arm, with no new safety signals.
Conclusions:
Although statistical significance was not reached in the primary population, FTD/TPI showed clinically meaningful DFS benefit in pts with resected oligometastatic disease and a trend towards increasing DFS benefits with increasing MTM/mL values.
Clinical trial information: NCT04457297
.

Number
Baseline MTM/ml
Median DFS

FTD/TPI(months)

Placebo
(months)

Primary population
243
0.40
9.30
5.55

HR, 0.79
P
= 0.107

Stage IV
66
0.68
9.76
3.96

HR, 0.53
P
= 0.012

Non-Stage IV
177
0.32
9.26
6.05

HR, 0.86
P
= 0.378