Early treatment of ctDNA-positive colorectal cancer did not improve disease-free survival in the phase 3 ALTAIR trial

Acting on a molecular relapse signal before scans turned positive failed to significantly extend disease-free survival, the Japanese-led randomized trial found.

A blood test can now flag colorectal cancer’s return months before a CT scan can. The harder question is whether acting on that early warning helps patients. In the phase 3 ALTAIR trial, the answer was no.

Investigators in Japan and Taiwan enrolled patients who had undergone curative resection of colorectal cancer, completed standard-of-care therapy, and then tested positive for circulating tumor DNA (ctDNA) — molecular evidence of residual disease — while showing no radiological sign of recurrence. Between July 2020 and June 2023, 243 such patients were randomized 1:1 to six months of the oral chemotherapy trifluridine/tipiracil (FTD/TPI; Lonsurf) or to placebo, in a double-blind design embedded in the CIRCULATE-Japan platform.

The primary endpoint was investigator-assessed disease-free survival (DFS). Median DFS was 9.30 months with FTD/TPI versus 5.55 months with placebo — a hazard ratio of 0.79 (95% CI 0.60–1.05, P = 0.107). The confidence interval crosses 1.0 and the result did not reach statistical significance, so the primary endpoint was not met.

A nearly four-month gap in median DFS that the trial could not confirm as real — a reminder that an encouraging point estimate is not a positive trial.

A signal without significance

The numerical separation is the kind of result that invites over-reading. But with only 243 patients, ALTAIR was not powered to call a hazard ratio of 0.79 a win, and its authors do not. Acting on a ctDNA relapse signal with FTD/TPI, they conclude, did not significantly improve DFS in patients without radiological disease.

The toxicity tradeoff was unambiguous. Grade 3 or higher hematologic adverse events affected 73.0% of FTD/TPI-treated patients versus 3.3% of placebo-treated patients, with no new safety signals.

ALTAIR tested a specific bet: that starting an established chemotherapy at the moment of molecular recurrence, rather than waiting for visible disease, would change outcomes. It does not settle whether a more active regimen, or a different drug, might. What it does show is that ctDNA positivity alone is not yet a validated trigger for this intervention — the detection technology is ahead of the treatment evidence. Larger trials testing other agents against molecular residual disease will determine whether the early-warning signal can be converted into benefit.