Cleared ctDNA within weeks predicted longer survival on immunotherapy in a 109-patient study

A prospective, 109-patient study tests whether cleared ctDNA within weeks predicts outcomes

Circulating tumor DNA has been proposed as an early signal of how well immunotherapy is working in advanced non-small cell lung cancer, but the researchers write that its clinical value still requires further validation. As part of the prospective clinical protocol NCT05995821, they performed targeted error-correction sequencing on 328 ctDNA samples and 109 matched white-blood-cell DNA samples from 109 patients with metastatic non-small cell lung cancer receiving anti-PD-(L)1 therapy, either alone or in combination. After resolving the cellular origin of 2,818 variants, the researchers defined landmark molecular response as undetectable ctDNA within 3 to 9 weeks of starting treatment.

The study also compared a single on-therapy ctDNA measurement against tracking ctDNA dynamics from baseline through the 3-to-9-week window, and examined how much molecular response varied within that window itself.

Pre-treatment ctDNA burden predicted survival; blood tumor mutation burden did not

Before treatment started, the amount of ctDNA in a patient’s blood predicted survival, while blood-based tumor mutation burden did not. The researchers also report that a tumor-naive approach informed by white-blood-cell DNA increased the number of patients whose ctDNA could be evaluated, without compromising the overall accuracy of the landmark molecular response readout.

Undetectable ctDNA within 3 to 9 weeks tracked with significantly longer survival

Comparing a single on-therapy ctDNA measurement with the change from baseline through 3 to 9 weeks, and examining the variability of molecular response within that window, the researchers found that undetectable ctDNA at the landmark timepoint predicted survival outcomes effectively. Landmark molecular response was significantly enriched among patients who went on to have progression-free survival of 6 months or more, both on immunotherapy alone (p=2.5e-05) and on chemo-immunotherapy (p=0.02). Patients with landmark molecular response had significantly longer progression-free survival (p=1.6e-06) and overall survival (p=2.5e-05) than patients classified as having molecular progression.

The abstract reports these results as p-values rather than as median survival times or hazard ratios, so the magnitude of the survival difference, in months, is not given.

“Landmark ctDNA molecular response provides a real-time, accurate approach for monitoring immunotherapy clinical outcomes. Although not currently validated for regulatory use, these findings demonstrate the potential validity of ctDNA as an early endpoint of immunotherapy response.”Niknafs et al., Clinical Cancer Research (2026)

Not yet a regulatory-grade test

The authors state plainly that landmark ctDNA molecular response is not currently validated for regulatory use. The study describes a clinical validity finding, that undetectable ctDNA within 3 to 9 weeks tracks with survival, rather than a clinical utility finding that acting on the result changes how a patient is treated or improves outcomes. The paper does not report an objective response rate by imaging, a comparison against RECIST-based radiographic assessment on the same timeline, or the specific sequencing platform’s turnaround time or cost.