Top Line: Are early changes in circulating tumor DNA prognostic of outcomes following chemoradiation and immunotherapy for NSCLC?
The Study: Radiation plays an essential role in controlling macroscopic disease in locally advanced and oliogometastatic lung cancer alongside ever improving systemic therapy regimens. We still largely rely on imaging to assess response and detect progression, but can we use circulating tumor DNA (ctDNA) to track molecular response to treatment? In this phase 2 trial, 26 patients with locally advanced NSCLC treated with chemoradiation and adjuvant immunotherapy had ctDNA profiling before treatment and mid-treatment. ctDNA was used to calculate two composite measures including circulating tumor fractional estimate (ctFE) and maximum variant allele frequency (maxVAF). MaxVAF reflects the most abundant somatic alteration in circulation but does not account for the overall genomic landscape of the tumor. ctFE integrates information across multiple genomic features to produce a global estimate of tumor DNA burden. At both baseline and midtreatment, ctFE burden was a strong predictor of OS and PFS. It outperformed both maxVAF and ctFE detectability. The dynamics of early ctFE change during treatment separated patients into three prognostic groups with median OS of 60.8, 13.0, and 2.9 months, respectively.
TBL: Molecular measures, such as ctDNA, could provide early estimates of response to standard treatment for NSCLC. Such information could one day help adapt treatment and potentially improve outcomes for early nonresponders. | Hashmi, Clin Cancer Res 2026
The Study: Radiation plays an essential role in controlling macroscopic disease in locally advanced and oliogometastatic lung cancer alongside ever improving systemic therapy regimens. We still largely rely on imaging to assess response and detect progression, but can we use circulating tumor DNA (ctDNA) to track molecular response to treatment? In this phase 2 trial, 26 patients with locally advanced NSCLC treated with chemoradiation and adjuvant immunotherapy had ctDNA profiling before treatment and mid-treatment. ctDNA was used to calculate two composite measures including circulating tumor fractional estimate (ctFE) and maximum variant allele frequency (maxVAF). MaxVAF reflects the most abundant somatic alteration in circulation but does not account for the overall genomic landscape of the tumor. ctFE integrates information across multiple genomic features to produce a global estimate of tumor DNA burden. At both baseline and midtreatment, ctFE burden was a strong predictor of OS and PFS. It outperformed both maxVAF and ctFE detectability. The dynamics of early ctFE change during treatment separated patients into three prognostic groups with median OS of 60.8, 13.0, and 2.9 months, respectively.
TBL: Molecular measures, such as ctDNA, could provide early estimates of response to standard treatment for NSCLC. Such information could one day help adapt treatment and potentially improve outcomes for early nonresponders. | Hashmi, Clin Cancer Res 2026