Integration of circulating tumor DNA and metabolic parameters for outcome prediction in unresectable locally advanced non-small cell lung cancer.

8080 Background: An effective biomarker to direct precise consolidation treatment after CRT is still lacking. Circulating tumor DNA (ctDNA) molecular residual disease (MRD) following curative-intent treatment strongly predicts recurrence in multiple tumor types, but whether further treatment can improve outcomes in patients with MRD remains unclear. Hereby, we applied CAPP-Seq ctDNA analysis to plasma samples collected before and after definitive chemoradiotherapy (CRT) or radiotherapy (RT) in unresectable LA-NSCLC. Methods: A total of 62 unresectable LA-NSCLC patients were prospectively enrolled, providing 62 baseline and 49 post-definitive CRT/RT plasma samples. All patients underwent a PET/CT scan at baseline and 33 patients received a mid-treatment PET/CT scan upon reaching a RT dose of 40Gy/20f during therapy. These 33 patients were randomly assigned to either receive or not receive adaptive dose-escalated RT. A group of patients who received immune checkpoint inhibitor (ICI) consolidation after CRT/RT was compared with patients who were ctDNA-/high △TMTV post-treatment. Results: ctDNA was detected at baseline in 44 (71.0%) patients. Pre-treatment ctDNA concentration was significantly correlated with TMTV (p = 0.004) and TLG (p = 0.010). Baseline ctDNA detection and concentration were not able to differentiate patients with varying treatment responses or predict survival. However, patients with undetectable ctDNA and low TMTV exhibited significantly better PFS (p = 0.024). One month after completing CRT or RT, ctDNA was detected in 25 (47.2%) patients. While the concentration of circulating free DNA (cfDNA) remained relatively stable (p = 0.652), both the mean ctDNA Variant Allele Frequency (VAF) (p = 0.002) and ctDNA concentration (p = 0.043) showed a significant decrease. Patients with undetectable ctDNA post-treatment exhibited significantly longer PFS and OS. A lower ∆TMTV was significantly associated with longer PFS and OS. Compared to the non-response group, the response group exhibited significantly lower change in △SUVmax (p = 0.024), with a trend towards lower change in TMTV, although not significant (p = 0.064). Compared with the matched 30 patient receiving ICI consolidation, those with negative ctDNA and high △TMTV after CRT demonstrated significantly better PFS (p = 0.042) and OS (p = 0.039). Conclusions: Baseline ctDNA combined with TMTV can enhance the predictive ability for survival. Post-CRT ctDNA and △TMTV possess strong prognostic capabilities. Patients who are ctDNA- and with high △TMTV may be exempt from ICI consolidation therapy.