Predictive value of circulating tumor DNA detection for long-term survival in patients with advanced lung cancer undergoing chemoimmunotherapy.

Abstract

8559 Background: Chemoimmunotherapy (ChemoIO) has emerged as the first-line standard treatment option for advanced non-small cell lung cancer (NSCLC) without drive gene mutation. However, only a portion of patients experienced long-term survival, even among those who achieved partial or complete response (PR or CR) in early assessments. This study assessed circulating tumor DNA (ctDNA) detection in predicting long-term survival in advanced NSCLC patients using a novel 2365-gene fixed panel integrating mutation, copy number variation (CNV), and fragmentomics (Frag). Methods: Based on the SheildingUltra panel developed by Geneseeq, using a discovery cohort composed of over 200 lung cancer and healthy plasma samples, AI-driven models were developed to improve the ctDNA detection sensitivity by incorporating mutations, CNV, and Frag. The enhanced panel was retrospectively validated in a cohort of 107 advanced NSCLC patients using plasma samples collected during PR/CR stages of ChemoIO. Moreover, the fixed panel was prospectively evaluated in an independent cohort of 38 patients who achieved PR/CR in early assessments, with blood samples collected both before treatment and on Day 1 of Cycle 5 (C5D1) of therapy. The value of ctDNA detection results for predicting long-term survival was subsequently evaluated in both cohorts. Results: The enhanced fixed panel demonstrated robust performance in the discovery cohort, effectively discriminating lung cancer patients from healthy individuals through the integration of mutations, CNV, and Frag. In the retrospective validation cohort including 107 patients in PR/CR status, ctDNA-negative patients had significantly longer progression-free survival (PFS) (median PFS: not reached [NR] vs. 14.1 months, hazard ratio (HR): 0.36 (95% confidence interval [CI]: 0.18-0.74), P =0.004) and overall survival (OS) (median OS: NR vs. NR, HR: 0.10 (95% CI:0.02-0.43), P≤0.001) compared to ctDNA-positive patients. In the prospective validation cohort, the ctDNA status determined from plasma collected at C5D1 successfully stratified patients into groups with long- and short- PFS and OS. The median PFS was NR for both groups, with a HR (95% CI) of 0.19 (0.04-0.92) and a p-value of 0.021. The median OS was also NR for both groups, with a HR (95% CI) of 4.56e-10 (0-infinity) and a p-value of 0.011. However, the pre-treatment ctDNA status was not significantly associated with survival. Conclusions: Using a novel ctDNA detection panel incorporating mutation, CNV, and Frag, we found the ctDNA status during the treatment may serve as a potential biomarker for predicting long-term PFS in advanced NSCLC patients undergoing ChemoIO. Additional prospective studies are needed to confirm these results and guide clinical decisions for optimal immunotherapy in NSCLC patients.