Effect of longitudinal ctDNA monitoring with resistance genomic signatures on prognostication in patients with EGFR-mutated advanced NSCLC.
Authors: Kumar Prabhash, Atul Bharde, Vichitra Behel, Mrunal Ratnaparkhi, Vanita Noronha, Vijay Maruti Patil, Anuradha Choughule, Pratik Chandrani, Amit Dutt, Bhagwat Jadhav, Sangeeta Prajapati, Sumit Haldar, Fauzul Mobeen, Nandini Sharrel Menon, Kanchan Hariramani, Madhura Basavalingegowda, Pankaj Chaturvedi, Jayant Khandare, Gowhar Shafi
Journal: Journal of Clinical Oncology (2024)

e20507 Background: Targeted therapies against activating receptor tyrosine kinases (TKi) (EGFR, ALK, ROS) mutations have significantly improved the SOC in NSCLC. Although mutant EGFR (mEGFR) targeting TKi show survival benefits, their efficacy is contingent upon the presence of de novo or emergent TKi mutations. A comprehensive gene panel (CGP) designed to detect a multitude of actionable and resistance signatures may enhance informed treatment decisions and outcome. Additionally, longitudinal monitoring of a patient may help to monitor the dynamics (disappearance/emergence) of actionable or resistance-conferring gene alterations for timely decisions on therapy alterations. Methods: In prospective clinical trial, ctDNA was evaluated at multipoint and longitudinally in 75 advanced NSCLC patients. On average 06 samples were collected from each patient at treatment initiation (baseline) and subsequently during maturation until one year. Libraries were prepared using a hybridization-capture method based on custom-designed OncoIndx 1080 CGP and sequenced (depth 5500 X) on Illumina Nextseq 2000 in a pair-end mode (150 x2). Variant calling was performed using a proprietary bioinformatics pipeline iCare. Results: Patients with mEGFR (exon 19 deletion and L858R variants) at the baseline, 60 % were accompanied by resistance signature of one or multiple pathogenic mutations in downstream components (PIK3CA, mTOR, PTEN, BRAF) of EGFR pathway, or other receptor TKs (ROS1, ERBB3, MET and RET), while 36 % showed presence of concurrent pathogenic TP53, RB1 or NF2 variants. Nearly 58 % of patients were clinically Non-respondent (NR) while the rest were Responders (R). Patients carrying resistance signatures at the treatment initiation and subsequently during treatment maturation showed dismal PFS (median 10.4 months, P &lt; 0.0001, HR:9.4, CI:3.2-27) and OS (median 10.4 months, P = 0.0004, HR:14.8, CI:4.7-46) compared to population without resistant signatures. Prevalence of resistant signatures at the baseline was highly enriched in the NR population (90 %), compared to the R population (20 %). Multivariate analysis indicated the presence of resistant signatures as an independent bad prognosticator (HR:8.4, CI: 2.8-12.4, P &lt; 0.0001). Tumor fraction value (TF) correlated well with clinical endpoints (AUC = 0.97, &lt; 0.0001), high TF value (cutoff 0.3) showed shorter OS compared to pts with low TF (HR:10, CI: 3.8-29.4, P &lt; 0.0001, median = 21.3 months). Conclusions: Inclusion of CGP as a standard of care may help to stratify patients who are EGFR positive yet may not respond to TKi due to the presence of resistance signatures, and provide the benefit of Tx modification. Longitudinal monitoring of ctDNA in advanced NSCLC patients showed distinct mutational signatures in the R and NR populations.