Association of comprehensive molecular genotyping and overall survival in patients with advanced non-squamous non-small cell lung cancer.
Authors: Aggarwal Charu , Marmarelis Melina Elpi , Hwang Wei-Ting , Scholes Dylan G. , McWilliams Tara , Singh Aditi Puri , Sun Lova , Kosteva John A. , Costello Michael Robert , Cohen Roger B. , Langer Corey J. , Gabriel Peter Edward , Shulman Lawrence N. , Thompson Jeffrey C. , Carpenter Erica L. 
Published: June 2022

9022 Background: Current guidelines recommend comprehensive molecular genotyping for newly diagnosed patients (pts) with metastatic non-squamous (non-Sq) NSCLC. We have previously demonstrated that concurrent plasma (P) and tissue (T) based next-generation sequencing (NGS) improves detection of clinically actionable mutations in pts with advanced NSCLC. We analyzed the impact of concurrent T+P NGS on comprehensiveness of molecular genotyping and on overall survival (OS). Methods: A retrospective cohort study of pts with newly diagnosed stage IV non-Sq NSCLC who received therapy at our institution between 01/2019 and 12/2020 was performed. Categories of NCCN guideline testing were defined, i) comprehensive: EGFR, ALK, BRAF, ROS1, MET, RET, and NTRK testing, ii) incomplete: 2-6 genes tested, and iii) no testing performed. The proportion of pts with comprehensive molecular testing performed, prior to 1st-line therapy and by detection modality (T NGS vs. T+P NGS), were compared using Fisher’s exact test. Median OS was estimated using Kaplan-Meier methodology from diagnosis to death or censored at most recent follow-up. Results: 335 patients were included in this analysis, 98.5% (330/335) underwent molecular testing: either comprehensive: n = 291 (86.9%), incomplete testing: n = 39 (11.6%); or no testing n = 5 (1.5%). Testing with T NGS was completed in 32.7% (108/330); 67.2% (222/330) underwent concurrent T+P NGS. These groups were well balanced for baseline characteristics, with the exception of a higher number of never smokers in T+P vs. T NGS (30.2% vs. 14.8%, p < 0.0001). Proportion of pts with comprehensive molecular testing was higher among pts with T+P NGS: 99.5% (221/222) vs. T NGS: 64.8% (70/108), p < 0.0001. All pts with T+P NGS testing had results available prior to 1st line therapy; 100% (204/204) compared to 60.7% (51/84) for T NGS, p < 0.0001. With median follow up of 20.5 months (mos, range 0.3 - 33.1), median OS was 18.6 mos. Median OS for pts tested with T+P NGS vs T alone was numerically longer at 23.2 vs. 14.1 mos, but not statistically significant (p = 0.078). However, regardless of testing modality, patients with comprehensive molecular genotyping had superior OS compared to those with incomplete or no testing (22.1 mos vs. 11.6 mos, p = 0.017). The institution of oral targeted therapy had no bearing on this difference in OS (test for interaction, p = 0.6509). Conclusions: Performance of concurrent T+P NGS testing was associated with a higher likelihood of comprehensive molecular genotyping, as well as improved availability of results, including prior to first line therapy. Patients with comprehensive genotyping have improved OS compared to patients with incomplete or no testing. These results support implementation of a concurrent T+P NGS approach upon initial diagnosis of metastatic non-Sq NSCLC.