Is Broad-Based Genomic Sequencing Prognostic in NSCLC?

Genomic sequencing in the community oncology setting can be challenging. To determine the association between genomic sequencing and treatment or survival among patients with advanced non–small-cell lung cancer (NSCLC) in a community setting, investigators retrospectively reviewed data in the Flatiron Health Database from 2011 to 2016 on 5688 patients (80% were smokers) from 191 community practices with unresectable nonsquamous NSCLC who received at least one line of systemic therapy.

Of these patients, 15.4% received multigene panel sequencing, and 84.6% received only EGFR or ALK testing. Broad-based genomic sequencing evaluated more than 30 genes and was performed prior to third-line therapy, whereas the EGFR and ALK testing was performed at any time.

Of the patients tested, 4.5% received broad-based sequencing–informed targeted therapy, 9.8% had routine EGFR or ALK-targeted therapy, and 85.1% did not receive targeted therapy. One-month mortality was similar with therapy based on broad-based sequencing or routine testing (41.1% and 44.4%, respectively), as was propensity score–matched survival (42.0% and 45.1%), although a simple cohort analysis reported a survival advantage with broad-based sequencing–informed therapy (hazard ratio, 0.69; P<0.001). The authors concluded that survival was not improved with therapy based on broad-based sequencing versus testing for EGFR or ALK alone.

Comment: This study provides important insight into community oncology practice. However, there are some major limitations to the analysis that do not support the authors' conclusions. The study was initiated when there were no FDA-approved tyrosine kinase therapies for ROS-1, BRAFV600E, RET, or MET exon 14 mutations, which may explain why only 36 of 125 patients with broad-based sequencing received targeted therapy and, hence, why there was no significant survival benefit. In addition, the study reported on patients who had broad-based testing prior to third-line therapy. It is well established that patients with oncogenic-driver mutations have improved survival when treated with targeted therapy early on in their disease course. The current testing guidelines from ACP-IASLC-AMP (J Thorac Oncol 2018; 13:323) recommend two testing options for patients with nonsquamous NSCLC: (1) a comprehensive cancer panel including EGFR, ALK, ROS-1, BRAF, MET, ERBB2, RET, and KRAS or (2) targeted testing of EGFR, ALK, ROS-1 then a KRAS single-gene test and, if negative, a second test with an expanded panel (BRAF, MET, ERBB2, RET). In this rapidly developing field where tyrosine kinase inhibitors are now commercially available or are in advanced clinical trials, testing for ERBB2, BRAFV600E, RET, MET exon 14, and NTRK fusion alterations should be highly encouraged.