Utility of comprehensive genomic profiling in directing treatment and improving patient outcomes in advanced non-small cell lung cancer

Background: With the identification of new targetable drivers and the recent emergence of novel targeted drugs, using comprehensive genomic profiling in lieu of the routine testing for classic drivers in the clinical care for advanced NSCLC has been increasingly advocated. However, the key assumption justifying this practice, that comprehensive genomic profiling could lead to effective anticancer therapies and improve patient outcomes, remains unproved. Methods: Comprehensive genomic profiling was prospectively applied in 1564 advanced NSCLC patients to identify potentially actionable genomic alterations. Patients were assigned to genotype-matched targeted therapies or nonmatched therapies based on the profiling results. Its utility in directing treatments was determined by the proportion of patients receiving genotype-matched targeted therapies and the proportion of patients being enrolled into genotype-matched clinical trials. Its impacts on patient outcomes were assessed by comparing progression-free survival (PFS) and overall survival (OS) between patients who received a genotype-matched and nonmatched therapy. Results: From October 2016 to October 2019, tumor genomic profiles were established in 1166 patients, leading to a matched targeted therapy in 37.7% (n = 440) and a genotype-matched trial enrollment in 20.9% of patients (n = 244). Potentially actionable alterations were detected in 781 patients (67.0%). For these patients, a genomic profiling-directed matched therapy significantly improved PFS (9.0 months vs 4.9 months, P < 0.001) and OS (3.9 years vs 2.5 years, P < 0.001) compared with a nonmatched therapy. Excluding patients with standard targeted therapies, genomic profiling led to a matched targeted therapy in 16.7% (n = 24) and a matched trial enrollment in 11.2% (n = 16) of patients. No PFS (4.7 months vs 4.6 months, P = 0.530) or OS (1.9 years vs 2.4 years, P = 0.238) benefit was observed with the use of genotype-matched targeted therapies in this population. Conclusions: Comprehensive genomic profiling is of clinical utility in assisting treatment selection, facilitating clinical trial enrollment, and improving patient outcomes in advanced NSCLC. However, for patients carrying alterations without standard-of-care targeted drugs, the interpretation of genomic profiling results should be careful given the low likelihood of benefit from the investigational or off-label use of targeted therapies in this population in the current treatment la