AUTHOR=Zhao Yiming , Wang Shuyuan , Yang Zhengyu , Dong Yu , Wang Yanan , Zhang Lele , Hu Hai , Han Baohui 

TITLE=Co-Occurring Potentially Actionable Oncogenic Drivers in Non-Small Cell Lung Cancer

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.665484

DOI=10.3389/fonc.2021.665484

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Several oncogenic drivers in non-small cell lung cancer (NSCLC) are considered actionable with available or promising targeted therapies. Although targetable drivers rarely overlap with each other, there were a minority of patients harboring co-occurring actionable oncogenic targets, whose clinical characteristics and prognosis are not yet clear.</p></sec><sec><title>Methods</title><p>A total of 3,077 patients with NSCLC who underwent molecular analysis by NGS were included, and their demographic and clinical data were retrospectively collected.</p></sec><sec><title>Results</title><p>Our study found that the frequency of NSCLC patients harboring co-occurring potentially actionable alterations was approximately 1.5% (46/3077); after excluding patients with <italic>EGFR</italic>-undetermined mutations, the incidence was 1.3% (40/3077); 80% (37/46) harbored both <italic>EGFR</italic> mutations and other potentially actionable drivers such as <italic>MET</italic> amplification (21.6%; 8/37) and alterations in <italic>ERBB2</italic> including mutations (27%; 10/37) and amplification (21.6%; 8/37); other combinations of potentially actionable drivers including alterations in <italic>ERBB2</italic>, <italic>KRAS</italic>, <italic>MET</italic>, <italic>ALK</italic>, and <italic>RET</italic> were also identified. Additionally, <italic>de novo MET</italic>/<italic>ERBB2</italic> amplification in patients harboring <italic>EGFR</italic>-mutant NSCLC treated with first-generation <italic>EGFR</italic> tyrosine kinase inhibitors (TKIs) was associated with shorter PFS (p &lt; 0.05). The efficacy of TKIs in NSCLC patients harboring other co-occurring potentially actionable drivers varied across different molecular subtypes.</p></sec><sec><title>Conclusions</title><p>Approximately 1.5% of NSCLCs harbored co-occurring potentially actionable oncogenic drivers, commonly involving <italic>EGFR</italic> mutations. Co-occurring actionable targets may impact the efficacy of TKIs; therefore, future clinical trials in these patients should be anticipated to tailor the combination or sequential treatment strategies.</p></sec>