In Search of an Oncogene Driver for Squamous Lung Cancer

Checkpoint inhibitor immunotherapies are playing an increasing role in the therapeutic armamentarium of advanced stage non–small cell lung cancer, regardless of histologic subtype. By contrast, advances in targeted therapy have largely bypassed patients with squamous cell cancers. Identification of new treatable oncogenic drivers has predominately been confined to the nonsquamous subset, or more specifically, adenocarcinoma. The favorable results of tyrosine kinase inhibitor (TKI) therapy among patients whose cancers exhibit these anomalies (eg, alterations in EGFR, ALK, ROS1, BRAF, MET, or RET) have resulted in their inclusion in current guidelines for molecular testing and regulatory approval for associated therapies in most of these genomic subsets. By comparison, no substantial progress has been made in the clinical application of targeted therapy for patients with squamous cancers during this same time, despite the discovery of a number of potential molecular targets and the initiation of associated clinical trials. For example, potentially actionable abnormalities in phosphoinositide 3-kinase (PI3K), cyclin-dependent kinases (CDK) 4/6, and fibroblast growth factor receptor (FGFR) were present in 8%, 19%, and 16% of squamous lung cancers, respectively, in patients screened for the Lung-MAP (S1400) master protocol in advanced squamous lung cancer. Unfortunately, the recently completed Lung-MAP genotype-directed substudies on each of these 3 targets, S1400B (PI3K-directed TKI), S1400C (CDK 4/6-directed TKI), and S1400D (FGFR-directed TKI), failed to reach predetermined efficacy endpoints, with response rates of only 4%, 6%, and 7% and median overall survival of 5.9, 7.2, and 7.5 months, respectively.

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