Missing the mark in FGFR1‐amplified squamous cell cancer of the lung

Notwithstanding the recent approval by the US Food and Drug Administration of several new treatments for patients with advanced squamous cell lung cancers (SQCLCs), the therapeutic options for patients with this disease remain dishearteningly limited. To understand why, we need only look at the progress made in lung adenocarcinoma (ADCL) as a foil: its advances highlight the widening biologic and therapeutic gulf in the management of these diseases. The issue at hand is molecular diversity: not the presence of it, but the nature of it. Both histologies are marked by somatic alterations that occur across a breadth of signaling pathways and at a variety of signaling depths. However, to our knowledge, actionable oncogenic drivers to date have been identified almost exclusively in ADCLs. Here too is our experience with ADCL normative, defining what actionability means: overall response rates of >50% and substantial extensions in survival. Whereas the defined oncogenic drivers in ADCL typically occur within mutually exclusive subsets of disease, the recurrent genomic alterations implicated in SQCLC occur in an overlapping pattern. The resulting disparity between these two histologies is vast. Greater than 60% of ADCLs bear what appears to be a primary, potentially actionable, oncogenic driver. As of today, in terms of validated targets, effectively 0% of SQCLCs can be said to harbor the same. There was an expectation around the time that The Cancer Genome Atlas published its comprehensive molecular profiling of 178 resected SQCLCs that this would change. With knowledge was to come power, and a burst of parallel activity by investigators across the world did indeed suggest that harnessing this knowledge would lead to dramatic clinical results. Much of the early trial activity focused on fibroblast growth factor receptor 1 (FGFR1) gene amplification. FGFR1 is a member of a family of 4 growth factor receptors that interact with at least 22 mitogenic and hormonal ligands. Downstream signaling occurs through the phosphatidylinositol-3 kinase (PI3K), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) pathways and controls cell migration, growth and proliferation, and embryonic development. FGFR1 amplification as a target was attractive for several reasons. First, the apparent frequency of the event was relatively high: as high as 20% to 25% of SQCLCs, depending on the assay and cutoff values used. Second, FGFR1 amplification had been validated as a druggable target in multiple models, including FGFR1-amplified lung cancer cell lines and SQCLC patientderived xenografts. Third, several small molecule kinase inhibitors already were in development, with many in phase 1 testing. Fourth, the anticipated predictive biomarker, FGFR1 amplification, could be readily assessed by commercial fluorescence in situ hybridization (FISH) probes. It is against this backdrop that Lim et al report the results of a phase 2 trial of dovitinib in patients with advanced SQCLCs harboring FGFR1 amplification in this issue of Cancer. A total of 26 patients were enrolled onto their study, which used a Simon 2-stage design built around a primary endpoint of overall response rate (ORR) (null hypothesis of 5% and an alternative hypothesis of 20%). The patients’ clinical characteristics were typical for the disease: the majority of patients were smokers, all were men, and approximately one-half had received> 1 prior line of therapy. FGFR1 amplification was determined by FISH. Patients with> 5 copies were eligible for the study, with a median number of copies approaching 7 (range, 5-48 copies). The results of the study were disappointing. The ORR was 11.5% (3 of 26 partial responses) with a median progression-free survival of 2.9 months and a median overall survival of 5 months. Notably, tumor profiling of the 3