Molecular Markers to Predict Response to Selective Fibroblast Growth Factor Receptor Inhibitors (fgfrinh) in Patients (pts) with FGFR-amplified (amp) or Mutated (mut) Tumors.

2581 Background: Several FGFR and ligand (11q) alterations have been described in cancer. While FGFR fusions are recognized biomarkers of response to FGFRinh, it is still unclear to what extent FGFRamp, FGFR mRNA high expression (mRNAh) or FGFRmut predict sensitivity in the clinic. Methods: Retrospective analysis of pts with molecularly-selected FGFRamp/mRNAh/mut tumors treated with FGFRinh in phase 1 trials at our institution. Mut were detected with IlluminaÒ or Foundation OneÒ. FGFR1-2amp were analyzed by in situ hybridization and mRNA levels by qRT-PCR or nCounterÒ. Clinical benefit (ClinBen) was defined as any tumor shrinkage plus disease control for ³ 4 months (m). Time to progression (TTP) was defined as time between start of FGFRinh and end for any cause. Results: From 2011 to 2016, 36 pts with FGFRamp(25)/mRNAh(5)/mut(6) received an FGFRinh (irreversible- [11 cases (c)] or reversible-FGFR1-4inh [23 c], isoform-specific FGFRinh [3 c] or combo with PI3Kinh [1 c]). Median age 55 yrs (34-76); median prior palliative lines was 3 (0-8); tumor types: breast (17), colorectal (3), esophagus (3), liver (3), lung (3), others (7). Median TTP was 1.67 m (CI 95%; 1.40-2.87). In the FGFRamp/mRNAh population (30), 7 pts achieved ClinBen (23%). 4 out of these seven pts had mRNAh (1 FGFR2amp breast with FGFR2 mRNAh, 1 bladder FGFR3 mRNAh and 2 liver FGFR4 mRNAh without known amp), and 2 pts harboured 11q co-amplification (1 FGFR2amp breast, 1 FGFR2amp head and neck). There was no correlation between ClinBen and level of FGFRamp in the overall population (p = 0.51) or in the breast cancer group (p = 0.29). Of 6 FGFRmut pts, one with bladder cancer had ClinBen (clonal oncogenic FGFR3 S249C). The remaining 5 unresponsive FGFRmut pts had subclonal events, some of these FGFRmut were of unknown functional significance, and had coexisting oncogene mut in MAPK or PI3K pathways. Conclusions: Our results suggest that ClinBen with FGFRinh in the FGFRamp setting is enriched in pts with high mRNA expression and/or ligand co-amplification, and in the FGFRmut population may be dependent on clonality and functionality of the event and co-existence of driver mut.