INTRODUCTION
Gastric cancer (GC) is the world’s third leading cause of cancer death and the fifth most serious malignancy for both sexes, responsible for more than 1 million new diagnoses and nearly 800,000 deaths annually.1 Most GCs are diagnosed at advanced stages due to late manifestations of symptoms with nausea, vomiting, lack of appetite, early satiety, weight loss and ascites.2,3
Standard of care systemic treatment options in Gastric adenocarcinomas have been largely limited to combination 5-Fluorouracil, Platinum agents, Taxanes and Irinotecan to a smaller extent. These chemotherapy agents remain the mainstay of systemic treatments and are used in a perioperative setting despite the advent of various targeted agents and immune checkpoint inhibitors (ICI). The use of targeted agents in gastric cancers was initially restricted to Trastuzumab, based on HER2 status determined by IHC. In recent years, other targeted agents such as Larotrectinib have been approved (as part of labelled pan-solid tumor indication) in addition to ICIs such as Nivolumab (based on CPS), Pembrolizumab (based on MSI / MMR status). Angiogenesis inhibitors have remained largely absent in treatment of gastric cancers until the approval of Ramucirumab, a monoclonal antibody (mAb) which targets VEGFR2.
Among other Angiogenesis factors, Fibroblast growth factor receptors (FGFR) are being studied as potential targets in varied different kinds of solid tumors including gastric cancers.4 FGFR is a transmembrane receptor family with four members (FGFR 1–4) that bind to fibroblast growth factors (FGFs)5, and play important developmental roles, from early embryogenesis to organ formation. A study of 4,853 tumors by next-generation sequencing (NGS), aberrant FGFR3 have been identified in 22% of Urothelial Carcinomas (UC), 4% of glioma, 3% of carcinoma of unknown primary and endometrial carcinoma, 2% of pancreatic, ovarian, and gastric carcinomas.6 A recent study identified the FGFR3/AKT axis as an escape pathway responsible for trastuzumab resistance in gastric cancer, thus indicating the inhibition of FGFR3 as a potential strategy to modulate this resistance.7
Pazopanib is a non-selective FGFR inhibitor described as a multi-targeted kinase inhibitor with inhibitory effects on VGEF (vascular endothelial growth factor), PEGF (platelet endothelial growth factor), stem-cell factor c-kit, and other factors. It also has been known to have FGFR directed activity as discussed in a case report which identified pazopanib as a targeted agent that may be considered for the treatment of patients with hormone positive, endocrine therapy–resistant metastatic breast cancer who harbour FGFR1 amplifications.8 Pazopanib, has shown promise in mUC particularly in patients with FGFR gene amplifications.9 Pazopanib is the Standard of Care treatment (labelled indication) for Renal Cell Carcinomas, Soft Tissue Sarcomas and Gastrointestinal Stromal Tumors (GIST).10Pazopanib has been tested with combination chemotherapy in advanced gastric cancer with promising results.11
Here, we report a case of gastric cancer that had an excellent durable response after FGFR3 directed therapy in combination with chemotherapy designed based on Encyclopaedic Tumor Analysis (ETA) which offers integrative multi-analyte investigations of the tumor and captures in depth information about the multi-layered tumor interactome.12