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