# Targeting FGFR Alterations in Gastroesophageal Cancer

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $716,314

## Abstract

PROJECT SUMMARY
Gastroesophageal adenocarcinoma (GEA) is the 4th leading cause of cancer deaths worldwide with a median
survival of 6.2 months for patients who present with metastatic disease. Up to 10% of GEA patients show
activation of fibroblast growth factor 2 (FGFR2) signaling due to FGFR2 gene amplification and/or fusion. FGFR2
overexpression is associated with lower response to chemotherapy and a poor prognosis. Clinical trials targeting
FGFR2 in GEA include the use of both antibodies and small molecules. A Phase 2 clinical trial combining
standard-of-care chemotherapy with an anti-FGFR2 monoclonal antibody (bemarituzumab) showed meaningful
but not yet statistically significant improvements in progression-free survival. Recent clinical data demonstrate
significant improvements in progression-free survival in GEA patients treated with an FGFR2 selective tyrosine
kinase inhibitor (TKI), RLY4008. However, resistance to TKIs emerge rapidly and we have identified on-target
resistance mutations in the FGFR2 kinase domain in GEA patients who progress on RLY4008. One approach to
overcome TKI resistance mutations is through combination therapy with antibody drug conjugates (ADC).
Standard antibodies, including bemarituzumab, do not significantly attenuate FGFR2 signaling likely due to the
bivalent nature of the antibodies that maintain receptor dimers in the absence of ligand. Biparatopic antibodies
(BipAbs) however, recognize two distinct epitopes on the same protein leading to enhanced pharmacologic
activity. Thus, we created 15 BipAbs from combinations of 6 FGFR2 antibodies targeting the extracellular domain
of FGFR2 which is retained in both FGFR2 amplified and FGFR2 fusion-positive GEA. Two of our FGFR2 BipAbs
show markedly increased avidity, receptor degradation mediated by lysosomal pathways, and in vitro and in vivo
activity against FGFR2-fusions. Furthermore, initial experiments show these two bipAbs are active in GEA cell
lines as ADCs. The significant clinical activity of the ADC trastuzumab-deruxtecan in HER2+ GEA suggests that
this linker-payload combination targeting FGFR2 should be tested in FGFR2+ GEA. In this proposal, we will 1)
utilize novel immune competent mouse models of FGFR2 amplified GEA or FGFR2 fusion-positive GEA to:
develop and test highly efficacious FGFR2 bipAbs and antibody-drug conjugates alone or in combination with
immune checkpoint inhibitors, and 2) develop combination strategies with FGFR2 bipAbs and TKIs by
understanding the mechanisms of resistance to FGFR2 selective TKI. We hypothesize that both approaches will
lead to enhanced responses to FGFR2 TKIs and delay the emergence of TKI resistance.

## Key facts

- **NIH application ID:** 10999105
- **Project number:** 1R01CA294689-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** NABEEL El-BARDEESY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $716,314
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999105

## Citation

> US National Institutes of Health, RePORTER application 10999105, Targeting FGFR Alterations in Gastroesophageal Cancer (1R01CA294689-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10999105. Licensed CC0.

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