Prevalence of FGFR2b Protein Overexpression in Advanced Gastric Cancers During Prescreening for the Phase III FORTITUDE-101 Trial

Abstract

Purpose: Fibroblast growth factor receptor 2 isoform IIIb (FGFR2b) protein overexpression is an emerging biomarker in gastric cancer and gastroesophageal junction cancer (GC). We assessed FGFR2b protein overexpression prevalence in nearly 3,800 tumor samples as part of the prescreening process for a global phase III study in patients with newly diagnosed advanced or metastatic GC.

Methods: As of June 28, 2024, 3,782 tumor samples from prescreened patients from 37 countries for the phase III FORTITUDE-101 trial (ClinicalTrials.gov identifier: NCT05052801) were centrally tested for FGFR2b protein overexpression by immunohistochemistry (IHC) and had evaluable results. FGFR2b positivity was defined as both any % tumor cells (TC) and ≥10% TC exhibiting moderate-to-strong (2+/3+) membranous FGFR2b staining. Prevalence was analyzed across patient and sample characteristics.

Results: FGFR2b protein overexpression at any % and ≥10%, 2+/3+ TC positivity was 37.8% (1,428/3,782 [95% CI, 36.2 to 39.3]) and 16.2% (612/3,782 [95% CI, 15 to 17.4]), respectively. Of any %, 2+/3+ TC-positive tumors, 42.9% (612/1,428 [95% CI, 40.3 to 45.4]) were FGFR2b ≥10%, 2+/3+ TC positive. FGFR2b prevalence was not notably different within multiple patient and sample characteristics examined (age, sex, collection method [biopsy v resection], collection site, location of primary tumor, and geographic region).

Conclusion: As of the data cutoff date, we report the largest prevalence assessment of FGFR2b protein overexpression in GC with more than one third (37.8%) of patients with GC exhibiting FGFR2b protein overexpression (any % TC, 2+/3+) by a validated IHC assay. Approximately 16% of patients had FGFR2b protein overexpression in ≥10% of TC. FGFR2b prevalence was similar across geographic regions and within defined patient and sample variables regardless of the level of expression.

FIG 1.

Study design of FORTITUDE-101. ^aAt least 10% of TC with moderate (2+) to strong (3+) membrane staining. Patients were initially eligible with any % of TCs with moderate (2+) to strong (3+) membrane staining; on November 18, 2022, the eligibility criteria were amended to require at least 10% of TC with moderate (2+) to strong (3+) staining. ^bmFOLFOX6 is administered as a combination of oxaliplatin and leucovorin IV infusions. FU is administered as bolus, followed by additional administration as IV infusion. ^cTreatment is until progression. FGFR2b, fibroblast growth factor receptor 2 isoform IIIb; FU, fluorouracil; IHC, immunohistochemistry; IV, intravenous; mFOLFOX6, modified fluorouracil, leucovorin, and oxaliplatin; R, random assignment; TC, tumor cells.

FIG 2.

Representative FGFR2b membranous staining at different intensities. Gastric cancers. (A) Gastric adenocarcinoma, surgical resection from primary lesion. (B) Tumor cells are negative for FGFR2b. (C) Gastric adenocarcinoma, biopsy from the stomach. (D) Cancer cells show partial membrane staining with weak (1+) intensity (arrow). (E) Gastric adenocarcinoma, biopsy from the stomach. (F) Tumor cells have complete or partial membrane staining with weak (1+) to moderate (2+; arrow) intensity. (G) Gastric adenocarcinoma, surgical resection from primary lesion. (H) Tumor cells show strong (3+) membrane staining (arrows) with FGFR2b. FGFR2b, fibroblast growth factor receptor 2 isoform IIIb; H&E, hematoxylin and eosin; IHC, immunohistochemistry.

FIG 3.

Examples of FGFR2b IHC staining with different collection methods. H&E and FGFR2b IHC staining in WSI and 10× magnification. (A) Surgically resected gastric adenocarcinoma. This patient case is positive for FGFR2b with ≥10% of TC with 2+ to 3+ intensity membranous staining. (B) Surgically resected gastric adenocarcinoma. A positive case for any percentage of TC with 2+ to 3+ intensity membranous staining. (C) Liver core-needle biopsies, metastatic gastric adenocarcinoma. More than 10% of TC show moderate (2+) membranous staining and are positive for ≥10%, 2+/3+ FGFR2b protein overexpression. (D) Gastric mucosal biopsies from primary gastric cancer. Some TC show moderate-to-strong membrane staining. This patient case exhibits FGFR2b protein overexpression at any % TC, 2+/3+ while <10% of TC were positive for FGFR2b protein overexpression. FGFR2b, fibroblast growth factor receptor 2 isoform IIIb; H&E, hematoxylin and eosin; IHC, immunohistochemistry; TC, tumor cells; WSI, whole-slide image.

FIG 4.

Prevalence of FGFR2b protein overexpression. ^a95% CI, 60.7 to 63.8. ^b95% CI, 20.3 to 22.9. ^c95% CI, 15.0 to 17.4. FGFR2b, fibroblast growth factor receptor 2 isoform IIIb; TC, tumor cells.

FIG 5.

Prevalence of FGFR2b (any %, 2+/3+ TC positive and ≥10%, 2+/3+ TC positive) by patient and sample characteristic subgroups. (A) FGFR2b protein overexpression prevalence for any %, 2+/3+ TC positivity by patient and sample characteristic subgroups. (B) FGFR2b protein overexpression prevalence for ≥10%, 2+/3+ TC positivity by patient and sample characteristic subgroups. With post hoc analyses using Pearson χ² test, FGFR2b prevalence was comparable (adjusted P value > .05) in subgroups on the basis of the examined factors for patient characteristics. Error bars represent 95% CIs. APAC, Asia-Pacific; EMEA, Europe, Middle East, and Africa; FGFR2b, fibroblast growth factor receptor 2 isoform IIIb; GC, gastric cancer; GEJC, gastroesophageal junction cancer; TC, tumor cells.