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.

1st Department of Medicine Laiko General Hospital National and Kapodistrian University of Athens School of Medicine Athens Greece

Amgen Inc Thousand Oaks CA

Department of Biomedical Sciences Humanitas University Pieve Emanuele Milan Italy

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute and Masaryk University Faculty of Medicine Brno Czech Republic

Department of Gastrointestinal Medical Oncology Harbin Medical University Cancer Hospital Harbin China

Department of Gastrointestinal Oncology National Cancer Center Hospital East Kashiwa City Japan

Department of Internal Medicine Yonsei Cancer Center Yonsei University College of Medicine Seoul South Korea

Division of Hematology Oncology Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA

Division of Medical Oncology Department of Medicine Faculty of Medicine Siriraj Hospital Mahidol University Bangkok Thailand

Fundacion Cardiovascular de Colombia Bucaramanga Colombia

Hematology Oncology and Transfusion Medicine Center Vilnius University Hospital Santaros Clinics Vilnius Lithuania

Hospital Universitario Miguel Servet Zaragoza Spain

Izmir Katip Celebi Universitesi Ataturk Egitim ve Arastirma Hastanesi Menemen Turkey

Medical Oncology and Haematology Unit IRCCS Humanitas Research Hospital Humanitas Cancer Center Rozzano Milan Italy

North Estonia Medical Centre Foundation Tallinn Estonia

Roche Diagnostics Solutions Tucson AZ

JCO Precis Oncol. 2025 Apr;9:e2500223. doi: 10.1200/PO-25-00223. PubMed

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Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–263. PubMed

Lordick F, Carneiro F, Cascinu S, et al. Gastric cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33:1005–1020. PubMed

Gullo I, Carneiro F, Oliveira C, et al. Heterogeneity in gastric cancer: From pure morphology to molecular classifications. Pathobiology. 2017;85:50–63. PubMed

Sato Y, Okamoto K, Kawano Y, et al. Novel biomarkers of gastric cancer: Current research and future perspectives. J Clin Med. 2023;12:4646. PubMed PMC

Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–697. PubMed

Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: Interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. 2023;402:2197–2208. PubMed

Wang F, Ba Y. Treatment strategies for patients with HER2-positive gastric cancer. Cancer Biol Med. 2024;20:934–941. PubMed PMC

Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet. 2021;398:27–40. PubMed PMC

Shitara K, Ajani JA, Moehler M, et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022;603:942–948. PubMed PMC

Rha SY, Oh DY, Yañez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): A multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24:1181–1195. PubMed

Gordon A, Johnston E, Lau DK, et al. Targeting FGFR2 positive gastroesophageal cancer: Current and clinical developments. Onco Targets Ther. 2022;15:1183–1196. PubMed PMC

Yashiro M, Kuroda K, Masuda G, et al. Clinical difference between fibroblast growth factor receptor 2 subclass, type IIIb and type IIIc, in gastric cancer. Sci Rep. 2021;11:4698. PubMed PMC

Han N, Kim MA, Lee HS, et al. Evaluation of fibroblast growth factor receptor 2 expression, heterogeneity and clinical significance in gastric cancer. Pathobiology. 2015;82:269–279. PubMed

Ahn S, Lee J, Hong M, et al. FGFR2 in gastric cancer: Protein overexpression predicts gene amplification and high H-index predicts poor survival. Mod Pathol. 2016;29:1095–1103. PubMed

Tojjari A, Nagdas S, Saeed A, et al. Deciphering the FGFR2 code: Innovative targets in gastric cancer therapy. Curr Oncol. 2024;31:4305–4317. PubMed PMC

Wainberg ZA, Enzinger PC, Kang YK, et al. Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): A randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2022;23:1430–1440. PubMed

Wainberg ZA, Kang YK, Lee KW, et al. Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: Final analysis of the randomized phase 2 FIGHT trial. Gastric Cancer. 2024;27:558–570. PubMed PMC

Bemarituzumab or placebo plus chemotherapy in gastric cancers with fibroblast growth factor receptor 2b (FGFR2b) overexpression (FORTITUDE-101) 2024. https://clinicaltrials.gov/study/NCT05052801

Gemo AT, Deshpande AM, Palencia S, et al. FPA144: A therapeutic antibody for treating patients with gastric cancers bearing FGFR2 gene amplification. Cancer Res. 2014;74:5446. abstr 5446.

Takatsu Y, Hiki N, Nunobe S, et al. Clinicopathological features of gastric cancer in young patients. Gastric Cancer. 2016;19:472–478. PubMed

Kim KC, Koh YW, Chang HM, et al. Evaluation of HER2 protein expression in gastric carcinomas: Comparative analysis of 1414 cases of whole-tissue sections and 595 cases of tissue microarrays. Ann Surg Oncol. 2011;18:2833–2840. PubMed

Cho EY, Park K, Do I, et al. Heterogeneity of ERBB2 in gastric carcinomas: A study of tissue microarray and matched primary and metastatic carcinomas. Mod Pathol. 2013;26:677–684. PubMed

Park DI, Yun JW, Park JH, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci. 2006;51:1371–1379. PubMed

Shan L, Ying J, Lu N. HER2 expression and relevant clinicopathological features in gastric and gastroesophageal junction adenocarcinoma in a Chinese population. Diagn Pathol. 2013;8:76. PubMed PMC

Yano T, Doi T, Ohtsu A, et al. Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep. 2006;15:65–71. PubMed

Yoon HH, Shi Q, Sukov WR, et al. Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas. Clin Cancer Res. 2012;18:546–554. PubMed PMC

Schoemig-Markiefka B, Eschbach J, Scheel AH, et al. Optimized PD-L1 scoring of gastric cancer. Gastric Cancer. 2021;24:1115–1122. PubMed PMC

Chao J, Fuchs CS, Shitara K, et al. Assessment of pembrolizumab therapy for the treatment of microsatellite instability–high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials. JAMA Oncol. 2021;7:895–902. PubMed PMC

Shitara K, Xu RH, Ajani JA, et al. Global prevalence of claudin 18 isoform 2 in tumors of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Gastric Cancer. 2024;27:1058–1068. PubMed PMC

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NCT05052801