FGFR2 overexpression

In conclusion, CAFs inhibited ferroptosis to decrease DDP sensitivity in NPC through secreting FGF5 and activating downstream FGFR2/Nrf2 signaling. The therapeutic strategy targeting FGF5/FGFR2 axis from CAFs might augment DDP sensitivity, thus decreasing the side effects of DDP in NPC treatment.

P1, N=80, Recruiting, Amgen | Trial primary completion date: Nov 2026 --> Mar 2026

Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%...CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials...Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.

P1, N=80, Recruiting, Amgen | Trial completion date: Sep 2027 --> Apr 2028 | Trial primary completion date: May 2026 --> Nov 2026

Decreased expression of miR-889-3p in OSCC tumours suggests that miR-889-3p functions as a tumour suppressor gene. Overexpression of FGFR2 further proves the role of miR-889-3p in the regulation of the FGFR2 pathway. This was further confirmed by showing differences in miR-889-3p expression in positive and negative LNM cases.

P1/2, N=303, Recruiting, Amgen | Trial completion date: Jul 2026 --> Jun 2027 | Trial primary completion date: Oct 2024 --> Sep 2025

Collectively, our findings reveal that the chromosomal conformational alterations, in addition to the well-known genetic mutations, are critical for PDAC tumorigenesis.

Among them, trastuzumab, as the first targeted drug for gastric cancer, effectively inhibits the proliferation and metastasis of tumor cells by targeting overexpressed HER2, and has become the standard treatment for HER2-positive gastric cancer patients. Ramucirumab, on the other hand, inhibits tumor angiogenesis by targeting VEGFR2 and has been used as second-line therapy for advanced gastric cancer patients. In addition, bemarituzumab targets overexpressed FGFR2, while zolbetuximab targets overexpressed CLDN18.2, significantly extending progression-free survival and overall survival in patients with gastric cancer in clinical trials. This article reviews the roles of tumor driver genes in the progression of gastric cancer; and the treatment strategies for gastric cancer based on targeting HER2, VEGF, FGFR2, CLDN18.2, MET and other tumor driver genes, aiming to provide reference for clinical application of targeted therapy for gastric cancer.

In FGFR2b-positive advanced GC, the combination of bemarituzumab-mFOLFOX6 led to numerically longer median PFS and OS compared with mFOLFOX6 alone. Efficacy was more pronounced with FGFR2b overexpression in ≥ 10% of tumor cells. Confirmatory phase 3 trials are ongoing (NCT05052801, NCT05111626).

P1, N=80, Recruiting, Amgen | Phase classification: P1b --> P1 | N=30 --> 80

our findings suggest that concurrent amplification of FGFR2 and MET in GC patients is associated with clinical aggressiveness and may contribute to non-responsiveness to chemotherapy or targeted therapy.

P1/2, N=303, Recruiting, Amgen | Phase classification: P1b/2 --> P1/2

In this single-arm, multi-center, phase 2 study, eligible patients had metastatic untreated HER2-negative gastric adenocarcinoma with centrally confirmed expression of PD-L1 (CPS≥5; DAKO 28-8) and FGFR2 (moderate (2+) and strong (3+) membranous staining in more than 1% of tumor cells; Abсam EPR24075-418). Patients received nivolumab 360 mg with CapeOX (capecitabine and oxaliplatin) every 3 weeks... An interim analysis demonstrates modest efficacy and an acceptable safety profile of nivolumab in combination with chemotherapy in patients with FGFR2-positive, PD-L1-positive metastatic GC. Further follow-up is ongoing. 1.

Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%-2.6% and 1.5%-2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.

P1b, N=180, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | Trial completion date: Mar 2026 --> Apr 2024 | Trial primary completion date: Mar 2025 --> Apr 2024

P1b, N=180, Recruiting, Amgen | Trial completion date: Oct 2025 --> Mar 2026 | Trial primary completion date: Oct 2024 --> Mar 2025

P1b, N=30, Recruiting, Amgen | Trial completion date: Mar 2025 --> Jan 2026 | Trial primary completion date: Dec 2023 --> Oct 2024

P2; N=23; Recruiting; Sponsor:Kidney Cancer Research Bureau

After 24 months of follow-up, patients with FGFR2b overexpression treated with bemarituzumab + mFOLFOX6 continued to show clinically meaningful outcomes over patients treated with placebo + mFOLFOX6; more pronounced efficacy was observed in patients with ≥10% of tumor cells with 2+/3+ FGFR2b IHC staining intensity. Randomized phase 3 trials focused on patients with ≥10% of tumor cells to confirm the observed clinical benefit of bemarituzumab are ongoing.

Animal experiments on a carbon tetrachloride (CCl) mouse model and a nonalcoholic steatohepatitis mouse model indicate that CYN treatment reduces liver fibrosis during fibrosis formation. These findings suggest that CYN prevents liver fibrosis formation at the cell level and in mouse models.

In vivo studies using patient-derived xenograft (PDX) models of high-risk NB (MYCN-amplified and ALKF1174L mutant) showed that combinations of either ponatinib or erdafitinib with lorlatinib decreased tumour growth and increased survival compared to PDXs treated with vehicle or either agent alone. In conclusion, these findings suggest that FGFR2 alters NB sensitivity to lorlatinib and modulation of this pathway in combination with ALK inhibition is a promising approach to improve NB treatment response and ultimately patient survival.

NXP800, a HSF1 inhibitor, demonstrated significant therapeutic activity in a cholangiocarcinoma PDX. Further studies are needed and being performed to determine the role of HSF1 inhibition in human cholangiocarcinoma.

Moreover, the combination of a PAI-1 inhibitor and anti-PD-1 therapy exhibited superior antitumor activity in mice. These findings offer novel insights into the molecular mechanisms underlying tumor deterioration and provide potential therapeutic targets for CRC treatment.

P1b, N=180, Recruiting, Amgen | Trial completion date: Aug 2025 --> Nov 2025

We demonstrated that FGFR2 high expression was the independent prognostic factor for recurrence of resected ICC.

P1b, N=180, Recruiting, Amgen | N=108 --> 180 | Trial primary completion date: Feb 2024 --> Jul 2024

FGFR2 is overexpressed in one third of patients, and its targeting with a specific monoclonal antibody bemarituzumab showed a significant improvement in survival...The combination of zolbetuximab and chemotherapy provides a survival benefit, correlated with the intensity of CLDN 18.2 expression...Finally, with the recent advent of immunotherapy, one of the future challenges will be to optimize it through combination strategies with targeted therapies. The combination of anti-angiogenic and immunotherapy seems promising in gastric cancer.

In this exploratory phase 2 study, despite no statistically significant improvement in progression-free survival, treatment with bemarituzumab showed promising clinical efficacy. Confirmatory phase 3 trials of bemarituzumab plus mFOLFOX6 powered to demonstrate statistical significance are being investigated in patients with previously untreated, FGFR2b-overexpressing, advanced gastric or gastro-oesophageal junction adenocarcinoma.

Circ_0008234 mediated GBC via the miR-204-5p/FGFR2 axis, providing a novel targeted therapy for gallbladder carcinoma.

Adding bemarituzumab, a first-in-class, anti-FGFR2b monoclonal antibody to mFOLFOX6 improved outcomes, indicating FGFR2b as a promising therapeutic target...FGFR2b overlap with PD-L1 is shown in the table. Table: 384P Conclusions Over 20% of sqNSCLC tissue samples overexpress FGFR2b, making it a promising therapeutic target for agents such as bemarituzumab.

P3, N=516, Recruiting, Amgen | Trial completion date: Jan 2025 --> Aug 2025 | Trial primary completion date: Jan 2025 --> Aug 2025

Our work sheds light on the potential role of FGFR2 in the development of ccRCC, suggesting that FGFR2 may serve as a prognostic marker and potential therapeutic target for patients with ccRCC.

In vitro analyses showed that FGF7/FGFR2 signalling: (a) abolished the effect of P4 on E2-promoted 3D cell growth and response to tamoxifen; (b) regulated ER and PR expression and activity; (c) increased formation of ER-PR complexes; and (d) reversed P4-triggered deregulation of ER-dependent genes. Our results demonstrate for the first time that the FGF7/FGFR2-JunB axis abolishes the modulatory effects of PR on ER-associated biological functions in premenopausal ER+ BCa. This may provide foundations for a better selection of patients for FGFR-targeting therapeutic strategies.

P2, N=155, Completed, Five Prime Therapeutics, Inc. | Active, not recruiting --> Completed

P3, N=702, Ongoing, Amgen Inc.

P1b, N=108, Recruiting, Amgen | Trial primary completion date: Jul 2024 --> Feb 2024

Our study suggested that FGFR2 expression can be used to classify HCC patients based on HCV infection. This FGFR2-based classification may lead to new therapeutic strategies against HCV-positive HCC subtypes.

In conclusion, SOX9 and FGF7 were prognostic biomarkers of CCA. WNT3A-TCF7-SOX9 axis could induce pemigatinib resistance in two independent pathways: (1)SOX9 directly promotes FGFR2 transcription and expression; (2)SOX9 elevates FGF7 expression, which could be secreted from CCA cells and activates FGFR2 phosphorylation in an autocrine pathway.

HER2-positive GC patients, without overexpression of FGFR2, exhibited an improved prognosis and response rate to trastuzumab combination chemotherapy. Assessment of intra-tumoral FGFR2 expression could be helpful in predicting the prognosis and response to trastuzumab in HER2-positive GC patients.

P1b, N=108, Recruiting, Amgen | Not yet recruiting --> Recruiting | Trial completion date: Feb 2025 --> Jul 2025 | Trial primary completion date: Feb 2024 --> Jul 2024

P1b, N=702, Recruiting, Amgen | Not yet recruiting --> Recruiting

P3, N=516, Recruiting, Amgen | Not yet recruiting --> Recruiting