bemarituzumab (AMG 552)

P1, N=180, Active, not recruiting, Amgen | Phase classification: P1b --> P1

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

Other targeted agents, such as bemarituzumab and DKN-01, are under active investigation. As new agents are incorporated into the treatment continuum, the questions of biomarker overlap, tumor heterogeneity, and toxicity management will need to be addressed.

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

Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.

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

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

Sponsored by No funding sources reported Background: Monoclonal antibody (Nivolumab, Trastuzumab, Bemarituzumab) with chemotherapy has shown benefit for patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. In summary, the use of Zolbetuximab alongside standard chemotherapy reduces mortality and disease progression, although it might increase the risk for grade ≥ 3 treatment-emergent AEs.

P3, N=528, Recruiting, Amgen | Phase classification: P1b --> P3

Our findings suggest that FGFR2b-targeted therapy, specifically when used in combination with chemotherapy (bemarituzumab_chemo), exhibited the greatest efficacy. This was followed by immunotherapy-based combination regimens (CPS ≥5, Sintilimab_chemo). Further, targeted combination therapy featuring CLAUDIN 18.2 (zolbetuximab_chemo) appeared beneficial based on individual patient characteristics. In the case of HER2-positive patients, the trastuzumab_chemo regimen is recommended, as most existing studies have excluded this subpopulation. These results have significant implications for both clinical decision-making and patient care in the realm of advanced gastric or gastroesophageal cancer treatment.

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=528, Recruiting, Amgen | Trial completion date: Jan 2027 --> Sep 2026 | Trial primary completion date: Jan 2027 --> Sep 2026

P1b, N=528, Recruiting, Amgen | Trial completion date: Sep 2026 --> Jan 2027 | Trial primary completion date: Sep 2026 --> Jan 2027

P3, N=516, Recruiting, Amgen | Trial completion date: Oct 2026 --> Aug 2025 | Trial primary completion date: Oct 2026 --> Aug 2025

P1b, N=528, Recruiting, Amgen | Trial completion date:Jan 2027 --> Sep 2026 | Trial primary completion date: Jan 2027 --> Sep 2026

P3, N=516, Recruiting, Amgen | Trial completion date: Aug 2025 --> Oct 2026 | Trial primary completion date: Aug 2025 --> Oct 2026

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

P1, N=6, Completed, Amgen

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.

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

P1b, N=528, Recruiting, Amgen | Trial completion date: May 2026 --> Jan 2027 | Trial primary completion date: May 2026 --> Jan 2027

CME Provider and Supporter(s): This event is organized and accredited by Research to Practice and supported through educational grants provided by Astellas, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Daiichi Sankyo Inc, and Lilly. Published findings with and optimal integration of ramucirumab into current clinical algorithms for metastatic gastric/GEJ cancer; role of this agent for patients experiencing disease progression on an immune checkpoint inhibitor Rationale for, available data with and ongoing investigation of novel combination approaches (eg, ramucirumab with TAS-102 or anti-PD-1 antibodies) Biologic rational for targeting claudin 18.2 in gastric/GEJ cancer; mechanism of action of and early efficacy and safety data with zolbetuximab for advanced gastric/GEJ adenocarcinoma with claudin 18.2 expression Emerging positive findings from the Phase III SPOTLIGHT study of first-line zolbetuximab in combination with chemotherapy for patients with claudin 18.2-positive metastatic gastric/GEJ cancer Mechanism of action of bemarituzumab; available efficacy and safety data with and ongoing Phase III evaluation of first-line bemarituzumab/chemotherapy for FGFR2b-positive metastatic gastric/GEJ cancer Other promising novel agents and strategies under investigation for HER2-negative gastric/GEJ cancer

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.

A selective FGFR2b monoclonal antibody bemarituzumab is currently being investigated in the first phase III randomized trial for patients with first line advanced GC, which may change the treatment paradigm for FGFR2b positive GC...Precision medicine is part of the wider approach in gastrointestinal cancers; however, it can be challenging due to heterogeneity and here circulating tumour DNA (ctDNA) for patient selection may have future clinical utility. In our review, we outline the FGFR pathway and focus on the developments and challenges of targeting FGFR2 driven gastroesophageal cancers.

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

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

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

Recently, the impressive results of two phase II FAST and FIGHT trials demonstrate proof-of-concept, suggesting that anti-CLDN18.2 antibody (zolbetuximab) and FGFR2-IIIb antibody (bemarituzumab) are promising approaches for patients with CLDN18.2-positive and FGFR2-IIIb-positive GC, respectively. In this review, we summarize the clinicopathological features and molecular profiles of DGC and highlight a potential therapeutic target based on the findings of pivotal clinical trials.

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

P1b, N=108, Not yet recruiting, Amgen