FGFR2b positive

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).

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

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.

MODULE 1: Current and Future Front-Line Management of Advanced Gastric and Gastroesophageal Junction (GEJ) Cancer Available efficacy and safety results from the Phase III CheckMate 649 study comparing first-line nivolumab in combination with chemotherapy or ipilimumab to chemotherapy alone for advanced gastric/GEJ adenocarcinoma; FDA approval and patient selection for up-front nivolumab/chemotherapy Mechanism of action of sintilimab; recently presented results from the Phase III ORIENT-16 trial comparing sintilimab with chemotherapy to chemotherapy alone as first-line treatment Biologic rationale for targeting claudin 18.2 in gastric/GEJ cancers; mechanism of antitumor activity of zolbetuximab Available efficacy and safety findings with first-line zolbetuximab/chemotherapy in patients with advanced claudin 18.2-positive gastric/GEJ adenocarcinoma; ongoing Phase III SPOTLIGHT and GLOW studies Frequency of FGFR2b overexpression in gastroesophageal cancers; mechanism of action of bemarituzumab Major efficacy and safety data from the Phase II FIGHT trial evaluating bemarituzumab/chemotherapy versus chemotherapy alone as first-line therapy for patients with FGFR2b-positive metastatic gastric/GEJ cancer; FDA breakthrough therapy designation MODULE 2: Contemporary Management of HER2-Positive Advanced Gastric and GEJ Cancer Principal outcomes from the Phase III KEYNOTE-811 trial supporting the FDA approval of first-line pembrolizumab/trastuzumab/chemotherapy for metastatic HER2-positive disease Updated results, including overall survival outcomes, from the Phase II DESTINY-Gastric01 study of trastuzumab deruxtecan (T-DXd) for patients with progressive HER2-positive gastric/GEJ cancer FDA approval of T-DXd for patients with HER2-positive gastric/GEJ cancer who have previously received a trastuzumab-based regimen; optimal incorporation into routine practice Recently presented efficacy and safety findings from the Phase II DESTINY-Gastric02 trial evaluating T-DXd in Western patients with HER2-positive gastric/GEJ cancer previously treated with a trastuzumab-based regimen Ongoing studies with T-DXd in earlier lines of treatment and/or in combination with other systemic therapies MODULE 3: Selection and Sequencing of Therapy for Relapsed Gastric and GEJ Cancer Optimal integration of ramucirumab into current clinical algorithms for metastatic gastric/GEJ cancer Available data with and ongoing investigation of novel ramucirumab-combination regimens Clinical research supporting the use of TAS-102 for heavily pretreated metastatic gastric/GEJ cancer; patient selection for treatment with TAS-102 Current role, if any, of anti-PD-1 monotherapy for patients with recurrent metastatic gastric/GEJ cancer; clinical implications of the voluntary withdrawal of third-line pembrolizumab Other promising agents and strategies under investigation for advanced gastric/GEJ cancer MODULE 4: Key Findings Informing the Treatment of Localized and Advanced Esophageal Cancer Design, eligibility criteria and primary findings from the Phase III KEYNOTE-590 study leading to the FDA approval of first-line pembrolizumab/chemotherapy for advanced esophageal and GEJ cancer; patient selection for this approach Major findings from the Phase III CheckMate 648 study evaluating nivolumab/chemotherapy, nivolumab/ipilimumab and chemotherapy alone for patients with unresectable advanced or metastatic squamous cell carcinoma of the esophagus Available Phase III clinical trial findings (eg, JUPITER-06, ORIENT-15) with investigational anti-PD-1 antibodies with chemotherapy as first-line treatment for esophageal squamous cell carcinoma Key efficacy and safety outcomes from the Phase III CheckMate 577 study of adjuvant nivolumab for patients with resected esophageal or GEJ cancer; recent FDA approval and appropriate integration into management algorithms

Recently, the clinical benefits of the FGFR2-IIIb-selective monoclonal antibody bemarituzumab for FGFR2b-positive GC patients were shown in a randomized phase II FIGHT trial of bemarituzumab combined with the first-line chemotherapy...In this review, we summarize the oncogenic roles of FGFR2 signaling and highlight the most recent advances in FGFR inhibitors based on the findings of pivotal clinical trials for patients with FGFR2-aberrant GC. Thus, the era of precision medicine for patients with FGFR2-aberrant GC will be opened.