Bemarituzumab is an investigational targeted therapy currently under development for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer. The therapy is designed to address a particular molecular alteration found in a subset of these aggressive cancers. Bemarituzumab has not yet received final approval from the U.S. Food and Drug Administration (FDA) for any indication. However, it is progressing through the regulatory pathway, supported by data from late-stage clinical trials.
The Target and Mechanism of Action
Bemarituzumab is a monoclonal antibody engineered to specifically target the Fibroblast Growth Factor Receptor 2b (FGFR2b) protein. This receptor is found on the surface of some cancer cells, and when it is overexpressed, it promotes aberrant signaling pathways that drive tumor cell proliferation and survival. The drug functions by physically binding to the FGFR2b receptor, which prevents external growth factors from attaching and activating the downstream signaling cascade within the cancer cell.
The therapy employs a dual mechanism to attack the tumor. First, by blocking the receptor, it directly inhibits the growth-promoting signals that the cancer cell relies upon. Second, the antibody has been specifically modified through a process called glycoengineering to enhance its ability to recruit immune cells. This modification increases the therapy’s potential to trigger Antibody-Dependent Cell-mediated Cytotoxicity (ADCC), essentially marking the tumor cell for destruction by the body’s own immune system.
The drug’s specificity for the FGFR2b isoform is intended to provide a focused treatment, concentrating its anti-cancer activity on tumors that express this biomarker. This targeted approach aims to maximize effectiveness while potentially limiting the systemic side effects often associated with traditional chemotherapy.
Clinical Evidence Supporting Approval
The primary evidence supporting a potential approval comes from the Phase 3 FORTITUDE-101 clinical trial, which evaluated bemarituzumab in combination with standard chemotherapy (mFOLFOX6). This pivotal study focused on patients with previously untreated, advanced gastric or GEJ adenocarcinoma whose tumors overexpressed the FGFR2b protein. The trial successfully met its pre-specified primary endpoint of Overall Survival (OS) at an interim analysis, demonstrating a significant improvement compared to chemotherapy alone.
Initial data showed that adding bemarituzumab resulted in a median Overall Survival of 17.9 months, compared to 12.5 months for the placebo-plus-chemotherapy group. Similarly, the Progression-Free Survival (PFS) was significantly prolonged, with patients receiving the targeted therapy reporting a median PFS of 8.6 months versus 6.7 months in the control group. These results suggested a meaningful clinical benefit in this specific patient population.
However, subsequent analysis of the FORTITUDE-101 data indicated an attenuation of the Overall Survival benefit over time, with later figures showing a smaller difference between the two arms. The safety profile also noted a higher frequency of ocular events, such as punctate keratitis and dry eye, in the bemarituzumab arm, which led to treatment discontinuation in a notable percentage of patients.
Patient Eligibility and Biomarker Testing
Bemarituzumab is being developed exclusively for a defined subset of patients with advanced gastric and GEJ cancer. Patients must have tumors that are non-Human Epidermal Growth Factor Receptor 2 (HER2) positive, which represents approximately 80 to 85% of advanced gastric and GEJ cases. Within this HER2-negative group, the treatment is restricted to those whose tumors overexpress the FGFR2b protein.
To determine eligibility, patients must undergo companion diagnostic testing prior to receiving the therapy. This testing typically involves the use of immunohistochemistry (IHC) on a tumor tissue sample. The specific criterion for treatment in the clinical trials required that the IHC test show overexpression of the FGFR2b protein in at least 10% of the tumor cells.
Approximately 30% of patients with HER2-negative advanced gastric or GEJ cancer are found to have the necessary FGFR2b overexpression. The companion diagnostic test plays a central role in clinical practice by identifying the appropriate candidates for this precision medicine.
Current Regulatory Status and Timeline
The development of bemarituzumab has been expedited by the FDA through the granting of Breakthrough Therapy Designation (BTD) in April 2021. BTD is a special status intended to accelerate the development and review of therapies that may demonstrate a substantial improvement over existing treatments for a serious condition. This designation signaled the FDA’s recognition of promising early data.
Following the successful interim analysis of the Phase 3 FORTITUDE-101 trial, the company is preparing for or has initiated the submission of a Biologics License Application (BLA) to the FDA. The positive Overall Survival outcome in FORTITUDE-101 serves as the primary basis for the anticipated regulatory filing. A final decision on approval would then be expected following the standard review cycle, though the BTD may shorten this timeline.
However, the regulatory path has faced complexities. A separate Phase 3 trial, FORTITUDE-102, which was investigating bemarituzumab in combination with chemotherapy and an immune checkpoint inhibitor, was stopped due to an analysis showing inadequate efficacy. This outcome, along with the noted attenuation of the OS benefit in FORTITUDE-101, adds layers of complexity to the FDA’s review process.