Phase 1b/3 Evaluation of Bemarituzumab, Chemotherapy, and Nivolumab in FGFR2b-Overexpressing Advanced Gastric and Gastroesophageal Junction Cancer

The primary objective of this study is to evaluate the **safety** and tolerability of bemarituzumab in combination with mFOLFOX6 and nivolumab in Phase 1b, and to compare the efficacy of bemarituzumab plus chemotherapy and nivolumab to placebo plus chemotherapy and nivolumab in Phase 3. The efficacy comparison in Phase 3 is assessed by overall survival (OS) in subjects with FGFR2b ≥ 10% 2+/3+ tumor cell staining. This is clinically relevant as it aims to determine the potential benefits of bemarituzumab in improving survival outcomes in patients with advanced gastric and gastroesophageal junction cancer with FGFR2b overexpression.

Secondary objectives include: - Phase 1b: Evaluating preliminary anti-tumor activity, characterizing the pharmacokinetic (PK) profile, and immunogenicity of bemarituzumab. - Phase 3: Comparing efficacy between treatment arms based on progression-free survival (PFS) in FGFR2b ≥ 10% 2+/3+ TC subjects, overall survival (OS), PFS in all randomized subjects, objective response (OR), duration of response (DOR), and disease control. Additionally, assessing safety and tolerability, subject-reported outcomes, quality of life (QoL), and characterizing the PK profile and immunogenicity of bemarituzumab when administered with chemotherapy and nivolumab.

The clinical trial involves a total of **342 participants** diagnosed with **gastric and gastroesophageal junction cancer** characterized by FGFR2b overexpression. The study population includes both male and female adults, with an age range that encompasses middle-aged to older adults. Participants were selected based on specific inclusion criteria, such as having unresectable, locally advanced, or metastatic adenocarcinoma, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. The trial includes individuals with measurable or evaluable disease according to RECIST v1.1 criteria. Participants are required to have adequate organ function and no contraindications to the study medications, including nivolumab and chemotherapy regimens such as mFOLFOX6 or CAPOX. The trial also considers lifestyle factors, such as the ability to take oral medication for those receiving CAPOX. The study population includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's safety and efficacy across diverse patient groups.

The clinical trial is designed to evaluate the safety, tolerability, and efficacy of **bemarituzumab** in combination with chemotherapy and **nivolumab** compared to chemotherapy and nivolumab alone in subjects with previously untreated advanced gastric and gastroesophageal junction cancer with FGFR2b overexpression. This study is structured as a randomized, double-blind, controlled trial, encompassing both Phase 1b and Phase 3 components. The trial is expected to conclude by January 2027, with recruitment having commenced in October 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as histologically documented gastric or gastroesophageal junction adenocarcinoma, ECOG performance status, and adequate organ function. Following successful screening, participants will be randomized to receive either the investigational treatment or the control regimen. The trial includes regular follow-up visits to monitor treatment-emergent adverse events, dose-limiting toxicities, and other clinical parameters. The end-of-study visit will evaluate overall survival and progression-free survival, among other endpoints.

The expected duration of participant involvement varies depending on the treatment regimen, with a maximum treatment period of up to 155 weeks for some components. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial aims to provide comprehensive data on the primary endpoints, including overall survival and treatment-related adverse events, as well as secondary endpoints such as objective response rate and duration of response.

**Nivolumab** is an experimental medication used in this clinical trial. It is provided as a **concentrate for solution for infusion** and is administered via **intravenous use**. The dosage is calculated based on body surface area, with a maximum daily dose of 360 mg/m² and a total maximum dose of 6960 mg/m² over a treatment period of up to 58 weeks. Nivolumab is a chemical substance and is classified under antineoplastic agents.

**Bemarituzumab** is another experimental medication in the study, provided as a **solution for infusion**. It is also administered intravenously. The dosage is based on body weight, with a maximum daily dose of 22 mg/kg and a total maximum dose of 743 mg/kg over a treatment period of up to 97 weeks. Bemarituzumab is a protein-based substance and is used in combination with other treatments in this trial.

**Oxaliplatin** is used as a non-experimental treatment in the trial. It is available as a **solution for infusion** and administered intravenously. The dosage is determined by body surface area, with a maximum daily dose of 130 mg/m² and a total maximum dose of 2470 mg/m² over a treatment period of up to 58 weeks. Oxaliplatin is a chemical substance and is part of the antineoplastic agents group.

**Folinic Acid** is included in the study to diminish the cytotoxic effects of chemotherapy. It is provided as a **solution for injection** and administered intravenously. The dosage is based on body surface area, with a maximum daily dose of 400 mg/m² and a total maximum dose of 28800 mg/m² over a treatment period of up to 143 weeks. Folinic Acid is a chemical substance.

A **Placebo for AMG 552** is used as a comparator in the trial. It does not contain any active substance and is used to evaluate the efficacy of Bemarituzumab in combination with other treatments. The placebo is administered in a manner consistent with the active treatment it is compared against.

**Capecitabine** is another non-experimental treatment used in the study. It is administered orally, with a dosage based on body surface area. The maximum daily dose is 1000 mg/m², and the total maximum dose is 51667 mg/m² over a treatment period of up to 155 weeks. Capecitabine is a chemical substance and classified as an antineoplastic agent.

**Fluorouracil** is also used as a non-experimental treatment in the trial. It is provided as a **solution for infusion** and administered intravenously. The dosage is based on body surface area, with a maximum daily dose of 2400 mg/m² and a total maximum dose of 218400 mg/m² over a treatment period of up to 155 weeks. Fluorouracil is a chemical substance and part of the antineoplastic agents group.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. In Phase 3, the primary endpoint is overall survival (OS), defined as the time from randomization until death from any cause. Subjects who are still alive will be censored at the date last known to be alive. Secondary endpoints in Phase 3 include progression-free survival (PFS), which is defined as the time from randomization until the first documentation of radiologic disease progression or death from any cause, whichever occurs first, in the absence of subsequent anticancer therapy. Additionally, objective response, defined as the best overall response of complete response (CR) or partial response (PR) as determined by the investigator per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), will be evaluated.

In Phase 1b, efficacy will be assessed by objective response, which includes CR and PR, as determined by the investigator per RECIST v1.1. The duration of response (DOR) is defined as the time from the first response to disease progression or death from any cause, whichever comes first. Disease control rate (DCR) is defined as CR, PR, and stable disease (SD). Progression-free survival (PFS) is defined as the time from the first dose of the investigational product until the first documentation of radiologic disease progression or death from any cause. Overall survival (OS) is also measured from the first dose of the investigational product until death from any cause.

Additional assessments in both phases include treatment-emergent adverse events, clinically significant changes in vital signs, visual acuity, and clinical laboratory tests. Pharmacokinetic (PK) parameters for bemarituzumab, including area under the concentration-time curve (AUC), maximum observed concentration (Cmax), and observed concentration at the end of a dose interval (Ctrough), will be evaluated. Anti-bemarituzumab antibody formation will also be assessed. Patient-reported outcomes will be measured using the EORTC Quality of Life Questionnaire Version 3.0 (QLQ-C30) and EuroQol 5-dimensional (EQ-5D-5L) to evaluate changes in quality of life and health-related symptoms.