Evaluation of the Efficacy and Safety of BAY 2927088 in Patients with Metastatic or Unresectable Solid Tumors Harboring HER2-Activating Mutations

The primary objective of this study is to evaluate the **efficacy** of BAY2927088 in terms of objective response rate (ORR) as assessed by blinded independent central review (BICR). This is clinically relevant as it aims to determine the potential of BAY2927088 in treating patients with advanced solid tumors harboring HER2 mutations, which could lead to improved therapeutic strategies for this patient population.

Secondary objectives include:

• Further evaluation of the efficacy of BAY2927088 on tumor growth as assessed by BICR and investigator.
• Further characterization of the efficacy of BAY2927088 on tumor growth as assessed by BICR and investigator.
• Evaluation of the efficacy of BAY2927088 in overall survival (OS).
• Assessment of the safety and tolerability of BAY2927088.
• Evaluation of patient-reported outcomes (PROs) of BAY2927088.

The clinical trial involves a total of **74 participants** diagnosed with **advanced solid tumors** and possessing a **HER2 mutation**. The study population includes both male and female subjects, aged 18 years and older, who have either received prior standard therapy suitable for their specific tumor type and stage or have no satisfactory alternative treatments available. Participants were selected based on documented histologically or cytologically confirmed locally advanced, unresectable, or metastatic solid tumor cancer, including colorectal carcinoma, biliary tract cancer, bladder and urothelial tract cancer, cervical cancer, endometrial cancer, and other solid tumors, excluding non-small cell lung cancer (NSCLC). The trial population includes individuals with at least one measurable lesion qualifying as a target lesion by RECIST 1.1 criteria. The study also considers vulnerable populations, ensuring a comprehensive evaluation of the investigational treatment's efficacy across diverse patient groups.

The clinical trial is designed as a **Phase 2 open-label basket study** to evaluate the efficacy and safety of the orally administered reversible tyrosine kinase inhibitor BAY 2927088 in participants with metastatic or unresectable solid tumors with **HER2-activating mutations**. The trial will employ a non-randomized, open-label design, allowing for the assessment of the drug's effects in a real-world setting. The study is expected to commence recruitment on March 31, 2025, and conclude by October 25, 2027, with a maximum treatment period of 36 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as documented histologically or cytologically confirmed locally advanced, unresectable, or metastatic solid tumor cancer, and a documented activating HER2 mutation. Following the screening, participants will receive the investigational product, BAY 2927088, in the form of a **coated tablet** administered orally. The primary endpoint of the study is the objective response rate (ORR) as assessed by blinded independent central review (BICR) using RECIST 1.1 criteria. Secondary endpoints include duration of response (DOR), time to response (TTR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), among others.

Study visits will include regular follow-up assessments to monitor the efficacy and safety of the treatment, with evaluations conducted by both BICR and investigators. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or at the discretion of the investigator. The expected length of participant involvement is up to 36 months, contingent upon individual response and tolerance to the treatment. The study aims to provide valuable insights into the therapeutic potential of BAY 2927088 for patients with advanced solid tumors harboring HER2 mutations.

The clinical trial involves the administration of the experimental medication **BAY 2927088**, a reversible tyrosine kinase inhibitor, in participants with metastatic or unresectable solid tumors with HER2-activating mutations. The medication is provided in the form of a **coated tablet** and is intended for **oral use**. The active substance in BAY 2927088 is chemically synthesized and identified as **3-(3-chloro-2-methoxyanilino)-2-{3-[(2S)-1,4-dioxan-2-ylmethoxy]pyridin-4-yl}-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one**. The maximum daily dose for this formulation is 30 mg, with a total maximum dose of 32.87 g over a treatment period of up to 36 weeks.

Another formulation of the experimental medication, **BAY 2927088 Bayer (CM)**, is also utilized in the study. This formulation is similarly provided as a **coated tablet** for **oral use**. The active substance is the same as in the previous formulation, and the maximum daily dose is 40 mg, with a total maximum dose of 48.83 g over the same treatment period of 36 weeks.

The third formulation, simply named **BAY 2927088**, is also a **coated tablet** for **oral use**. It contains the same active substance, BAY 2927088, and follows the same dosing regimen as the BAY 2927088 Bayer (CM) formulation, with a maximum daily dose of 40 mg and a total maximum dose of 48.83 g over 36 weeks.

All formulations are manufactured by **BAYER AG** and are not designated as pediatric formulations. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.

The efficacy of the investigational product BAY 2927088 will be assessed in a Phase 2 open-label basket study involving participants with metastatic or unresectable solid tumors characterized by **HER2-activating mutations**. The primary endpoint for evaluating efficacy is the objective response rate (ORR) as determined by a blinded independent central review (BICR) using RECIST 1.1 criteria. Secondary endpoints include duration of response (DOR), time to response (TTR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), all assessed per RECIST 1.1 by both BICR and investigators. Additionally, the study will monitor the number of participants experiencing treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) as per CTCAE v 5.0, as well as changes in quality of life metrics using the EORTC QLQ-C30 questionnaire.