Phase 3 Study of BAY 2927088 vs. Standard of Care in HER2-Mutant Advanced NSCLC

The primary objective of this study is to evaluate the effect of **BAY 2927088** compared with standard of care (SoC) in progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) with HER2-activating mutations. This is clinically relevant as PFS is a critical endpoint in oncology trials, reflecting the time during which a patient's disease does not worsen, thus providing insights into the treatment's efficacy in delaying disease progression.

Secondary objectives include:

• Evaluating the efficacy of BAY 2927088 compared with SoC in overall survival (OS), which is a key measure of treatment benefit in terms of extending life.
• Assessing the efficacy of BAY 2927088 compared with SoC in objective response rate (ORR), indicating the proportion of patients with tumor size reduction.
• Further characterizing the efficacy of BAY 2927088 compared with SoC, providing a comprehensive understanding of its therapeutic potential.
• Assessing the safety and tolerability of BAY 2927088 compared with SoC, ensuring the treatment's risk-benefit profile is acceptable.
• Evaluating patient-reported outcomes (PROs) of BAY 2927088 compared with SoC, which are essential for understanding the treatment's impact on patients' quality of life.

The clinical trial involves a total of **133 participants** diagnosed with **advanced non-small cell lung cancer** with a HER2 (ERBB2) mutation. The study population includes both male and female subjects, aged 18 years and older, who are either at the legal age of consent or above, depending on the country. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of locally advanced non-squamous NSCLC, unsuitable for definitive therapy, or metastatic non-squamous NSCLC at screening. The trial includes individuals with a documented activating HER2 mutation in the tyrosine kinase domain, assessed by a tissue molecular test in a CLIA-certified or equally accredited laboratory. Participants have not received prior systemic therapy for locally advanced or metastatic disease and have not been treated with HER2 ex20ins-targeted therapy. Those who have completed adjuvant or neoadjuvant therapy at least 12 months prior to screening are eligible. The trial population is eligible to receive treatment with selected platinum-based doublet-chemotherapy and pembrolizumab. The study considers lifestyle factors such as diet and physical activity, although specific habits are not detailed. The trial includes a vulnerable population, ensuring comprehensive representation of the affected demographic.

The clinical trial is designed as a **randomized**, open-label, active-controlled, multicenter study to evaluate the efficacy and safety of orally administered BAY 2927088 compared with standard of care in patients with locally advanced or metastatic **non-small cell lung cancer** (NSCLC) with HER2-activating mutations. The primary objective is to assess progression-free survival (PFS) as per RECIST 1.1, evaluated by a blinded independent central review. Secondary endpoints include overall survival, objective response rate, disease control rate, duration of response, and adverse events categorized by severity. The trial is expected to commence recruitment on October 28, 2024, and conclude by May 15, 2028.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, confirmed diagnosis of NSCLC, and documented HER2 mutation. The trial will exclude individuals with prior systemic therapy for advanced disease or previous HER2-targeted treatments. Following the screening, participants will be randomized to receive either BAY 2927088 or a platinum-based doublet-chemotherapy regimen with pembrolizumab. The treatment period will last up to 36 weeks for BAY 2927088, with follow-up visits scheduled to monitor safety and efficacy outcomes.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include disease progression, unacceptable toxicity, or withdrawal of consent. The expected duration of participant involvement is approximately 36 weeks, with additional follow-up for survival and long-term safety assessments. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the integrity and reliability of the data collected.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **KEYTRUDA** (pembrolizumab) is utilized as a **monoclonal antibody** in the form of a 25 mg/mL concentrate for solution for infusion. It is administered via **IV infusion** with a maximum daily dose of 9.5 mg and a total dose limit of 6.88 g over a treatment period of up to 24 weeks. The product is re-labeled for clinical trial use and is manufactured by Merck Sharp & Dohme B.V.

**Carboplatin Kabi** is another treatment used in the trial, provided as a 10 mg/mL concentrate for solution for infusion. This **chemical** agent is administered through **IV infusion** with a maximum daily dose of 35.7 mg and a total dose limit of 3 g over a maximum treatment period of 84 days. The product is re-labeled for clinical trial use and is produced by Fresenius Kabi Deutschland GmbH.

**Cisplatin Hikma** is administered as a 1 mg/mL concentrate for solution for infusion. This **chemical** compound is delivered via **IV infusion** with a maximum daily dose of 6.18 mg and a total dose limit of 519 mg over a treatment period of up to 84 days. The product is re-labeled for clinical trial use and is manufactured by Hikma Farmacêutica (Portugal), S.A.

**BAY 2927088 Bayer** is the experimental medication in the trial, provided as a **coated tablet**. This **chemical** compound is administered orally with a maximum daily dose of 30 mg and a total dose limit of 32.8 g over a treatment period of up to 36 weeks. The product is manufactured by Bayer AG.

**Pemetrexed Fresenius Kabi** is used as a comparator, provided as a 25 mg/mL concentrate for solution for infusion. This **chemical** agent is administered via **IV infusion** with a maximum daily dose of 41.2 mg and a total dose limit of 30 g over a treatment period of up to 735 days. The product is re-labeled for clinical trial use and is produced by Fresenius Kabi Deutschland GmbH.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of BAY 2927088 compared to standard-of-care therapies in patients with locally advanced or metastatic non-small cell lung cancer with HER2-activating mutations.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression Free Survival (PFS)**, which will be evaluated according to RECIST 1.1 criteria and assessed by a Blinded Independent Central Review (BICR). Secondary endpoints include Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR), and Duration of Response (DOR), all of which will also be assessed per RECIST 1.1 by both BICR and the investigator. Additionally, adverse events will be categorized by severity using CTCAE v 5.0.

Patient-reported outcomes will be measured using the Non-small cell lung cancer Symptom Assessment Questionnaire (NSCLC-SAQ) and the EORTC QLQ-C30. Changes from baseline in total scores and individual domain scores, such as cough, pain, dyspnea, fatigue, and appetite, will be evaluated. Time to deterioration in these scores will also be assessed. The schedule for these assessments will be aligned with the trial's protocol, ensuring systematic data collection and analysis throughout the study duration.