Evaluation of MCLA-129, a Bispecific Antibody Targeting EGFR and c-MET, Alone and in Combination with Chemotherapy and Osimertinib in Advanced Solid Tumors

The primary objective of this Phase 1/2 study is to evaluate the **Objective Response Rate** (ORR) of MCLA-129, a human anti-EGFR and anti-c-MET bispecific antibody, in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumors. This is clinically relevant as ORR is a critical measure of the efficacy of cancer therapies, indicating the proportion of patients with a significant reduction in tumor size. Additionally, the study aims to characterize the safety and tolerability of MCLA-129 both as a single agent and in combination with chemotherapy and **osimertinib**, which is essential for understanding the potential adverse effects and overall risk-benefit profile of the treatment. The pharmacokinetics (PK) of MCLA-129 will also be characterized to understand the drug's absorption, distribution, metabolism, and excretion, which is crucial for optimizing dosing regimens. Furthermore, the study will evaluate antitumor activity in terms of **progression-free survival** (PFS) and duration of response (DOR), as well as overall survival, providing comprehensive insights into the long-term benefits of the treatment.

The clinical trial involves a total of **49 participants** diagnosed with **solid tumors**, including non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), among other solid tumors. The study population comprises both male and female subjects, aged 18 years and older, with an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on their adequate cardiac and organ function, as well as a life expectancy of at least 12 weeks. The trial includes individuals with applicable mutations as determined by the investigator. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial population includes vulnerable groups, although specific details about these groups are not provided.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy and safety of MCLA-129, a human anti-EGFR and anti-c-MET bispecific antibody, in patients with advanced non-small cell lung cancer (NSCLC) and other **solid tumors**. The trial is structured in two phases: Phase 1 focuses on dose escalation, while Phase 2 involves dose expansion. The primary objectives include determining the Objective Response Rate (ORR), characterizing the safety and tolerability of MCLA-129 both as a single agent and in combination with chemotherapy and **osimertinib**, and evaluating pharmacokinetic parameters. The trial also aims to assess antitumor activity in terms of progression-free survival (PFS), duration of response (DOR), and overall survival (OS).

The trial is expected to last until July 2025, with recruitment having commenced in January 2022. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and organ function. Subsequent visits will include regular follow-up assessments to monitor treatment response and adverse events. The end-of-study visit will conclude the participant's involvement, during which final evaluations will be conducted. The expected length of participant involvement is contingent upon individual response to treatment and overall health status, with early termination possible in cases of significant adverse events or disease progression.

Participants will receive MCLA-129 via **intravenous** infusion, with the potential addition of chemotherapy agents such as **paclitaxel**, **docetaxel**, and **carboplatin**, or the oral administration of **osimertinib**. The trial's inclusion criteria require participants to have a life expectancy of at least 12 weeks and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The study excludes individuals who do not meet these criteria or who experience severe adverse reactions necessitating discontinuation. The trial's design ensures rigorous monitoring and data collection to achieve its scientific objectives while maintaining participant safety.

The clinical trial involves the administration of several **experimental medications**. **Paclitaxel** is utilized in the form of a concentrate for solution for infusion. It is administered intravenously. The specific dosage and frequency of administration are determined based on the trial protocol and patient-specific factors. **Paclitaxel** is a chemical substance and is not a pediatric formulation. The product has undergone relabelling as part of its preparation for the trial.

**Docetaxel** is another experimental medication used in this study. It is also provided as a concentrate for solution for infusion and administered intravenously. Like **Paclitaxel**, the dosage and frequency are tailored according to the trial's requirements. **Docetaxel** is a chemical substance and is not formulated for pediatric use.

**Carboplatin** is included in the trial as a concentrate for solution for infusion, administered intravenously. The dosing schedule is determined by the trial protocol. **Carboplatin** is a chemical substance and has been relabelled for the purposes of this study. It is not a pediatric formulation.

**Osimertinib** is administered in the form of a film-coated tablet, taken orally. The dosage and frequency are specified in the trial protocol. **Osimertinib** is a chemical substance and has been relabelled for the trial. It is not intended for pediatric use.

The trial also includes **MCLA-129**, a human anti-EGFR and anti-c-MET bispecific antibody, provided as a solution for infusion. It is administered intravenously. **MCLA-129** is a protein-based substance and is not a pediatric formulation. The trial aims to evaluate the safety, tolerability, and pharmacokinetics of **MCLA-129** both as a single agent and in combination with chemotherapy and **Osimertinib**.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus is on evaluating the efficacy and safety of the experimental medications in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumors.

The efficacy of the clinical trial will be assessed using several primary endpoints. These include the **Objective Response Rate (ORR)**, which measures the proportion of patients with a predefined reduction in tumor size, and the **Progression-Free Survival (PFS)**, which evaluates the length of time during and after treatment that a patient lives with the disease without it worsening. Additionally, the **Duration of Response (DOR)** will be assessed to determine the time period during which a tumor continues to respond to treatment without growth. **Overall Survival (OS)**, which measures the time from the start of treatment until death from any cause, will also be evaluated.

The trial will also characterize the safety and tolerability of the investigational product, MCLA-129, both as a single agent and in combination with chemotherapy and **osimertinib**. Pharmacokinetic parameters such as CEOI, Cmax, C0h, AUC, CL, Vss, tmax, and t1/2 will be analyzed to understand the drug's behavior in the body. The frequency and severity of adverse events, serious adverse events, and any treatment discontinuations or modifications will be documented to ensure comprehensive safety monitoring.