Phase 3 Randomized Study of Zanidatamab Plus Chemotherapy Versus Trastuzumab Plus Chemotherapy in Metastatic HER2-Positive Breast Cancer

The primary objective of this Phase 3, randomized, open-label, multicenter, controlled study is to compare the **efficacy** of **zanidatamab** plus chemotherapy versus **trastuzumab** plus chemotherapy in patients with metastatic HER2-positive breast cancer who have progressed on, or are intolerant to, previous trastuzumab deruxtecan treatment. This comparison is clinically relevant as it aims to determine the potential superiority or non-inferiority of zanidatamab in improving patient outcomes in a population with limited treatment options.

Secondary objectives include:

• Further comparing the efficacy of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy.
• Evaluating the **safety** and **tolerability** of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy.
• Assessing the pharmacokinetics (PK) of zanidatamab in combination with chemotherapy.
• Evaluating the **immunogenicity** of zanidatamab plus chemotherapy.
• Assessing patient-reported tolerability of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy.
• Evaluating the effect of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy on patient-reported physical functioning.

The clinical trial involves a total of **291 participants** diagnosed with **metastatic HER2-positive breast cancer**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adult participants. The trial population was selected based on specific inclusion criteria, such as having a creatinine clearance of at least 30 mL/minute, a left ventricular ejection fraction (LVEF) of 55% or higher, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants are required to have histologically confirmed HER2-positive breast cancer and must have progressed on or shown intolerance to previous T-DXd treatment. Both male and female participants must adhere to contraception guidelines during and after the study intervention period. The trial includes individuals with a life expectancy of at least six months and those with adequate hematologic and hepatic function. Participants with a history of treated or clinically inactive central nervous system (CNS) metastases are also eligible. The study does not exclude vulnerable populations, and participants are expected to have measurable disease per RECIST version 1.1 and be eligible for one of the chemotherapy options listed in the physician's choice of chemotherapy.

The clinical trial is a **Phase 3**, randomized, open-label, multicenter, controlled study designed to evaluate the efficacy and safety of **zanidatamab** in combination with physician's choice chemotherapy compared to **trastuzumab** in combination with physician's choice chemotherapy for the treatment of participants with metastatic **HER2-positive breast cancer**. The trial aims to compare the efficacy of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy. The study is expected to commence recruitment on November 20, 2024, and is estimated to conclude by April 15, 2031.

Participants will be randomly assigned to receive either zanidatamab or trastuzumab, each in combination with one of the following chemotherapy options: **eribulin**, **gemcitabine**, **vinorelbine**, or **capecitabine**. The trial will involve multiple study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, creatinine clearance, left ventricular ejection fraction, and performance status. Participants must have histologically confirmed HER2-positive breast cancer and have progressed on or are intolerant to previous trastuzumab deruxtecan treatment.

Following the screening visit, participants will undergo regular follow-up visits to monitor progression-free survival, overall survival, and other secondary endpoints such as objective response rate and duration of response, assessed by both independent central review and investigators. The frequency of treatment-emergent adverse events and serious adverse events will also be evaluated. The trial will conclude with an end-of-study visit to assess the final outcomes and any long-term effects of the treatment.

The expected length of participant involvement is up to 9 months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The study will adhere to rigorous scientific and ethical standards to ensure the safety and well-being of all participants throughout the trial duration.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Zanidatamab**, marketed under the sponsor product code JZP598, is a protein-based substance provided as a powder for concentrate for solution for infusion. It is administered via **IV injection** or **IV infusion**. The maximum daily dose is 2400 mg, with a total maximum dose of 28800 mg over a treatment period of 9 months. This medication is not a pediatric formulation and is classified as an antineoplastic agent.

**Trastuzumab** is used as a comparator treatment in this study. It is a protein-based substance available in the pharmaceutical form PHF00016MIG and is administered through **IV injection** or **IV infusion**. The maximum daily dose is 14 mg/kg, with a total maximum dose of 80 mg/kg over a 9-month period. This medication is also not formulated for pediatric use.

**Vinorelbine** is another auxiliary treatment in the trial, provided in the pharmaceutical form PHF00230MIG. It is a chemical substance administered via **IV injection** or **IV infusion**. The maximum daily dose is 25 mg/m², with a total maximum dose of 600 mg/m² over the course of 9 months. It is classified as an antineoplastic agent and is not a pediatric formulation.

**Eribulin mesylate** is included as an auxiliary treatment, available in the pharmaceutical form PHF00231MIG. This chemical substance is administered through **IV injection** or **IV infusion**. The maximum daily dose is 1.4 mg/m², with a total maximum dose of 33.6 mg/m² over a 9-month period. It is also classified as an antineoplastic agent and is not intended for pediatric use.

**Capecitabine** is another auxiliary treatment, provided in the pharmaceutical form PHF00009MIG. It is a chemical substance administered orally. The maximum daily dose is 2000 mg/m², with a total maximum dose of 336000 mg/m² over 9 months. This medication is classified as an antineoplastic agent and is not a pediatric formulation.

**Gemcitabine hydrochloride** is used as an auxiliary treatment, available in the pharmaceutical form PHF00230MIG. It is a chemical substance administered via **IV injection** or **IV infusion**. The maximum daily dose is 1000 mg/m², with a total maximum dose of 24000 mg/m² over a 9-month period. It is classified as an antineoplastic agent and is not formulated for pediatric use.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of **zanidatamab** plus chemotherapy versus **trastuzumab** plus chemotherapy in participants with metastatic HER2-positive breast cancer who have progressed on or are intolerant to previous trastuzumab deruxtecan treatment.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **progression-free survival** (PFS) as per RECIST version 1.1, assessed by blinded independent central review (BICR). Secondary endpoints include overall survival, confirmed objective response rate (ORR) per RECIST version 1.1 assessed by both BICR and investigators, duration of response (DOR) per RECIST version 1.1 assessed by both BICR and investigators, and PFS per RECIST version 1.1 assessed by investigators. Additional secondary endpoints involve the frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) graded by NCI CTCAE version 5.0, frequency of dose reductions, and frequency of treatment discontinuations due to TEAEs.

Further assessments include serum concentrations of zanidatamab over time post-dosing, and the frequency, duration, and onset of anti-zanidatamab antibodies and neutralizing antibodies, if applicable. Patient-reported outcomes will be evaluated using the PRO-CTCAE and EORTC Item Library, with a descriptive summary of symptomatic adverse events while on treatment. The FACIT-GP5 will be used to assess overall side-effect bother. The EORTC QLQ-C30 will be utilized to evaluate the proportion of patients with maintained or improved physical and role function, as well as changes from baseline and time to worsening of select scores from the EORTC QLQ-C30, EORTC IL341, and PGI-S.