A Phase 3, randomized, open-label, multicenter, controlled study 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 (EmpowHER 303)

Prior treatment

• Has any condition that would prevent treatment with the physician’s choice of chemotherapy.
• Has a history of prior allogeneic bone marrow, stem cell, or solid organ transplantation.
• Has a history of trauma or major surgery within 4 weeks prior to randomization.
• The washout periods for prior anticancer therapies before randomization are as follows: a. Prior therapies with monoclonal antibodies including ADCs: washout period ≤ 3 weeks b. Prior therapies with small molecule targeted therapies: washout period of ≤ 2 weeks or 5 half-lives, whichever is shorter c. No washout period needed for endocrine therapy. − No washout period for gonadotropin-releasing hormone agonists.
• Prior participation in a zanidatamab clinical study.
• Receipt of a live vaccine within 4 weeks prior to enrollment.
• Participants known to have a complete lack of the enzyme dihydropyrimidine dehydrogenase who are assigned to receive chemotherapy capecitabine in combination with the study treatment.
• Primary cancer in the previous 3 years prior to randomization, except non-melanoma skin cancer/in situ disease.

Other illness

• Has clinically confirmed leptomeningeal disease, in the opinion of the investigator.
• Has any serious underlying medical or psychiatric condition that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site.
• Has any issue or condition that in the opinion of the investigator would contraindicate the participant’s participation in the study or confound the results of the study
• Has a known hypersensitivity to any components of the study drugs, including chemotherapy.
• Has uncontrolled or significant cardiovascular disease
• Has toxicity related to prior cancer therapy that has not resolved to ≤ Grade 1
• Has uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
• Has an infection with HIV-1 or HIV-2. (Exception: Participants with well‑controlled HIV [ie, CD4 > 350/mm3 and undetectable viral load] are eligible.)
• Has active hepatitis B or C infection.
• Has an active SARS-CoV-2 infection.
• Has a history of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of zanidatamab.

Other

• Female participants who are breastfeeding or pregnant, and female and male participants planning a pregnancy.
• Is unable to receive trastuzumab treatment due to medical contraindications

• Is at least 18 years of age or of the legal adult age per local standard at the time of signing the informed consent.
• Has measurable disease per RECIST version 1.1.
• Is eligible to receive one of the chemotherapy options listed in the physician’s choice of chemotherapy (eribulin, gemcitabine, vinorelbine, capecitabine or taxane) (Section 4.1). Taxane choice includes either docetaxel or weekly paclitaxel).
• Participants with history of treated and/or clinically inactive CNS metastases are eligible, provided they do not require ongoing treatment with corticosteroids or anticonvulsants for CNS metastases, they do not have symptoms attributable to CNS metastases, and they have at least one measurable extracranial lesion. a. Treated CNS metastases are defined as follows: • Participant must have received definitive local therapy (ie, surgical resection, radiotherapy). Prior stereotactic radiosurgery or stereotactic radiotherapy should be completed ≥ 7 days before the randomization of the participant. A minimum of ≥ 14 days must have elapsed between the end of whole brain radiotherapy and the study randomization of the participant in the study.; and • Participant must have recovered to ≤ Grade 1 or baseline from the acute toxic effect associated with the treatment ≥ 7 days prior to randomization of the participant in the study. b. Clinically inactive CNS metastases are defined as follows: • Previously identified and untreated brain lesions that are ≤ 5 mm and radiographically stable on at least 2 consecutive imaging assessments (one performed during screening and prior to randomization) at least 28 days apart; or • Brain metastases identified at screening must receive local therapy prior to randomization, and the participant must meet eligibility criteria (as described above) for participants with treated brain metastases.
• Has a life expectancy of at least 6 months, in the opinion of the investigator.
• Has adequate hematologic parameters
• Has adequate hepatic function
• Must have received at least 1 prior line of HER2-directed therapy for their metastatic disease.
• Has creatinine clearance ≥ 50 mL/minute as calculated per local institutional guidelines.
• Has LVEF ≥ 55% as determined by either echocardiogram or MUGA obtained within 4 weeks before the first dose of study intervention.
• Has ECOG performance status of 0 or 1.
  • 14a. Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 7 months after the last dose of study intervention or the contraception period for the combination chemotherapy of choice per local guidance/standard practice. This requirement aligns with the contraception period recommended for trastuzumab and is longer than the recommended contraception period for zanidatamab, which is 4 months, and for all other allowed chemotherapy options.
  • 14b. A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: - Is a WONCBP; - Is a WOCBP and using a contraceptive method that is highly effective during the study intervention period and for at least 7 months after the last dose of study intervention. This requirement aligns with the contraception period recommended for trastuzumab and is longer than the recommended contraception period for zanidatamab, which is 5 months, and for all other allowed chemotherapy options. Therefore, 7 months is considered sufficient to collect details of all pregnancies.
• Is capable of giving signed informed consent
  • 2.Has histologically confirmed HER2-positive breast cancer according to ASCO–CAP Guidelines as evaluated by a sponsor-designated central laboratory (Wolff, 2018). a. Most recently available tissue blocks or freshly cut slides from all participants must be submitted to confirm HER2 positivity by a sponsor-designated central laboratory. If archived tissue is not available, aA fresh tumor biopsy is required to confirm HER2 positivity if one of the following criteria is met: (1) a prior biopsy in the metastatic setting showed HER2-negative disease, (2) the participant progressed on or before the initial disease assessment on the immediate prior line of therapy, or (3) archival tissue is insufficient, unevaluable, or unavailable. Only participants with HER2-positive test results confirmed by central laboratory testing will be eligible for randomization. b. The investigator has an option to prescreen for HER2 status of the participants by a sponsor-designated central laboratory (with a separate prescreening ICF) within 12 months prior to C1D1).
• Participants with unresectable or metastatic HER2 positive breast cancer who have progressed on, or are intolerant to, previous T-DXd treatment.