Trastuzumab Deruxtecan (T-DXd) With Pyrotinib in First-line HER2-positive Unresectable or Metastatic Breast Cancer Trial

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures
2. Aged at least 18 years.
3. Pathologically documented breast cancer that：
4. is advanced or metastatic;
5. is confirmed as HER2-positive Immunohistochemistry 3+（IHC3+） or in situhybridization+(ISH+) in the pathological examination/rechecking of primarylesions or metastatic lesions performed by the Research site's PathologLaboratory;
6. hormone receptor (HR)-positive or HR-negative disease
7. No prior chemotherapy or HER2-targeted therapy for advanced or metastatic breastcancer or only 1 previous line of endocrine therapy in the metastatic setting.Participants who have received chemotherapy or HER2-targeted therapy in theneo-adjuvant or adjuvant setting are eligible if > 6 months from treatment tometastatic diagnosis
8. Asymptomatic or treated brain metastases not needing urgent neurosurgical interventionor dehydration treatment and glucocorticoid treatment is allowed：
9. Untreated brain metastases (BM) at contrast brain screening MRI/CT
10. Previously local therapy treated stable or progressing brain metastases (BM).
11. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
12. Having at least one measurable lesion according to RECIST 1.1.
13. left ventricular ejection fraction ≥ 50% within 28 days at screening.
14. Life expectancy ≥ 12 weeks at screening.
15. Adequate organ and bone marrow function within 28 days before randomization/enrolmentas described below. Organ and bone marrow function criteria must also be met whenlaboratory tests are repeated within 3 days before Cycle 1 Day 1. Note: Transfusion (red blood cell or platelet) or Granulocyte Colony-Stimulating Factor administrationis not allowed within 2 weeks prior to the day on which marrow function is assessed:

• Absolute neutrophils count (ANC) ≥1.5x109/L (band neutrophil and segmentedneutrophil), platelets ≥100x109/L and Hb ≥90g/L [no blood transfusion or noerythropoietin (EPO) dependence within 7 days before enrollment].
• Hepatic: total bilirubin ≤1× upper limit of normal (ULN) if no liver metastasesor <2×ULN in the presence of documented Gilbert's syndrome (unconjugatedhyperbilirubinemia) or liver metastases at baseline; Alkaline phosphatase,alanine transaminase (ALT) and aspartate transaminase (AST) ≤1.5 ULN (or ≤5 ULNin case of known liver involvement); Serum albumin ≥ 2.5 g/dL.
• Renal: Creatinine clearance (CCr) ≥30mL/min as determined by Cockcroft-Gault (using actual body weight);
• International normalized ratio (INR) and prothrombin time (PT) ≤1.5 times ULN forpatients not receiving therapeutic anticoagulation

11. Has adequate treatment washout period before screen, defined as: Major surgery ≥ 4 weeks Radiation therapy including palliative stereotactic radiationtherapy to chest≥ 4 weeks Palliative stereotactic radiation therapy to other anatomicareas including whole brain radiation ≥ 2 weeks Hormonal therapy ≥ 3 weeksChloroquine/Hydroxychloroquine ≥ 14 days
12. Male and female. Contraceptive use by men or women should be consistent with localregulations regarding the methods of contraception for those participating in clinicalstudies.
13. Negative pregnancy test (urine or serum) for women of childbearing potential who aresexually active with a non-sterilised male partner.
14. Female participants must be 1 year post-menopausal, surgically sterile, or using onehighly effective form of birth control (a highly effective method of contraception isdefined as one that can achieve a failure rate of less than 1% per year when usedconsistently and correctly). Women of childbearing potential who are sexually activewith a non-sterilised male partner must agree to use one highly effective method ofbirth control from the time of screening and must agree to continue using suchprecautions for 7 months after the last dose of study treatment (see Table 4 forcomplete list of highly effective birth control methods). Female patients must refrainfrom egg cell donation and breastfeeding while on study and for 7 months after thelast dose of study treatments. Non sterilised male partners of a woman of childbearingpotential must use a male condom plus spermicide (condom alone in countries wherespermicides are not approved) throughout this period. Not engaging in heterosexualactivity (sexual abstinence) for the duration of the study and drug washout period isan acceptable practice if this is the preferred usual lifestyle of the participant;however, periodic or occasional abstinence, the rhythm method, and the withdrawalmethod are not acceptable methods of contraception.
15. Male participants who intend to be sexually active with a female partner ofchildbearing potential must be surgically sterile or using an acceptable method ofcontraception (see Table 4) from the time of screening throughout the total durationof the study and the drug washout period (4 months after the last dose of studytreatment) to prevent pregnancy in a partner. Male participants must not donate orbank sperm during this same time period. Not engaging in heterosexual activity (sexualabstinence) for the duration of the study and drug washout period is an acceptablepractice if this is the preferred usual lifestyle of the participant; however,periodic or occasional abstinence, the rhythm method, and the withdrawal method arenot acceptable methods of contraception.

Exclusion Criteria:

1. Ineligible for any of the agents on the study. Participants with contraindications topyrotinib per local prescribing information or to T-DXd per the T-DXd Investigator'sBrochure cannot be enrolled to the study.
2. Previous IP（pyrotinib or T-DXd）assignment in the present study, or prior treatmentwith any other HER2 TKI agent.
3. Prior exposure to antibody drug conjugate that comprises of an exatecan derivativethat is a topoisomerase I inhibitor.
4. Any concurrent anticancer treatment. A 3-week washout period is required for femaleparticipants using hormone replacement therapy and for participants receivingendocrine therapy for HR positive tumours.
5. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study.
6. Refractory nausea, vomiting and diarrhea, chronic gastrointestinal disease, orprevious significant bowel resection.
7. Has substance abuse or any other medical conditions such as clinically significantcardiac or psychological conditions, that may, in the opinion of the investigator,interfere with the subject's participation in the clinical study or evaluation of theclinical study results.
8. History of another primary malignancy except for malignancy treated with curativeintent with no known active disease within 5 years before the first dose of studytreatment and of low potential risk for recurrence. Exceptions include basal cellcarcinoma of the skin and squamous cell carcinoma of the skin that has undergonepotentially curative therapy, adequately resected non-melanoma skin cancer, curativelytreated in situ disease, other solid tumours curatively treated.
9. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline. Note: Participants maybe enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to >Grade 2 for at least 3 months prior to first exposure to study intervention and managed withstandard of care treatment) that the investigator deems related to previous anticancertherapy, including:

• Chemotherapy-induced neuropathy
• Fatigue
• Residual toxicities from prior immuno-oncology treatment: Grade 1 or Grade 2endocrinopathies which may include:

1. Hypothyroidism/hyperthyroidism
2. Type 1 diabetes
3. Hyperglycemia
4. Adrenal insufficiency
5. Adrenalitis
6. Skin hypopigmentation (vitiligo)
7. Has spinal cord compression or clinically active central nervous system metastases,defined as untreated and symptomatic, or requiring therapy with corticosteroids oranticonvulsants to control associated symptoms. Participants with clinically inactivebrain metastases may be included in the study. Participants with treated brainmetastases that are no longer symptomatic and who require no treatment withcorticosteroids or anticonvulsants may be included in the study if they have recoveredfrom the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsedbetween the end of whole brain radiotherapy or stereotactic radiotherapy andenrollment.
8. Has active primary immunodeficiency, known HIV infection, or active hepatitis B or Cinfection, such as those with serological evidence of viral infection within 28 daysof Day 1 of Cycle 1. Participants positive for hepatitis C virus (HCV）antibody areeligible only if polymerase chain reaction is negative for HCV RNA. Participantsshould be tested for HIV prior to enrolment if required by local regulations orInstitutional Review Board/Ethics Committee. Subjects with past or resolved hepatitisB virus (HBV) infection are eligible only if they meet all of the following criteria:

• HBsAg(-) (for > 6 months off anti-viral treatment),
• antibody to hepatitis B core antigen (+) (IgG or total Ig), HBV DNA undetectable,
• Absence of cirrhosis or fibrosis on prior imaging or biopsy,
• Absence of HCV co-infection or history of HCV co-infection.
• Access to a local Hepatitis B expert during and after the study.

12. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
13. Participants with a medical history of myocardial infarction (MI) within 6 monthsbefore first exposure to study intervention, symptomatic congestive heart failure (NewYork Heart Association Class II to IV), participants with troponin levels above ULN atscreening (as defined by the manufacturer), and without any myocardial relatedsymptoms, should have a cardiologic consultation before enrollment to rule out MI.
14. History of (non-infectious) interstitial lung disease(ILD)/pneumonitis that requiredsteroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot beruled out by imaging at screening.
15. Lung criteria:
16. Lung-specific intercurrent clinically significant illnesses including, but notlimited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3months of study enrolment, severe asthma, severe chronic obstructive pulmonarydisorder (COPD), restrictive lung disease, pleural effusion, post Corona VirusDisease 2019 pulmonary fibrosis, etc,).
17. Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoidarthritis, Sjogren's, sarcoidosis, etc.) where there is documented, or asuspicion of pulmonary involvement at the time of screening. Full details of thedisorder should be recorded in the electronic Case Report Form (eCRF) forparticipants who are included in the study.
18. Prior pneumonectomy.
19. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviralvaccines are not considered attenuated live vaccines) within 30 days prior to thefirst exposure to study intervention. Note: Participants, if enrolled, should notreceive live vaccine during the study and up to 30 days after the last dose of studyintervention.
20. Judgment by the investigator that the participant should not participate in the studyif the participant is unlikely to comply with study procedures, restrictions andrequirements.
21. Pregnant or breastfeeding female participants.