Safety and Efficacy of T-DXd vs. CDK4/6i-based ET as First-line Therapy of HR-positive and HER2-low/Ultralow Advanced Breast Cancer Patients Classified as Non-luminal Subtype

Inclusion Criteria:

1. Patients must be capable to understand the purpose of the study and have signedwritten informed consent form (ICF) prior to beginning specific protocol procedures.

2. Female or male patients ≥ 18 years of age at the time of signing ICF.

3. ECOG performance status of 0-1.

4. Minimum life expectancy of ≥ 12 weeks at screening.

5. Evidence of HER2-low expression (1+ by immunohistochemistry (IHC) or 2+ and negativeby an in situ hybridization [ISH] test) or HER2-ultralow (IHC 0 with faint membranestaining and in ≤ 10% of tumor cells) breast cancer according to the most recentAmerican Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP)guidelines determined by a MEDSIR's designated central laboratory, using Ventana 4B5antibody. This assessment has to be done on the most recently available (archived ornewly collected) formalin-fixed, paraffin-embedded (FFPE) tumor tissue blocks (≤ 6weeks or FFPE of a tumor sample obtained after last prior systemic therapy) fromcore or excisional biopsy from a locally recurrent (breast or locoregional lymphnodes) or metastatic tumor lesion, excluding bone metastases.

6. Non-luminal breast cancer subtype as per central PAM50 analysis determined in themost recently available (archived or newly collected) FFPE tumor tissue blocks (≤ 6weeks or FFPE of a tumor sample obtained after last prior systemic therapy) fromcore or excisional biopsy from a locally recurrent (breast or locoregional lymphnodes) or metastatic tumor lesion with the exception of bone metastases.

7. Patients must have HR-positive (estrogen receptor [ER] and/or progesterone receptor [PgR]-positive defined as ≥ 1% positive stained cells) status according to the mostrecent ASCO/CAP guidelines locally determined prior to study entry.

8. Unresectable locally recurrent or metastatic breast cancer documented bycomputerized tomography (CT) scan or magnetic resonance imaging (MRI) that is notamenable to resection with curative intent.

9. Evaluable disease according to RECIST v.1.1. Patients with bone-only disease are notallowed. Patients with bone metastases with soft tissue masses measuring > 10 mm areeligible.

10. Patients must have endocrine resistance criteria:

• disease progression during adjuvant ET or within the first year of completingadjuvant ET; or endocrine sensitivity criteria:

• de novo metastatic disease or disease progression ≥ 12 months after completingadjuvant ET with at least one of the following requirements:

• Estrogen receptor ≤ 50% positive stained cells;

• and/or high histological grade or Ki67 > 50% on primary tumor;

• and/or liver metastases;

• and/or known non-luminal subtype as per local PAM50 analysis.

11. No prior treatment with any systemic therapy for advanced disease.

12. Patients treated with a CDK4/6i in the adjuvant setting with a treatment-freeinterval (TFI) ≥ 12 months following CDK4/6i treatment completion are eligible.

13. Patients have adequate bone marrow, liver, and renal function:

• Hematological (without platelet, red blood cell transfusion, and/or granulocytecolony-stimulating factor support within 14 days before first study treatmentdose): White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x 109/L, and hemoglobin ≥ 9.0 g/dL (≥ 5.6mmol/L).

• Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit ofnormal (x ULN) (≤ 3 x ULN in patients with liver metastases or know history ofGilbert's disease); alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 x ULN inpatients with liver/or bone metastases); aspartate transaminase (AST) andalanine transaminase (ALT) ≤ 3 x ULN (≤ 5 x ULN in patients with livermetastases).

• Renal: Creatinine clearance ≥ 30 mL/min as determined by Cockcroft Gault (usingactual body weight).

• Coagulation: International normalized ratio or prothrombin time and eitherpartial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN.

14. Resolution of all acute toxic effects of prior anti-cancer therapy to Grade ≤ 1 asdetermined by the US National Cancer Institute (NCI)-Common Terminology Criteria forAdverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicitiesnot considered a safety risk for the patient at investigator's discretion).

15. Women of childbearing potential who are sexually active with a non-sterilized malepartner must have a negative serum pregnancy test within 14 days before studytreatment initiation. In addition, they must agree to use one highly effectivemethod of birth control from the time of screening until 7 months after the lastdose of T-DXd, or within the time period specified per local prescribing guidelinesafter the final dose of physician's choice of CDK4/6i plus ET. Female patients mustrefrain from egg cell donation and breastfeeding during this same period.

16. Male participants who are sexually active with a female partner of childbearingpotential must be surgically sterile or using an acceptable method of contraceptionfrom the time of screening until 4 months after the last dose of T-DXd, or withinthe time period specified per local prescribing guidelines after the final dose ofphysician's choice of CDK4/6i plus ET. Male participants must not donate or banksperm during this same period.

17. Patients must be accessible for treatment and follow-up.

Exclusion Criteria:

1. Current participation in another therapeutic clinical trial, except othertranslational studies.

2. Treatment with approved or investigational cancer therapy within 3 weeks prior toinitiation of study drug.

3. Treatment with chloroquine/hydroxychloroquine within 14 days prior to initiation ofstudy drug.

4. Have previously been treated with T-DXd and/or fulvestrant. Note: patients whoexperienced relapse after more than 1 year from completion of fulvestrant areeligible. Note I: previous treatment with anti-HER2 therapies in (neo-) adjuvant setting willbe allowed for participants who showed conversion from HER2-positive expression inprimary breast tumor sample to HER2-low or HER2-ultralow expression (HER2 loss) inrelapsed tumor sample.

5. Patients with advanced, symptomatic, visceral spread, that are at risk oflife-threatening complications in the short term (including patients with massiveuncontrolled effusions [pleural, pericardial, and/or peritoneal] and pulmonarylymphangitis).

6. Impairment of gastro-intestinal (GI) function or GI disease that may significantlyalter the absorption of CDK4/6i, such as history of GI surgery which may result inintestinal blind loops and patients with clinically significant gastroparesis, shortbowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease, ordiarrhea of CTCAE Grade > 1.

7. Known central nervous system (CNS) involvement (brain metastases and/orleptomeningeal carcinomatosis). Subjects with clinically inactive brain metastasesmay be included in the study. Subjects with treated brain metastases that are nolonger symptomatic and who require no treatment with corticosteroids oranticonvulsants may be included in the study if they have recovered from the acutetoxic effect of radiotherapy.

8. Have a concurrent malignancy or malignancy within 5 years of study enrollment withthe exception of carcinoma in situ of the cervix and basal cell carcinoma orsquamous cell carcinoma of the skin that has been previously treated with curativeintent. For other cancers considered to have a low risk of recurrence, discussionwith the Sponsor's Medical Monitor is required.

9. Known allergy or hypersensitivity reaction to any of the investigational medicinalproducts (IMPs) or their inactive ingredients.

10. Palliative radiotherapy with a limited field of radiation within 2 weeks or withwide field of radiation or to more than 30% of the bone marrow within 4 weeks priorto start of study treatment.

11. Major surgical procedure or significant traumatic injury within 4 weeks before thefirst dose of study treatment or anticipation of need for major surgery within thecourse of the study treatment.

12. Has an active cardiac disease or a history of cardiac dysfunction or conductionabnormalities including, but not confined, to any of the following:

• Participants with a medical history of myocardial infarction within 6 monthsbefore screening, symptomatic congestive heart failure (NYHA Class II to IV),unstable angina pectoris, or a recent (< 6 months) cardiovascular eventincluding stroke. Participants with troponin levels above ULN at screening (asdefined by the manufacturer), and without any myocardial related symptoms,should have a cardiologic consultation to rule out myocardial infarction.

• Left ventricular ejection fraction (LVEF) < 55% as determined by multigatedacquisition (MUGA) scan or echocardiogram (ECHO).

• History of arrhythmia (multifocal premature ventricular contractions, bigeminy,trigeminy, or ventricular tachycardia), which is symptomatic or requirestreatment (NCI-CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillationdespite treatment, or asymptomatic sustained ventricular tachycardia.Participants with atrial fibrillation controlled by medication or arrhythmiascontrolled by pacemakers will be permitted to enroll.

• QT interval corrected by Fridericia's formula (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG).

• History of QT prolongation associated with other medications that requireddiscontinuation of that medication, or any current concomitant medication knownto prolong the QT interval and cause Torsades de Pointes.

• Congenital long QT syndrome, family history of long QT syndrome, or unexplainedsudden death under 40 years of age in first-degree relatives.

13. Clinically severe pulmonary compromise resulting from intercurrent pulmonaryillnesses including, but not limited to, any underlying pulmonary disorder (e.g.,pulmonary emboli within 3 months of the study enrolment, severe asthma, severechronic obstructive pulmonary disease, restrictive lung disease, pleural effusion,post COVID-19 pulmonary fibrosis, etc.), and any autoimmune, connective tissue, orinflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis,Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy (complete).

14. Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis thatrequired steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitisthat cannot be ruled out by imaging at screening.

15. Pregnant or lactating women or patients not willing to apply highly effectivecontraception as defined in the protocol.

16. Current known infection with hepatitis B virus (HBV), or hepatitis C virus (HCV).Patients with past HBV infection or resolved HBV infection (defined as having anegative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B coreantibody [HBcAb] test, accompanied by a negative HBV DNA test), and > 6 months offanti-viral treatment are eligible. Those participants should be closely monitoredfor HBV reactivation and have access to a local hepatitis B expert during and afterthe study.

17. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

18. Patients with HCV co-infection or history of HCV co-infection.

19. Patients with cirrhosis or fibrosis on prior imaging or biopsy.

20. Has an active primary immunodeficiency or known human immunodeficiency virus (HIV)infection.

21. Other active uncontrolled infection at the time of enrollment.

22. Receipt of live or attenuated vaccine within 30 days prior to the first dose ofstudy treatment.

23. A history of uncontrolled seizures, CNS disorders, or serious and/or unstablepre-existing psychiatric disability judged by the investigator to be clinicallysignificant and adversely affecting compliance to study drugs or interfering withsubject safety.

24. Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to bepotent CYP3A4 inducers (for examples, see the Prohibited Medications Section).

25. Known substance abuse or any other concurrent severe and/or uncontrolled medicalcondition that would, in the investigator's judgment, contraindicate patientparticipation.

26. Inability or unwillingness to comply with the requirements of the protocol in theopinion of the investigator.