Trastuzumab Deruxtecan vs Endocrine Therapy in Low-HER2 HR+ Advanced Breast Cancer

Inclusion Criteria:

1. Histologically or cytologically confirmed hormone receptor-positive advanced breastcancer patients

2. Have recurrent, metastatic, or unresectable disease

3. Have HER2-low expression status, defined as IHC 2+/ISH- or IHC 1+,with avalidated assay by ASCO/CAP guidelines

4. Have no previous history of HER2-positive breast cancer (IHC 3+ or ISH+) byASCO/CAP guidelines

5. The hormone receptor (HR) status is defined by ER/PR IHC nuclear staining, andER or PgR ≥1% is defined as hormone receptor-positive status

6. Patients who progressed on 1st line endocrine + CDK4/6 inhibitor therapy foradvanced breast cancer and received no other systemic therapy for advanced breastcancer. The all FDA-approved CDK4/6 inhibitors (palbociclib, ribociclib, andAbemaciclib) are allowed, and combination with aromatase inhibitors or fulvestrantare both allowed.

7. Patients who have received chemotherapy or adjuvant endocrine therapy in theneo-adjuvant or adjuvant setting are eligible.

8. Female patients with ≥19 years of age

9. Radiologic or objective evidence of disease progression on or after the lastsystemic therapy prior to starting study treatment

10. Patients must have at least one measurable lesion by RECIST 1.1 criteria, which wasnot previously irradiated or showed objective progression after irradiation to thatlesion

11. Patients must have an adequate tumor tissue sample available for assessment of HER2by central laboratory and other exploratory biomarker analyses

12. Patients with ECOG performance status 0 or 1

13. Both pre- and post-menopausal patients are eligible, and pre-menopausal patientsshould receive ovarian function suppression treatment (GnRH agonist injection orsurgical bilateral oophorectomy) while receiving fulvestrant or aromatase inhibitortreatment in the control arm.

14. Adequate organ function for treatment Adequate organ and bone marrow function within 14 days before randomization/enrolment as described below:" a) Haemoglobin: ≥ 9.0 g/dL NOTE: Participants requiring ongoing transfusions orgrowth factor support to maintain haemoglobin ≥9.0 g/dL are not eligible. (Red bloodcell transfusion is not allowed within 1 week prior to C1D1) b) Serum albumin: ≥ 2.5g/dL c) International normalised ratio or Prothrombin time and either partialthromboplastin or activated partial thromboplastin time: ≤ 1.5 × ULN d) Absoluteneutrophil count (ANC) ≥1500 cells/mm3

• granulocyte-colony stimulating factor administration is not allowed within 1week prior to C1D1 ) e) Platelets ≥100,000 cells/mm3

• Platelet transfusion is not allowed within 1 week prior to C1D1) f) Estimatedcreatinine clearance ≥50 mL/min, or serum creatinine <1.5x institution upperlimit of normal (ULN) g) Bilirubin≤1.5 x ULN

• if no liver metastases or < 3×ULN in the presence of documented Gilbert'ssyndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline h)AST (SGOT) ≤2.5 x ULN (5.0 x ULN if hepatic metastases) i) ALT (SGPT) ≤2.5 xULN (5.0 x ULN if hepatic metastases)

11. 12-Lead electrocardiogram (ECG) with normal tracing or non-clinically significantchanges that do not require medical intervention

12. QTc interval ≤470 msec and without history of Torsades de pointes based on averageof the screening triplicate 12-lead ECG

13. Pointes or other symptomatic QTc abnormality

14. LVEF (by MUGA or echocardiogram) of ≥50% within 28 days beforerandomization/enrollment

15. No history of pneumonitis other than radiation pneumonitis

16. The patient has provided signed informed consent

17. Neither pregnant or breastfeeding female patients

18. Fertile women who are not in pregnancy or breastfeeding should use effectivecontraception for a period from two weeks before the start of research treatment,during treatment and up to seven months after last dose of study treatment

19. No other concurrent severe and/or uncontrolled medical disease which couldcompromise study participation, including any of the following:

20. Adequate treatment washout period before enrollment are below -Major surgery ≥ 4weeks -Radiation Therapy including palliative stereotactic radiation therapy tochest ≥ 4 weeks -Palliative stereotactic radiation therapy to other anatomic areasincluding whole brain radiation ≥ 2 weeks -Anti-Cancer chemotherapy [Immunotherapy (non-antibody based therapy)], retinoid therapy, hormonal therapy ≥ 3 weeks -Antibody based anti-cancer therapy ≥ 4 weeks -Targeted agents and small molecules ≥ 2 weeks or 5 half-lives, whichever is longer -Nitrosoureas or mitomycin C ≥ 6 weeks -Chloroquine/Hydroxychloroquine ≥ 14 days -Cell-free and CART, peritoneal shunt ordrainage of pleural effusion, ascites or pericardial effusion ≥ 2 weeks prior toscreening assessment

Exclusion Criteria:

1. Previous history of T-DXd or Dato-Dxd treatment for advanced breast cancer

2. Severe Cardiac disease (e.g., uncontrolled hypertension, congestive cardiac failure,ventricular arrhythmias, active ischemic heart disease, myocardial infarction withinthe past year, Left Ventricular Ejection Fraction (LVEF) > grade 2)

3. Patients with a medical history of myocardial infarction (MI) within 6 months beforerandomization/enrolment, symptomatic congestive heart failure (CHF) (New York HeartAssociation Class II to IV), Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms,should have a cardiologic consultation before enrollment to rule out MI.

4. Current active hepatic or biliary disease (except for Gilbert syndrome, asymptomaticgallstones, liver metastasis or stable chronic liver disease per investigatorassessment)

5. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals

6. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviralvaccines are not considered attenuated live vaccines) within 30 days prior to thefirst dose of T-DXd.

7. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined asno worsening to >Grade 2 for at least 3 months prior to [randomization/enrollment/Cycle 1 Day 1] and managed with standard of caretreatment) that the investigator deems related to previous anticancer therapy, suchas:

• Chemotherapy-induced neuropathy

• Fatigue

• Residual toxicities from prior IO treatment: Grade 1 or Grade 2endocrinopathies which may include:

1. Hypothyroidism/hyperthyroidism

2. Type 1 diabetes

3. Hyperglycaemia

4. Adrenal insufficiency

5. Adrenalitis

6. Skin hypopigmentation (vitiligo)

7. Lung-specific intercurrent clinically significant illnesses including, but notlimited to, any underlying pulmonary disorder (i.e., pulmonary emboli within threemonths prior to study enrollment, severe asthma, severe chronic obstructivepulmonary disorder [COPD], restrictive lung disease, significant pleural effusionetc.), and any autoimmune, connective tissue or inflammatory disorders withpulmonary involvement (i.e.,rheumatoid arthritis, Sjogren's syndrome, sarcoidosisetc.), and/or prior pneumonectomy.

8. Has as a history of (non-infectious) ILD/ pneumonitis, has current ILD/pneumonitis,or where suspected ILD/pneumonitis cannot be ruled out by imaging atscreening.Presence of spinal cord compression, symptomatic CNS metastases, or CNSmetastases that require local CNS-directed therapy (such as radiotherapy orsurgery). Patients with treated brain metastases should be neurologically stable (for 4 weeks post treatment and prior to study enrollment) and without steroidtherapy over physiologic dose (> 10mg prednisolone/day) for at least 2 weeks beforeadministration of study drug.

9. Significantly altered mental status prohibiting the understanding of the study, orwith psychological, familial, sociological, or geographical condition potentiallyhampering compliance with the study protocol and follow-up schedule

10. Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection,or active hepatitis B or C infection. Subjects with past or resolved hepatitis Bvirus (HBV) infection who are anti-HBc positive (+) are eligible only if they areHBsAg negative (-). Patients positive for hepatitis C antibody are eligible only ifpolymerase chain reaction is negative for HCV RNA. Subjects should be tested for HIVprior to randomization/enrollment if required by local regulations or institutionalreview board (IRB)/ethics committee (EC).

11. Multiple primary malignancies within 5 years, except adequately resectednon-melanoma skin cancer, curatively treated in-situ disease, other solid tumorscuratively treated, or contralateral breast cancer.

12. Patients unable to swallow orally administered medication and patients withgastrointestinal disorders likely to interfere with absorption of the studymedication.

13. Pregnant or breast-feeding women.

14. Previous allogeneic bone marrow transplant.

15. Patients with a known hypersensitivity to T-DXd

16. History of severe hypersensitivity reactions to other monoclonal antibodies

17. Prior treatment with antibody drug conjugate that comprised an exatecan derivativethat is a topoisomerase I inhibitor