A Randomized Secondary Adjuvant Treatment Intervention Study Comparing Trastuzumab-Deruxtecan to SOC Therapy in eBC Patients With Molecular Relapse

Inclusion Criteria:

Patients will be eligible for study participation if they comply with the following criteria:

1. Written informed consent for all study procedures according to local regulatoryrequirements prior to beginning specific protocol procedures.

2. Females or males, ≥ 18 years and ≤ 75 years of age.

3. Invasive breast carcinoma as revealed by local pathology that is either:

4. HER2-positive defined as an immunohistochemistry (IHC) score of 3+ and/orpositive by in situ hybridization (ISH) in Her2 2+ tumors (as defined in 2018American Society of Clinical Oncology - College of American Pathologists [ASCO-CAP] guidelines)

5. HER2-low defined as an immunohistochemistry (IHC) score of 1+ or an IHC scoreof 2+ with a mandatory negative in situ hybridization (ISH), as defined in 2018American Society of Clinical Oncology - College of American Pathologists [ASCO-CAP] guidelines.

6. Complete resection of the tumor with resection margins free of invasive carcinoma (R0).

7. Participation in the SURVIVE study and evidence of molecular relapse (as assessedbased on a positive ctDNA result obtained in the SURVIVE-study)

8. No evidence of metastatic relapse as revealed by a CT-scan (Abdomen/Chest) and aSPECT bone scan that must be performed within 8 weeks before randomization (M0).

9. Completion of surgery, (neo-)adjuvant chemotherapy (if applicable) and radiationtherapy (if applicable, whichever occurred last) at least 6 months beforerandomization.

10. Adjuvant/Postneoadjuvant treatment with Trastuzumab, Pertuzumab, T-DM1,Capecitabine, Pembrolizumab, and Olaparib must be discontinued upon randomizationinto Arm A (treatment with trastuzumab deruxtecan). The washout periods (see Table

2. must be complied with. Endocrine therapy (i.e. Tamoxifen, Letrozol, Anastrozol,Fulvestrant or Exemestane) can be administered simultaneously to treatment withtrastuzumab deruxtecan.

9. Known HR status, per local laboratory assessment, as defined by ASCO-CAP guidelines (≥1%): HR-positive status defined by either positive estrogen receptor (ER) and/orpositive progesterone receptor (PR) status. HR-negative status defined by both knownnegative ER and known negative PR

10. Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior to randomization

11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening

12. Adequate organ and bone marrow function within 28 days before randomization asdescribed in table 1. Organ and bone marrow function criteria must also be met whenlaboratory tests are repeated within 3 days before Cycle 1 Day 1. Transfusion (redblood cell or platelet) or G-CSF administration is not allowed within 2 weeks priorto the day on which marrow function is assessed.

13. Adequate treatment washout period before treatment with trastuzumab deruxtecan (incase of randomization into cohort A), defined in table 2.

14. Female subjects: Evidence of post-menopausal status or negative serum pregnancy testfor females of childbearing potential who are sexually active with a non-sterilizedmale partner. For women of childbearing potential, a negative result for serumpregnancy test (test must have a sensitivity of at least 25 mIU/mL) must beavailable at the screening visit and urine beta-human chorionic gonadotropin (β-HCG)pregnancy test prior to each administration of Investigational Medicinal Product (IMP).

15. Women of childbearing potential are defined as those who are not surgicallysterile (underwent bilateral salpingectomy, bilateral oophorectomy, or completehysterectomy) or post-menopausal. Women will be considered post-menopausal ifthey have been amenorrhoeic for 12 months without an alternative medical cause.

16. Female patients of childbearing potential who are sexually active with anon-sterilized male partner must use at least one highly effective method ofcontraception (see 5.5.1.) from the time of screening and must agree tocontinue using such precautions for 7 months after the last dose of IMP. Notall methods of contraception are highly effective. Female patients must refrainfrom breastfeeding while on study and for 7 months after the last dose of IMP.Complete heterosexual abstinence for the duration of the study and drug washoutperiod is an acceptable contraceptive method if it is line with the patient'susual lifestyle (consideration must be made to the duration of the clinicaltrial); however, periodic or occasional abstinence, the rhythm method, and thewithdrawal method are not acceptable.

17. Female subjects must not donate, or retrieve for their own use, ova from thetime of randomization and throughout the study treatment period, and for atleast 7 months after the final study drug administration. They should refrainfrom breastfeeding throughout this time. Preservation of ova may be consideredprior to enrollment in this study.

18. Male subjects: Non-sterilized male patients who are sexually active with a femalepartner of childbearing potential must use a condom with spermicide from screeningto 4 months after the final dose of IMP. Complete heterosexual abstinence for theduration of the study and drug washout period is an acceptable contraceptive methodif it is in line with the patient's usual lifestyle (consideration must be made tothe duration of the clinical trial); however, periodic or occasional abstinence, therhythm method, and the withdrawal method are not acceptable. It is stronglyrecommended for the female partners of a male patient to also use at least onehighly effective method of contraception throughout this period, as described insection 5.5.1. In addition, male patients should refrain from fathering a child, orfreezing or donating sperm from the time of randomization/enrolment, throughout thestudy and for 4 months after the last dose of IMP. Preservation of sperm should beconsidered prior to enrolment in this study.

Exclusion Criteria:

1. Stage IV (metastatic) breast cancer.

2. Patients with a history of any secondary primary malignancy are ineligible with thefollowing exceptions:

• ipsi- or contralateral non-invasive carcinoma of the breast (DCIS)

• other, curatively treated in-situ disease

• adequately treated non-melanoma carcinoma of the skin

3. Prior treatment with T-DXd.

4. Combination of T-DXd with any other anti-cancer treatment is not permitted, exceptfor endocrine therapy.

5. 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 ofthe clinical study results.

6. Patients with a medical history of myocardial infarction (MI) within 6 months beforefirst exposure to study intervention, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), Subjects with troponin levels above ULNat screening (as defined by the manufacturer), and without any myocardial relatedsymptoms, should have a cardiologic consultation before enrollment to rule out MI.

7. Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG.

8. History of (non-infectious) Interstitial lung disease (ILD) / pneumonitis thatrequired steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitiscannot be ruled out by imaging at screening.

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

10. Active primary immunodeficiency, known uncontrolled active HIV infection or activehepatitis B or C infection. Patients positive for hepatitis C (HCV) antibody areeligible only if polymerase chain reaction is negative for HCV RNA. Subjects shouldbe tested for HIV prior to randomization/enrolment if required by local regulationsor institutional review board (IRB)/ethics committee (EC).

11. Lung criteria:

12. Lung-specific intercurrent clinically significant illnesses including, but notlimited to, any underlying pulmonary disorder (for example pulmonary emboliwithin three months of the study enrollment, severe asthma, severe COPD,restrictive lung disease, pleural effusion etc.)

13. Any autoimmune, connective tissue or inflammatory disorders (for exampleRheumatoid arthritis, Sjogren's, sarcoidosis et cetera) where there isdocumented, or a suspicion of pulmonary involvement at the time of screening.Full details of the disorder should be recorded in the electronic case reportform (eCRF) for patients who are included in the study.

14. Prior pneumonectomy (complete)

15. Participants with past or resolved HBV infection are eligible only if they meet allof the following criteria:

• HBsAg (-) (for > 6 months off anti-viral treatment),

• Anti-HBc (+) (IgG or total Ig),

• HBV DNA undetectable,

• Liver architecture normal (absence of any liver pathology including absence ofcirrhosis 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. Suchparticipants should be closely monitored for HBV reactivation.

13. 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. Note: Patients, if enrolled, should not receive live vaccine during the study and upto 30 days after the last dose of IMP.

14. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Note: Toxicities related to endocrine therapy should be documented but does not leadto exclusion of patient from the study. Also, subjects may be enrolled with chronic, stable Grade 2 toxicities (defined asno worsening to >Grade 2 for at least 3 months prior to first exposure to studyintervention and managed with standard of care treatment) that the investigatordeems related to previous anticancer therapy, such as:

15. Chemotherapy-induced neuropathy

16. Fatigue

17. Residual toxicities from prior immune-oncology treatment: Grade 1 or Grade 2endocrinopathies which may include: i. Hypothyroidism/hyperthyroidism ii. Type 1 diabetes iii. Hyperglycemia iv. Adrenalinsufficiency v. Adrenalitis vi. Skin hypopigmentation (vitiligo)

18. Known allergy or hypersensitivity to study treatment or any of the study drugexcipients.

19. History of severe hypersensitivity reactions to other monoclonal antibodies.

20. Pregnant or breastfeeding female patients, or patients who are planning to becomepregnant.