Sacituzumab Govitecan in Primary HER2-negative Breast Cancer

Inclusion Criteria:

1. Written informed consent prior to beginning specific protocol procedures, includingexpected cooperation of the patients for the treatment and follow-up, must beobtained and documented according to the local regulatory requirements.

2. Age at diagnosis at least 18 years.

3. Willingness and ability to provide archived formalin fixed paraffin embedded tissue (FFPE) block from surgery after neoadjuvant chemotherapy and from core biopsy beforestart of neoadjuvant chemotherapy, which will be used for centralized prospectiveconfirmation of HR status, HER2 status, Ki-67 and tumor-infiltrating lymphocytes (TILs) and for retrospective exploratory correlation between genes, proteins, andmRNAs relevant to sensitivity/resistance to the investigational agents. For patientswith bilateral carcinoma, FFPE blocks from both sides have to be provided forcentral testing.

4. Histologically confirmed unilateral or bilateral primary invasive carcinoma of thebreast, confirmed histologically by core biopsy. The lead tumor has to be defined bythe investigator based on the inclusion criteria for the respective subtype and onthe risk status.

5. Centrally confirmed HER2-negative (IHC score 0-1 or FISH negative according toASCO/CAP guideline) and either

• HR-positive (≥1% positive stained cells) disease or

• HR-negative (<1% positive stained cells) assessed preferably on tissue frompostneoadjuvant residual invasive disease of the breast, or if not possible, ofresidual nodal invasion. If not evaluable, core of diagnostic biopsy will beused. In case of bilateral breast cancer, HER2-negative status has to beconfirmed for both sides.

6. Patients with residual invasive disease after neoadjuvant chemotherapy at high riskof recurrence defined by either:

• For HR-negative: any residual invasive disease > ypT1mi and/or ypN1>1mm

• For HR-positive disease: a CPS+EG score ≥ 3 or CPS+EG score 2 and ypN+ usinglocal ER and grade assessed on core biopsies taken before start of neoadjuvanttreatment.

7. Adequate surgical treatment including resection of clinically evident disease andipsilateral axillary lymph node dissection. SNB before NACT is discouraged. Axillarydissection before NACT is not permitted. Axillary dissection, including TargetedAxillary Dissection (TAD) should be performed according to guidelines. Histologiccomplete resection (R0) of all invasive and in situ tumors is required.

8. Patients must have received neoadjuvant taxane-based chemotherapy for 16 weeks (anthracyclines are permitted). This period must include 6 weeks of a taxanecontaining neoadjuvant chemotherapy (exception: for patients with progressivedisease that occurred after at least 6 weeks of taxane-containing neoadjuvantchemotherapy, a total treatment period of less than 16 weeks is also eligible).

9. No clinical evidence for locoregional or distant relapse during or afterpreoperative chemotherapy. Local progression during chemotherapy is not an exclusioncriterion if adequate local control could be obtained.

10. In case of local progression during neoadjuvant therapy, distant metastases must beexcluded by adequate imaging (CT/MRI recommend) prior to entering the trial.

11. Immune checkpoint inhibitor / immunotherapy during (neo)adjuvant therapy is alloweduntil the completion of radiotherapy.

12. Patients with known gBRCA1/2 mutation without indication to adjuvant olaparibtherapy are allowed to participate in the trial.

13. An interval of less than 16 weeks since the date of final surgery or less than 10weeks from completing radiotherapy (whichever occurs last) and the date ofrandomization is required.

14. Radiotherapy should be delivered before the start of study treatment. Radiotherapyto the breast is indicated in all patients with breast conserving surgery and to thechest wall and lymph nodes according to local guidelines as well as in all patientswith cT3/4 or ypN+ disease treated by mastectomy.

15. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

16. Resolution of all acute toxic effects of prior anti-cancer therapy or surgicalprocedure or radiotherapy to NCI CTCAE v 5.0 grade ≤ 1 (except alopecia or othertoxicities not considered a safety risk for the patients at the investigator´sdiscretion).

17. Estimated life expectancy of at least 5 years irrespective of the diagnosis ofbreast cancer.

18. The patient must be accessible for scheduled visits, treatment and follow-up.

19. Normal cardiac function after neoadjuvant chemotherapy must be confirmed accordingto local guidelines. Results for LVEF must be above the normal limit of theinstitution.

20. Laboratory requirements: Hematology

• Absolute neutrophil count (ANC) ≥1.5 x 109 / L

• Platelets ≥100 x 109 / L

• Hemoglobin ≥10 g/dL (≥6.2 mmol/L) Hepatic function

• Total bilirubin <1.25x UNL

• AST and ALT ≤1.5x UNL

• Alkaline phosphatase ≤2.5x UNL Renal Function

• <1.25x ULN creatinine or creatinine clearance ≥30 ml/min (according toCockroft-Gault, if creatinine is above UNL).

21. Negative pregnancy test (urine or serum) within 14 days prior to randomization forall women of childbearing potential. A woman is considered to be of childbearingpotential if she is not postmenopausal. Postmenopausal is defined as:

• Age ≥60 years

• Age <60 years and ≥12 continuous months of amenorrhea with no identified causeother than menopause

• Surgical sterilization (bilateral oophorectomy and/or hysterectomy).

22. For women of childbearing potential and males with partners of childbearingpotential: agreement to remain abstinent (refrain from heterosexual intercourse) oruse contraceptive methods that result in a failure rate of < 1% per year during thetreatment period and for at least 6 months after the last dose of sacituzumabgovitecan for female patients and for at least 3 months for male patients; for atleast 6 months after the last dose of capecitabine or carboplatin/cisplatin forfemale patients and for at least 3 months after the last dose of capecitabine or 6months after the last dose of carboplatin/cisplatin for male patients. Examples ofnon-hormonal contraceptive methods with a failure rate of < 1% per year include:bilateral tubal ligation; male partner sterilization; intrauterine devices.

23. Complete staging work-up prior to the initiation of neoadjuvant chemotherapy.Missing staging investigations must be performed prior to randomization.

Exclusion Criteria:

1. Known hypersensitivity reaction to one of the compounds or substances used in thisprotocol.

2. Patients with definitive clinical or radiologic evidence of stage IV cancer (metastatic disease) are not eligible.

3. Patients with known gBRCA1/2 mutation and indicated or planned adjuvant olaparibtherapy if available.

4. Patients with a history of any malignancy are ineligible with the followingexceptions:

• Patient has been disease-free for at least 5 years and is at low risk forrecurrence of that malignancy

• CIS of the cervix, basal cell and squamous cell carcinomas of the skin.

5. Female patients: pregnancy or lactation at the time of randomization or intention tobecome pregnant during the study and up to 6 months after sacituzumab govitecan andup to 6 months after treatment with capecitabine or carboplatin/cisplatin.

6. Severe and relevant co-morbidity that would interact with the application ofcytotoxic agents or the participation in the study, including Gilbert´s disease,Crigler-Najjar-Syndrome, known hepatitis B, hepatitis C, known HIV positivity orknown autoimmune disease other than diabetes, vitiligo, or stable thyroid disease,vitiligo, or other autoimmune skin disease with dermatologic manifestations only arepermitted provided all of the following conditions are met:

• Rash must cover < 10% of body surface area

• Disease is well controlled at baseline and requires only low-potency topicalcorticosteroids

• No occurrence of acute exacerbations of the underlying condition requiringpsoralen plus ultraviolet A radiation (PUVA), methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high-potency or oral corticosteroidswithin the previous 12 months.

7. Any condition that interferes with the safe administration of the treatment ofphysician´s choice in case the patient is randomized into the TPC arm.

8. Known or suspected congestive heart failure (>NYHA I) and/or coronary heart disease,angina pectoris requiring antianginal medication, previous history of myocardialinfarction, evidence of prior infarction on ECG, uncontrolled or poorly controlledarterial hypertension (i.e. BP >150/90 mmHg under treatment with at maximum threeantihypertensive drugs), rhythm abnormalities requiring permanent treatment (excluding chronic atrial fibrillation not requiring a pacemaker), clinicallysignificant valvular heart disease, supraventricular and nodal arrhythmias requiringa pacemaker or not controlled with medication;conduction abnormality requiring apacemaker.

9. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitisobliterans), drug-induced pneumonitis, idiopathic pneumonitis or active pneumonitison chest CT scan.

10. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving chemotherapy.

11. History of significant neurological or psychiatric disorders including psychoticdisorders, dementia or seizures that would prohibit the understanding and giving ofinformed consent.

12. Any condition that, in the opinion of the investigator, would interfere withevaluation of study treatment or interpretation of patient safety or study results.

13. Known allergic reactions to irinotecan.

14. Concurrent treatment with:

• Chronic corticosteroids prior to study entry with the exceptions of intranasaland inhaled corticosteroids or systemic corticosteroids at physiological doses,which are not to exceed 10 mg/day of prednisone, or equivalent corticosteroid.