NeoAdj. Therapy Comparing Sacituzumab Govitecan (SG) vs. SG+Pembrolizumab in Low-risk, Triple-neg. EBC (ADAPT-TN-III)

Inclusion Criteria:

1. ER + PR negative or low positive (≤10% positive cells in IHC), and HER2 negative (i.e., IHC 0 - 1+ or IHC 2+ with FISH negative) breast cancer

2. All patients, independent from gender

3. ≥18 years at diagnosis

4. Histologically confirmed unilateral, primary invasive carcinoma of the breast Note:bilateral, multicentric, or multifocal carcinoma may be included, if there is aclear target lesion, that is subject to treatment decisions and solely evaluated anddocumented for study purposes.

5. Clinical stage I: cT1a-c, cN0 (clinical stage II only, if patient does not qualifyfor neoadjuvant polychemotherapy+PEM, e.g., elderly population, per investigator´sdecision)

6. No clinical evidence for distant metastasis (M0)

7. Tumour block available for central pathology review

8. Performance Status ECOG ≤ 1 or KI ≥ 80%

9. Negative pregnancy test (urine or serum) within 7 days prior to registration inpremenopausal patients

10. 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

11. The patient must be willing and able to comply with the requirements andrestrictions in this protocol and accessible for treatment and follow-up

12. Laboratory requirements:

• Leucocytes ≥3.5 109/L,

• Neutrophils > 1.5 109/L,

• Platelets ≥100 109/L,

• Haemoglobin ≥10 g/dL,

• AP < 5.0 ULN,

• AST ≤2.5 x ULN,

• ALT ≤2.5 x ULN,

• Total bilirubin ≤1 x ULN,

• Creatinine ≤1.5 × ULN OR clearance ≥30 mL/min for participant with creatininelevels >1.5 × institutional ULN

13. Clinical assessments:

• LVEF within normal limits of each institution, measured by echocardiography andnormal ECG (within 42 days prior to treatment)

14. The following age-specific requirements apply:

• Women aged <50 years will be considered post-menopausal if they have beenamenorrhoeic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone (LH) and follicle-stimulatinghormone (FSH) levels in the post-menopausal range for the site.

• Women aged ≥ 50 years will be considered post-menopausal if they have beenamenorrhoeic for 12 months or more following cessation of all exogenoushormonal treatments.

15. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubtwill be required to use one of the contraception methods outlined for women ofchild-bearing potential if they wish to continue their HRT during the study.Otherwise, they must discontinue HRT to allow confirmation of post-menopausal statusprior to randomization/study enrolment. For most forms of HRT, at least 2-4 weekswill elapse between the cessation of therapy and the blood draw; this intervaldepends on the type and dosage of HRT. Following confirmation of theirpost-menopausal status, they can resume use of HRT during the study without use of acontraceptive method.

16. Female patients of childbearing potential who are sexually active with anon-sterilized male partner must use at least one highly effective method ofcontraception, presented in Table 1 (see Section 4.4.2), from the time of screeningand must agree to continue using such precautions for 7 months after the last doseof IMP. Not all methods of contraception are highly effective. Female patients mustrefrain from breastfeeding while on study and for 7 months after the last dose ofIMP. Complete heterosexual abstinence for the duration of the study and drug washoutperiod is an acceptable contraceptive method if it is line with the patient's usuallifestyle (consideration must be made to the duration of the clinical trial);however, periodic, or occasional abstinence, the rhythm method, and the withdrawalmethod are not acceptable.

17. Female patients must not donate, or retrieve for their own use, ova from the time ofrandomisation and throughout the study treatment period, and for at least 7 monthsafter the final study drug administration. They should refrain from breastfeedingthroughout this time. Preservation of ova may be considered prior to enrolment inthis study.

18. A male participant must agree to use a contraception as detailed in Appendix C ofthis protocol during the treatment period and for at least 7 months after the lastdose of study treatment and refrain from donating sperm during this period.

Exclusion Criteria:

1. Known hypersensitivity reaction to the compounds or incorporated substances of theIMPs

2. Prior malignancy with a disease-free survival of < 5 years, except curativelytreated basalioma of the skin or pTis of the cervix uteri

3. Any history of invasive breast cancer

4. Previous or concurrent treatment with cytotoxic agents for any non-oncologicalreason unless clarified with sponsor

5. Concurrent treatment with other experimental drugs

6. Participation in another interventional clinical trial with or without anyinvestigational not marketed drug within 30 days prior to study entry

7. Concurrent pregnancy; patients of childbearing potential or potentially childbearingpartners of male patients must implement a highly effective (less than 1% failurerate) non-hormonal contraceptive measures during the study treatment

8. Breast feeding woman

9. Reasons indicating risk of poor compliance

10. Patients not able to consent

11. Known polyneuropathy ≥ grade 2

12. Severe and relevant co-morbidity that would interact with the application ofcytotoxic agents or the participation in the study including recovery from majorsurgery, autoimmune disease, known psychiatric/substance abuse disorders, acutecystitis, ischuria, and chronic kidney disease

13. Uncontrolled infection requiring i.v. antibiotics, antivirals, or antifungals

14. History of pneumonitis

15. Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection,or active hepatitis B or C infection. Patients positive for hepatitis C (HCV)antibody are eligible only if polymerase chain reaction is negative for HCV RNA.Patients should be tested for HIV prior to randomisation if required by localregulations or ethics committee (EC).

16. Have active hepatitis B virus (HBV) or hepatitis C virus (HCV). In patients with ahistory of HBV or HCV, patients with detectable viral loads will be excluded.

• Patients who test positive for hepatitis B surface antigen (HBsAg). Patientswho test positive for hepatitis B core antibody (anti-HBc) will require HBV DNAby quantitative polymerase chain reaction (PCR) for confirmation of activedisease.

• Patients who test positive for HCV antibody will require HCV RNA byquantitative PCR for confirmation of active disease. Patients with a knownhistory of HCV or a positive HCV antibody test will not require a HCV antibodyat screening and will only require HCV RNA by quantitative PCR for confirmationof active disease.

17. Patients who test positive for HIV antibody.