NeoAdjuvant Therapy Comparing Sacituzumab Govitecan+Pembrolizumab vs. SoC Chemotherapy in Clinical Stage II-III, Triple-negative Early Breast Cancer

TNBC is a heterogeneous disease with distinct pathological, genetic, and clinical features among subtypes. Treatment results for high-risk primary TNBC remain poor compared to other breast cancer subtypes. Preoperative chemotherapy is the standard of care for patients with stage II or III primary TNBC. Multiple lines of clinical evidence demonstrate that TNBC patients who achieve a pCR to NACT, (ypT0/is ypN0), have an excellent long-term prognosis. A meta-analysis of individual patient data confirmed a strong association of pCR after NACT with improved long-term event-free survival (EFS, hazard ratio \[HR\] 0.24) and overall survival (OS, HR 0.16) benefit. Taxane- and anthracycline-based neoadjuvant regimens generally result in pCR rates between 25-50% \[REFs\], whereas the addition of platinum increases pCR rates to approximately 50-55%. The KEYNOTE-522 trial has demonstrated that the addition of the immune-checkpoint inhibitor PEM to anthracycline- (AC), taxane- and platinum-based NACT resulted in a significant increase in pCR rates to nearly 65%, associated with a significant reduction of recurrences (EFS, HR 0.65 at 5 years) and improvement of OS (HR 0.66). Based on these results, the KEYNOTE-522 regimen has been approved by the FDA and EMA and has become the standard of care for patients with stage II or III TNBC. Despite this significant progress, two major questions remain unresolved which will be investigated in the ADAPT-TN-IV trial: 1. Do all patients require the full 6 months of NACT as per KEYNOTE-522 or is there a subgroup of patients who are sufficiently treated with 12 weeks of NACT plus PEM? 2. Can incorporation of ADCs into the KEYNOTE-522 regimen improve response and outcomes in patients without an optimal early response? The outcome of patients with residual disease after 24 weeks of NACT and PEM remains suboptimal and there is an urgent need for more effective strategies. ADCs such as SG have demonstrated superior efficacy compared to standard chemotherapy in metastatic TNBC, resulting in substantially higher response rates and improved progression-free (PFS) and OS. Combination studies of ADCs and immunotherapy in metastatic TNBC have demonstrated significant activity, suggesting possible synergistic activity It is therefore a logical next step to investigate, whether the incorporation of SG in the NACT regimen can improve pCR rates and EFS results in patients who have residual clinical disease after 12 weeks of NACT with CARBO/PAC + PEM.

Inclusion Criteria: Minimal eligibility criteria to be met for registration in the clinical trial: 1. TNBC: ER = 0%, PR = 0%, and HER2- (i.e., immunohistochemistry \[IHC\] with DAKO score ≤ 1 or fluorescence in situ hybridization \[FISH\]-negative) 2. or TNBC-like: ER ≤ 10% positive cells in IHC, PR \< 10% positive cells in IHC, and HER2- (i.e., IHC with DAKO score ≤ 1 or FISH negative) 3. All patients, independent from gender 4. ≥18 years at diagnosis 5. Histologically confirmed unilateral, primary invasive carcinoma of the breast Note: bilateral, multicentric, or multifocal carcinoma may be included, if there is a clear target (primary) lesion, that is subject to treatment decisions and solely evaluated and documented for study purposes. Histological confirmation of all lesions as TNBC is mandatory. 6. Clinical stage II-III at baseline 7. No clinical evidence for distant metastasis (M0) 8. Cognitive and language skills to complete quality of life (QoL) questionnaires Additional eligibility criteria to be met for assignment to cohort I or II: 9. Completed 9-12 weeks of NACT with CARBO + PEM or PAC q1w + PEM q3w with the last dose of NACT given less than 2 weeks ago. Patients may also be considered if their NACT treatment was switched to nab-PAC due to intolerance to PAC. * Patients with progressive disease during taxane-CARBO treatment are allowed to participate in cohort II after consultation with sponsor, provided that at least 6-9 weeks of NACT with taxane-CARBO q1w and PEM q3w have been administered * Patients experiencing toxicities due to PEM, in case of contraindications or other medical reasons against PEM administration (with or without permanent discontinuation of PEM) can nevertheless be included, even if PEM will not be administered anymore. The number of patients starting the study without PEM is limited to 10%. 10. Tumour block available for central pathology review 11. Performance Status ECOG ≤ 1 or Karnofsky Index ≥ 80% 12. Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements 13. The patient must be capable of giving informed consent and be willing and able to comply with the requirements and restrictions in this protocol and accessible for treatment and follow-up 14. Laboratory requirements (female and male patients, ≤ 14 days old) * Neutrophils \> 1.5 109/L, * Platelets \> 100 109/L, * Total bilirubin \< 1 x upper level of normal (ULN), * ASAT (sGOT) \< 2.5 x ULN, * ALAT (sGPT) \< 2.5 x ULN, * Creatinine ≤1.5 × ULN OR clearance ≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN 15. Clinical assessments: \- Normal Electrocardiogram (ECG) (within 42 days prior to induction treatment) 16. Negative pregnancy test (urine or serum) within ≤ 14 days prior to registration in premenopausal patients and immediate implementation of adequate contraceptive measures. Note: Pregnancy testing is to be repeated according to Schedule of Activities. 17. The following age-specific requirements apply: * Women aged \