Sacituzumab Govitecan in Primary HER2-negative Breast Cancer

Phase III, prospective, multi-center, randomized, open label, parallel group, study in patients with HER2-negative breast cancer with residual disease after neoadjuvant chemotherapy with 1:1 allocation to:

* Arm A: Sacituzumab govitecan (days 1, 8 q3w for eight cycles);
* Arm B: treatment of physician´s choice (TPC, defined as capecitabine or platinum-based chemotherapy for eight cycles or observation.

Treatment in either arm will be given for eight cycles.

In patients with HR-positive breast cancer, endocrine-based therapy, which includes the use of CDK4/6 inhibitors, will be administered according to local guidelines. The start of endocrine therapy will be at the discretion of the investigator; however, it will be encouraged to start after surgery/radiotherapy in patients without additional cytotoxic agents.

Adjuvant pembrolizumab can be given until the completion of radiotherapy before randomization. Within the study the use of pembrolizumab in patients with TNBC who received pembrolizumab as neoadjuvant therapy is allowed as monotherapy in the TPC arm, according to the approval of pembrolizumab in this setting.

Neoadjuvant chemotherapy (NACT) allows monitoring of tumor response to treatment and a pathological complete response (pCR) is associated with superior survival. This association is strongest in the most aggressive subtype, i.e. in patients with triple-negative breast cancer (TNBC). Patients with TNBC not achieving a pCR have a 5-year event free survival rate of about 50%. The association between pCR and prognosis is less pronounced in HR-positive/HER2-negative patients. However, the CPS+EG scoring system for prognosis after neoadjuvant chemotherapy, taking into account clinical stage, post treatment pathological stage, estrogen receptor status and grade, leads to an improved estimate of prognosis allowing to select patients at high risk of relapse for post-neoadjuvant therapy. Patients with TNBC not achieving a pCR as well as those with HR-positive/HER2-negative tumors and a CPS+EG score of 3 or 2/ypN+ are at high risk of relapse, warranting additional experimental therapies after NACT.

There is proof of concept, that post-neoadjuvant therapy can significantly improve survival. First data was provided by the CREATE X trial, randomizing patients with residual tumor after neoadjuvant chemotherapy to either capecitabine or observation. CREATE X included HER2-negative patients and demonstrated a significant improvement in disease-free survival (DFS) and overall survival (OS) in the overall population, which was confined to the TNBC subgroup.

Recently, the randomized post-neoadjuvant phase III KATHERINE study demonstrated an improved invasive disease-free survival in HER2-positive patients without pCR after trastuzumab +/- pertuzumab treated postoperatively with T-DM1, an antibody-drug-conjugate compared to trastuzumab.

Sacituzumab govitecan has demonstrated unprecedented activity in heavily pretreated patients with metastatic triple-negative and HR-positive/HER2-negative breast cancer, even after prior immune-checkpoint inhibitors or CDK4/6 and mTOR inhibitors. Based on the results of the phase I/II study, sacituzumab govitecan was granted a breakthrough therapy designation for the treatment of patients with advanced or metastatic TNBC who have received at least two previous lines of treatment for metastatic disease. The efficacy of sacituzumab govitecan in advanced TNBC was confirmed in the phase III ASCENT trial. Based on this study, sacituzumab govitecan received regular approval. Additionally, the TROPiCS-02 study showed an improvement in progression-free survival and OS over single-agent chemotherapy and a manageable safety profile in patients with heavily pre-treated HR-positive/HER2-negative endocrine-resistant, unresectable locally advanced or metastatic BC.

Eligibility Criteria:
Inclusion Criteria:

1. 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.
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 before start of neoadjuvant chemotherapy, which will be used for centralized prospective confirmation of HR status, HER2 status, Ki-67 and tumor-infiltrating lymphocytes (TILs) and for retrospective exploratory correlation between genes, proteins, and mRNAs relevant to sensitivity/resistance to the investigational agents. For patients with bilateral carcinoma, FFPE blocks from both sides have to be provided for central testing.
4. Histologically confirmed unilateral or bilateral primary invasive carcinoma of the breast, confirmed histologically by core biopsy. The lead tumor has to be defined by the investigator based on the inclusion criteria for the respective subtype and on the risk status.
5. Centrally confirmed HER2-negative (IHC score 0-1 or FISH negative according to ASCO/CAP guideline) and either

   * HR-positive (≥1% positive stained cells) disease or
   * HR-negative (\<1% positive stained cells) assessed preferably on tissue from postneoadjuvant residual invasive disease of the breast, or if not possible, of residual nodal invasion. If not evaluable, core of diagnostic biopsy will be used. In case of bilateral breast cancer, HER2-negative status has to be confirmed for both sides.
6. Patients with residual invasive disease after neoadjuvant chemotherapy at high risk of 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+ using local ER and grade assessed on core biopsies taken before start of neoadjuvant treatment.
7. Adequate surgical treatment including resection of clinically evident disease and ipsilateral axillary lymph node dissection. SNB before NACT is discouraged. Axillary dissection before NACT is not permitted. Axillary dissection, including Targeted Axillary Dissection (TAD) should be performed according to guidelines. Histologic complete 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 taxane containing neoadjuvant chemotherapy (exception: for patients with progressive disease that occurred after at least 6 weeks of taxane-containing neoadjuvant chemotherapy, a total treatment period of less than 16 weeks is also eligible).
9. No clinical evidence for locoregional or distant relapse during or after preoperative chemotherapy. Local progression during chemotherapy is not an exclusion criterion if adequate local control could be obtained.
10. In case of local progression during neoadjuvant therapy, distant metastases must be excluded by adequate imaging (CT/MRI recommend) prior to entering the trial.
11. Immune checkpoint inhibitor / immunotherapy during (neo)adjuvant therapy is allowed until the completion of radiotherapy.
12. Patients with known gBRCA1/2 mutation without indication to adjuvant olaparib therapy are allowed to participate in the trial.
13. An interval of less than 16 weeks since the date of final surgery or less than 10 weeks from completing radiotherapy (whichever occurs last) and the date of randomization is required.
14. Radiotherapy should be delivered before the start of study treatment. Radiotherapy to the breast is indicated in all patients with breast conserving surgery and to the chest wall and lymph nodes according to local guidelines as well as in all patients with 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 surgical procedure or radiotherapy to NCI CTCAE v 5.0 grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patients at the investigator´s discretion).
17. Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast cancer.
18. The patient must be accessible for scheduled visits, treatment and follow-up.
19. Normal cardiac function after neoadjuvant chemotherapy must be confirmed according to local guidelines. Results for LVEF must be above the normal limit of the institution.
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 to Cockroft-Gault, if creatinine is above UNL).
21. Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential. A woman is considered to be of childbearing potential if she is not postmenopausal. Postmenopausal is defined as:

    * Age ≥60 years
    * Age \<60 years and ≥12 continuous months of amenorrhea with no identified cause other than menopause
    * Surgical sterilization (bilateral oophorectomy and/or hysterectomy).
22. For women of childbearing potential and males with partners of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 6 months after the last dose of sacituzumab govitecan for female patients and for at least 3 months for male patients; for at least 6 months after the last dose of capecitabine or carboplatin/cisplatin for female patients and for at least 3 months after the last dose of capecitabine or 6 months after the last dose of carboplatin/cisplatin for male patients. Examples of non-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 this protocol.
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 olaparib therapy if available.
4. Patients with a history of any malignancy are ineligible with the following exceptions:

   * Patient has been disease-free for at least 5 years and is at low risk for recurrence 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 to become pregnant during the study and up to 6 months after sacituzumab govitecan and up to 6 months after treatment with capecitabine or carboplatin/cisplatin.
6. Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study, including Gilbert´s disease, Crigler-Najjar-Syndrome, known hepatitis B, hepatitis C, known HIV positivity or known autoimmune disease other than diabetes, vitiligo, or stable thyroid disease, vitiligo, or other autoimmune skin disease with dermatologic manifestations only are permitted 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 topical corticosteroids
   * No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation (PUVA), methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
7. Any condition that interferes with the safe administration of the treatment of physician´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 myocardial infarction, evidence of prior infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP \>150/90 mmHg under treatment with at maximum three antihypertensive drugs), rhythm abnormalities requiring permanent treatment (excluding chronic atrial fibrillation not requiring a pacemaker), clinically significant valvular heart disease, supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;conduction abnormality requiring a pacemaker.
9. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis or active pneumonitis on 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 psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
12. Any condition that, in the opinion of the investigator, would interfere with evaluation 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 intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or equivalent corticosteroid.