- * Male/female participants who are at least 18 years of age on the day of signing
informed consent with histologically confirmed diagnosis of locally advanced or
metastatic, histologically documented hormone receptor positive (ER and/or PR
expression >1%) and HER2- breast cancer by local testing, not amenable to surgical
therapy will be enrolled in this study.
- HER2 negativity is defined as either of the following by local laboratory
assessment: IHC 0, IHC 1+ or IHC2+/in situ hybridisation (ISH/FISH) negative as
per American Society of Clinical Oncology (ASCO)-College of American Pathologists
Guideline (CAP) guideline82.
- ER and/or PR positivity are defined as >1% of cells expressing HR via IHC
analysis as per ASCO-CAP guideline83.
- The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.
- Postmenopausal, as defined by at least one of the following criteria:
- Age ≥60 years;
- Age <60 years and cessation of regular menses for at least 12 consecutive months
with no alternative pathological or physiological cause (in the absence of
chemotherapy, tamoxifen, toremifene, or ovarian suppression); and serum estradiol
and FSH level within the laboratory's reference range for postmenopausal females;
- Documented bilateral oophorectomy,
- Medically confirmed ovarian failure OR
Pre/perimenopausal, i.e., not meeting the criteria for being postmenopausal:
Pre/perimenopausal women can be enrolled if amenable to be treated with the LHRH agonist.
Patients must have commenced treatment with LHRH agonist at least 4 weeks prior to
- * No more than one prior line of chemotherapy for recurrent locally advanced or
- Prior radiation therapy for metastatic disease is permitted. Subjects who were treated
with radiation therapy may participate as long as at least 2 weeks have elapsed since
the last dose of radiation therapy or have recovered from the effects of radiation
before treatment start whichever is the latest.
- Disease refractory to aromatase inhibitors or fulvestrant or tamoxifen, defined as
recurrence during or within 12 months after the end of adjuvant treatment or
progression during or within 1 months after the end of treatment for advanced disease.
Notes: Endocrine therapy do not have to be the last treatment prior to first treatment
administration. Other prior anticancer endocrine therapy in combination with CDK 4/6
inhibitors or PI3K-pathway-targeted therapies (including PI3K, mTOR, PDK and AKT
inhibitors) are also allowed. Patients who have received fulvestrant, exemestane and
tamoxifen may be eligible
- * Availability of formalin-fixed paraffin-embedded (FFPE) tumor block, taken less than
12 months before the start of the treatment during metastatic disease, if not
available, confirmation by the Medical monitor will be required to include the patient
in the study. A study-specific pathology report should be associated with the sample
(every effort should be done to obtain the sample after the previous therapeutic
regimen for advanced disease). The tumor tissue should be of good quality based on
total and viable tumor content and must be evaluated centrally for PAM50 analysis
prior to enrollment. Patients whose tumor tissue is not evaluable for central testing
are not eligible unless a biopsy from metastatic lesion is performed for this purpose.
a) Acceptable samples include core needle biopsies for deep tumor tissue or
excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or
mucosal lesions or biopsies from bone metastases.
c) Fine needle aspiration, brushing, cell pellet from pleural effusion and lavage
samples are not acceptable.
- HER2-E subtype as per PAM50 analysis confirmed by the designated laboratory.
- * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed within 7 days prior to the date of enrollment.
- * Life expectancy ≥ 12 weeks
- * Measurable disease or non-measurable (but evaluable), as defined by RECIST v1.1.
(Note: Previously irradiated lesions can be considered as measurable disease only if
disease progression has been unequivocally documented at that site since radiation).
- Adequate hematologic and end-organ function
- Baseline left ventricular ejection fraction (LVEF) ≥ 50% measured by echocardiography
(ECHO) or Multiple Gate Acquisition (MUGA) scan.
• A male participant must agree to use contraception as detailed in Appendix 3 of this
protocol during the treatment period and for at least 120 days form the last doses of
neratinib and refrain from donating sperm during this period.
- A female participant is eligible to participate if she is not pregnant (see Appendix
3), not breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR
- A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the
treatment period and for at least 120 days from the last dose of neratinib.
- Prior treatment with any ERBB2-directed TKI (eg, lapatinib, afatinib, dacomitinib,
- Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or
cumulative doxorubicin dose >450 mg/m2. If another anthracycline or more than one
anthracycline has been used, the cumulative dose must not exceed the equivalent of 450
- Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart
failure (New York Heart Association functional classification of ≥2), unstable angina
(symptomatic angina pectoris within the past 180 days that required the initiation of
or increase in anti-anginal medication or other intervention), myocardial infarction
within 12 months of enrollment, or ventricular arrhythmia (except for benign premature
- Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg,
Crohn's disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] Common
Terminology Criteria for Adverse Events Version 5.0 [CTCAE v.5.0] diarrhea of any
etiology at baseline).
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to C1D1 (see
Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required.
- Presence of any acute toxic effects from prior anti-cancer therapy or major surgical
procedures to NCI CTCAE version 5.0 Grade ≤ 1 (except alopecia or other toxicities not
considered a safety risk for the patient at investigator´s discretion). Note:
Placement of central venous access catheter(s) (e.g., port or similar) is not
considered a major surgical procedure and is therefore permitted.
- Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with
indwelling catheters, such as PleurX® are allowed).
- Uncontrolled hypercalcemia (>1.5 mmol/L [>6 mg/dL] ionized calcium or serum calcium
[uncorrected for albumin] >3 mmol/L [>12 mg/dL] or corrected serum calcium >ULN) or
clinically significant (symptomatic) hypercalcemia
- * Has a known additional malignancy that is progressing or has required active
treatment within the past 3 years. Note: Participants with basal cell carcinoma of the
skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g. breast carcinoma,
cervical cancer in situ) that have undergone potentially curative therapy are not
- Has known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically
stable and on a chronic stable dose of ≤ 2 mg total daily of dexamethasone (or
equivalent) during the last 14 days.
- * Has a history of (non-infectious) pneumonitis that required steroids or has current
- * Prior solid organ transplantation
- Has an active infection requiring systemic therapy.
- * Has a known history of Human Immunodeficiency Virus (HIV).
- * Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is
detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required
unless mandated by local health authority.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
- Unable or unwilling to swallow tablets.
- Known hypersensitivity to any component of the investigational product, required
combination therapy, or loperamide.
- Patients being treated with drugs recognized as being strong inhibitors or inducers of
the isoenzyme CYP3A4/P-gp isoform of cytochrome P450: Ritonavir (antiretroviral),
carbamazepine, phenobarbital, phenytoin (antiepileptics), St John's wort (Hypericum
perforatum) (herbal product), rifampicin, Rifabutin (antimycobacterial), Ketoconazole,
Itroconazole, Voriconazole (antifungal), Telithromycin, Clarithromycin (antibiotic).
Co-administration with moderate CYP3A4/P-gp inhibitors: fluconazole (antifungal),
diltiazem, verapamil (calcium-channel blockers), erythromycin (antibiotic), Severe
hepatic impairment (Child-Pugh C)) within the last 5 days prior to first treatment
- * Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of neratinib.