Clinical Study for the Treatment of Breast Cancer: the Patient Will Receive Afatinib Plus Letrozole or Letrozole Alone

The purpose of the study is to compare the efficacy of treatment with afatinib plus letrozole to treatment with letrozole alone in women diagnosed with a specific type of breast cancer.

This is an open-label, multicenter, international, randomized, Phase II clinical trial that will assess the efficacy and safety of letrozole in combination with afatinib(oral epidermal growth factor receptor (EGFR ) inhibitor) versus letrozole monotherapy for the first-line treatment of postmenopausal women with ER+, Human Epidermal Growth Factor Receptor 2 (HER2) negative advanced breast cancer with low ER expression.

In order to assess the level of estrogen receptor (ER) expression we will use a semi-quantitative scoring system (McClelland, 1990) defined as :

H-score = (% of cells stained at intensity category 1x1) + (% of cells stained at intensity category 2x2) + (% of cells stained at intensity category 3x3).

This formula results in an H-score in the range of 0-300 where 300 equals 100% of tumor cells stained strongly (i.e., 3+). Low ER expression will be defined as tumor sample with H-score below 160 (Finn, 2009).

All subjects who consented for the study must submit a tumor sample to the designated central laboratory for central confirmation of ER / Progesterone receptor (PR) and HER2 statuses and determination of the H-score. This will be assessed prior to randomization.

Subjects with HER2 negative, ER+ advanced breast cancer with low ER expression defined as H-score between 1 and 159 will enter screening phase and perform the required screening assessments.

Eligible subjects will be randomly assigned in a 1:1 ratio and stratified according to sites of disease (bone only disease vs. other) and prior administration of hormonal therapy in neo/adjuvant setting (Yes vs. No) to either:

Arm A : Continuous regimen of oral letrozole 2.5 mg until progression of disease or any other study treatment discontinuation criteria.

or Arm B : Continuous regimen of oral letrozole 2.5 mg daily plus oral afatinib 30 mg daily until progression of disease or any other study treatment discontinuation criteria.

IN ADDITION the following applies whichever comes first:

* If the patients treated with the combination of afatinib and letrozole (arm B) discontinue the trial treatment (whatever the reason) before 30 November 2018, the patients from the other arm (arm A, letrozole alone) still on treatment will also be discontinued from the trial at the same time. They may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion.
* If the patients treated with afatinib and letrozole (arm B) have not discontinued the trial treatment by 30 November 2018, all patients currently on treatment in the trial (including the ones only treated by letrozole alone (arm A)) will be discontinued from the trial at that time. They may continue receiving their treatment if in alignment with their treating physician judgment as follows:
* Patients in arm A: may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion.
* Patients in arm B: may continue receiving afatinib in the context of alternative drug supply outside the clinical trial as appropriate according to local legislation. Additionally, they may continue receiving letrozole using commercial drug as standard of care according to their treating physician discretion.

Once the patient is discontinued from trial treatment and has undergone the End of Treatment Visit, she will be permanently discontinued from the trial and treated as per local clinical practice.

Eligibility Criteria:
Inclusion Criteria:

* Signed and dated informed consent.
* Postmenopausal females, 18 years of age or older.
* Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of locally recurrent disease not amenable to resection or radiation therapy with curative intent, or metastatic disease.
* HER2 negative breast cancer. Central testing (required for all subjects) must demonstrate that the tumor is HER2 negative by FISH or Immunohistochemistry (IHC).
* ER positive breast cancer. Central testing (required for all subjects) must demonstrate that the tumor is ER+ with low expression (H-score \[1-159\]).
* Paraffin-embedded tumor block(s) or 15 to 20 unstained slides available for centralized assessment of ER, PR, and HER2.
* Measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or bone-only non measurable disease.
* Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1.
* Adequate hematological, hepatic and renal functions.
* Baseline left ventricular ejection fraction (LVEF) 50%.
* Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria:

* Brain metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease.
* Prior treatment with any type of systemic therapy for advanced disease.
* Prior treatment with letrozole in (neo)adjuvant setting with disease-free interval ≤ 12 months from completion of treatment until randomization.
* Prior treatment with any anti HER-family targeted therapy in (neo)adjuvant setting.
* Any concurrent or previous malignancy within 5 years prior to randomization, except for adequately and radically treated basal or squamous skin cancer, or carcinoma in situ of the cervix, or other non-invasive/in-situ neoplasm.
* Non-measurable disease according to RECIST 1.1, with the exception of bone-only non-measurable disease.
* Known pre-existing interstitial lung disease.
* Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom.
* History or presence of clinically relevant cardiovascular abnormalities as per investigator assessment.
* Any other concomitant serious illness or organ system dysfunction as per investigator assessment
* Any contraindication to oral agents.
* Active hepatitis B infection, active hepatitis C infection or known HIV carrier.
* Known or suspected active drug or alcohol abuse.
* Known hypersensitivity to afatinib or letrozole or the excipients of any of the trial drugs.
* Concomitant treatment with strong inhibitor of P-gp.
* Any ongoing acute clinically significant toxic effect of prior anticancer therapy or any persisting complication of prior surgery.
* Subjects with known history of keratitis, ulcerative keratitis or severe dry eye.
* Participation in the active phase of other clinical trials of investigational agents in which last study treatment was administered within 2 weeks prior to randomization