Intervention: Letrozole
Trial phase: Phase 2
ATC code: L02BG04
SMILES: N#Cc1ccc(C(c2ccc(C#N)cc2)n2cncn2)cc1
Sex: Female
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 23
Group description: Letrozole 2.5 mg
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