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

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

A Randomized Open-label Phase II Study of Letrozole Plus Afatinib Versus Letrozole Alone in First-line Treatment of Advanced ER+, HER2- Postmenopausal Breast Cancer With Low ER Expression

Study was completed as per amended protocol. Protocol was amended to close enrollment earlier than initially planned (study continued as per plan).

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.

Progression Free Survival (PFS) is defined as the time from randomization until date of progression (assessed by Response Evaluation Criteria in Solid Tumors - RECIST) or death due to any cause, whichever occurs first. For evaluation of PFS, the randomization date for each patient was the "start date". If the status at the last assessment date was "Non-complete response/ Non-progressive disease" or "Complete response", then the patient was considered "censored". If the status at the last assessment for any tumor was "Progressive disease", then the patient was considered as having an event. Progressive disease is defined using RECIST v1 .1 as a ≥ 20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more target or non-target new lesions and/or unequivocal progression of existing non-target lesions.

Tumor assessments were every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.

Overall Survival is defined as the time from randomization until death to any cause. For subjects in which treatment is discontinued for reasons different than Progression Disease: after treatment and up to documentation of disease progression: Overall Survival is assessed every 12 weeks

Under treatment: every 4 wks up to 9 months (average) for subject in the Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months

Objective response rate (ORR) is defined as the proportion of randomized subjects achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST). As per RECIST (version 1.1): CR is defined as disappearance of all target and non target lesions - lymph node (LN) <10mm. PR is defined as at least a 30% decrease in the Sum of Diameters, taking as reference the Baseline Sum of Diameters

Tumor assessment: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.

As per Response Evaluation Criteria In Solid Tumors (RECIST). Time to progression (TTP) is defined as the time interval from date of randomization to date of the first documented objective tumor progression.

Tumor assessments: every 12 weeks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B.

Participants who experienced at least one Treatment Emergent Adverse Event (TEAE) are presented. Participants with at least one serious TEAE, those who had at least one TEAE related to letrozole or afatinib (serious/non-serious), including participants who experienced a grade 3/4 TEAE, or who discontinued/died as a result of their TEAE are listed by treatment arm. Adverse events were tabulated by system organ class, preferred term and toxicity grade by treatment arm. For subjects in which treatment was discontinued for reasons different than progression of disease, the assessment was conducted every 12 weeks following treatment, and up to documentation of disease progression. ** Enrollment was closed prematurely due to low recruitment (only 44 participants enrolled) compared to what was initially planned (150 participants), therefore no statistical evaluations were completed. Adverse event data collected are described per arm but no statistical comparison was made.

Under treatment: every 4 wks up to 9 months (average) for subjects in Arm A or up to 14 months (average) for subjects in Arm B. After documentation of disease progression up to the end of the study: every 6 months up to 42 months

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