A Study to Compare the Safety and Efficacy of an Aromatase Inhibitor in Combination With Lapatinib, Trastuzumab or Both for the Treatment of Hormone Receptor Positive, HER2+ Metastatic Breast Cancer

This Phase III, multicenter, open-label study randomized subjects to one of the three treatment arms:

1. Treatment group A: lapatinib 1000 mg PO once daily + trastuzumab (loading dose of 8 mg/kg) followed by the maintenance dose of 6 mg/kg IV q3weeks + an AI (either letrozole, anastrozole, or exemestane) of Investigator's choice PO once daily.
2. Treatment group B: trastuzumab (loading dose of 8 mg/kg) followed by maintenance dose of 6 mg/kg IV q3weeks + an AI (either letrozole, anastrozole, or exemestane) of Investigator's choice PO once daily.
3. Treatment group C: lapatinib 1500 mg PO once daily + an AI (either letrozole, anastrozole, or exemestane) of Investigator's choice PO once daily.

Treatment continued until disease progression, death, or unacceptable toxicities, whichever came first.

Subjects who discontinued study treatment for reasons other than disease progression were followed-up every 12 weeks until disease progression or death, until the start of post-study treatment anti-cancer therapy (including radiotherapy and surgery), withdrawal of consent, or lost to follow-up, whichever came first.

• Lapatinib (Drug): 1000 mg by mouth once a day
• Trastuzumab (Drug): Loading dose of 8 mg/kg IV followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks)
• Aromatase Inhibitor (Drug): Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator's choice given by mouth once daily
• Lapatinib (Drug): 1500 mg by mouth once daily

Primary outcomes

• Progression Free Survival (PFS) Events in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI) [From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 5 years]: The Number of Participants with Progression free survival (PFS) events in the Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) arm vs. Trastuzumab + Aromatase Inhibitor (AI) arm was based on assessments by the Investigator.
• Median Kaplan Meier Estimates for PFS in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI) [From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 5 years]: Progression free survival (PFS) was defined as the interval of time between the date of randomization and the earliest date of disease progression (with radiological evidence) or death from any cause, or to the date of censor. Disease progression was based on assessments by the Investigator.

Secondary outcomes

• Progression Free Survival (PFS) [From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 11 years]: Progression free survival (PFS) was defined as the interval of time between the date of randomization and the earliest date of disease progression (with radiological evidence) or death from any cause, or to the date of censor. Disease progression was based on assessments by the Investigator.
• Overall Survival (OS) [From date of randomization until date of death from any cause, assessed up approximately 11 years]: The Number of Participants with Overall Survival (OS) events was based on assessments by the Investigator.
• Overall Response Rate (ORR) [Up approximately 11 years]: Overall Response Rate (ORR) was defined as the proportion of participants achieving either a Complete Response (CR) or Partial Response (PR). The ORR was calculated from the Investigator's assessment of response based on RECIST 1.1. Subjects with an unknown or missing response were treated as non-responders; i.e. they were included in the denominator when calculating the percentages. Subjects who do not have measurable disease contributed to the Response Rate based analyses, for the evaluation of CR, SD and PD.
• Clinical Benefit Rate (CBR) [Up approximately 11 years]: Clinical Benefit Rate (CBR) was defined as the percentage of patients with evidence of Complete Response (CR), Partial Response (PR), or maintaining Stable Disease (SD) for at least 6 months while on study, according to the investigator assessment of response per RECIST 1.1 criteria.
• Time to Response [From date of randomization until the earliest date of Complete Response (CR) or Partial Response (PR), assessed up approximately 11 years]: Time to Response (TTR) was defined as the time from randomization to the earliest date of Complete Response (CR) or Partial Response (PR)
• Duration of Response (DoR) [From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up approximately 11 years]: Duration of Response (DOR) was defined as the duration between the date of first documented Complete Response (CR) or Partial Response (PR) and the date of first documented sign of Progressive Disease or Death, or to the date of censor.
• Mean Change in the Quality of Life (QoL) Status Relative to Baseline FACT-B Overall and Subscale Scores at Last On Treatment Assessment [Day 1 (pre-dose), up approximately 11 years]: Quality of life was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. It is a 37-item (27 general questions and 10 breast cancer specific questions) self-reporting instrument consisting of 5 dimensions: physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and a breast cancer subscale (BCS). The followings were the score ranges for each self-reporting subscale: • PWB : 0-28 • SWB : 0-28 • EWB : 0-24 • FWB : 0-28 • BCS : 0-40 FACT-B Total Outcome Index (TOI) = PWB + FWB + BCS (range:0 - 96) FACT-B Total Score = PWB + SWB + EWB + FWB + BCS (range:0-148) FACT-G Total Score = PWB + SWB + EWB + FWB (range:0-108). For all the FACIT scales and symptom indices, the higher the score the better QoL

Sex: Female, ages: 18 Years to any

Inclusion Criteria

Subjects eligible for enrollment in the study must meet all of the following criteria:

1. Signed written informed consent. In Korea and Japan, subjects between >=18 and <20 years of age must also have a legal representative sign the written informed consent.
2. Post-menopausal female subjects >=18 years of age. Post-menopausal as defined by any of the following:

   * Subjects at least 60 years of age.
   * Subjects under 60 years of age and amenorrhic for at least 12 consecutive months AND follicle-stimulating hormone (FSH) and estradiol levels in postmenopausal range (utilizing ranges from the local laboratory facility).
   * Prior bilateral oophorectomy.
   * Prior radiation castration with amenorrhea for at least 6 months
3. Subjects must have a history of histologically confirmed breast cancer, with a clinically confirmed diagnosis of metastatic disease \[confirmed by histology, cytology or other clinical means (e.g. CT, MRI)\]. Subjects may have either measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
4. Tumors that are ER+ and/or PgR+ by local laboratory
5. Documentation of HER2 overexpression or gene amplification, in the invasive component of either the primary tumor or metastatic disease site as defined as:

   * 3+ by Immunohistochemistry (IHC) and/or
   * HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization \[FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of ≥2.0\]
6. Subject must have received at least one prior regimen containing trastuzumab in combination with chemotherapy for breast cancer:.

   * Subject has ONLY received prior trastuzumab in combination with chemotherapy as neoadjuvant and/or adjuvant treatment. OR
   * Subject has received ONE prior trastuzumab-containing regimen for metastatic disease (and has progressed), and may or may not have received prior trastuzumab in combination with chemotherapy as neoadjuvant and/or adjuvant treatment.
7. Subject must have received prior endocrine therapy (such as aromatase inhibitors or selective estrogen receptor modulators). 8. Subjects who have a life expectancy of > 6 months as assessed by the treating investigator

9\. Subjects must have baseline Left Ventricular Ejection Fraction (LVEF) ≥50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA) 10. Subject must have an ECOG performance status of 0-1 11. All prior treatment related toxicities must be CTCAE (Version 4.0) ≤ Grade 1 at the time of randomization 12. Completion of screening assessments 13. Adequate baseline organ function. 14. Subjects must meet all of the following criteria:

* QTc <450msec or
* QTc <480msec for subjects with bundle branch block The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB) or to Fridericia's formula (QTcF), machine or manual over read, for males and females. The specific formula that will be used in a protocol should be determined prior to initiation of the study, and the formula used to determine inclusion and discontinuation should be the same throughout the study. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period

Exclusion criteria:

1. History of another malignancy. Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
2. Subjects with extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumor, or the disease is considered by the investigator to be rapidly progressing or life threatening (subjects who are intended for chemotherapy)
3. Serious cardiac illness or medical condition including but not confined to:

   * Uncontrolled arrhythmias
   * Uncontrolled or symptomatic angina
   * History of congestive heart failure (CHF)
   * Documented myocardial infarction <6 months from study entry
4. Known history of, or clinical evidence of, central nervous system (CNS) metastases or leptomeningeal carcinomatosis
5. Have acute or currently active/requiring anti-viral therapy hepatic or biliary disease (with the exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
6. Have a concurrent disease or condition that may interfere with study participation, or any serious medical disorder that would interfere with the subject's safety (for example, active or uncontrolled infection or any psychiatric condition prohibiting understanding or rendering of informed consent)
7. Have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
8. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study agents or their excipients that, in the opinion of the Investigator or GSK medical monitor, contraindicates their participation
9. Any prohibited medication.
10. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.

Participant flow

Outcome results

• Progression Free Survival (PFS) Events in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI) (Primary), Count of participants, Participants: Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) 62; Trastuzumab + Aromatase Inhibitor (AI) 75 (p 0.0063)
• Median Kaplan Meier Estimates for PFS in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI) (Primary), Median, Months: Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) 11.0 (8.3 to 13.8); Trastuzumab + Aromatase Inhibitor (AI) 5.6 (5.4 to 8.3)
• Progression Free Survival (PFS) (Secondary), Median, Months: Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) 11.1 (10.0 to 15.3); Lapatinib + Aromatase Inhibitor (AI) 8.3 (7.1 to 11.0); Trastuzumab + Aromatase Inhibitor (AI) 5.7 (5.5 to 8.3)
• Overall Survival (OS) (Secondary), Count of participants, Participants: Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) 38; Lapatinib + Aromatase Inhibitor (AI) 45; Trastuzumab + Aromatase Inhibitor (AI) 39
• Overall Response Rate (ORR) (Secondary), Number, Percentage of Participants: Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) 32.3 (24.2 to 41.2); Lapatinib + Aromatase Inhibitor (AI) 22.8 (15.7 to 31.2); Trastuzumab + Aromatase Inhibitor (AI) 17.2 (11.0 to 25.1)
• Clinical Benefit Rate (CBR) (Secondary), Number, Percentage of Participants: Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) 51.6 (42.5 to 60.7); Lapatinib + Aromatase Inhibitor (AI) 43.1 (34.2 to 52.3); Trastuzumab + Aromatase Inhibitor (AI) 34.4 (26.1 to 43.6)
• Time to Response (Secondary), Median, Days: Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) 85.0 (72 to 1031); Lapatinib + Aromatase Inhibitor (AI) 86.5 (65 to 1175); Trastuzumab + Aromatase Inhibitor (AI) 86.0 (67 to 337)
• Duration of Response (DoR) (Secondary), Median, Months: Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) 22.5 (11.1 to 33.1); Lapatinib + Aromatase Inhibitor (AI) 11.1 (5.6 to NA); Trastuzumab + Aromatase Inhibitor (AI) 11.8 (5.4 to 28.1)
• Mean Change in the Quality of Life (QoL) Status Relative to Baseline FACT-B Overall and Subscale Scores at Last On Treatment Assessment (Secondary), Least squares mean, score on a scale: Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) -4.2 +/- 1.48; Lapatinib + Aromatase Inhibitor (AI) -6.3 +/- 1.51; Trastuzumab + Aromatase Inhibitor (AI) -2.4 +/- 1.51
• All Collected Deaths (Post hoc), Count of participants, Participants: Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) 0; Lapatinib + Aromatase Inhibitor (AI) 0; Trastuzumab + Aromatase Inhibitor (AI) 0

Adverse events

Time frame: Adverse Events (AEs) were collected from first dose of study medication until the last dose plus 30 days post-treat follow-up, assessed up to approximately 131 months. Deaths were recorded from study start date until end of survival follow-up phase (end of study), assessed up to approximately 132 months.

Serious adverse events by term

9 more terms not shown.

Other adverse events by term

10 more sites not listed.

• Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol. 2018 Mar 10;36(8):741-748. doi: 10.1200/JCO.2017.74.7824. Epub 2017 Dec 15. PMID 29244528
• Results publication: Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. doi: 10.1200/JCO.20.01894. Epub 2020 Aug 21. PMID 32822287

• Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals