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

• ClinicalTrials.gov Identifier: NCT01160211
• Recruitment Status: Completed
• First Posted: July 12, 2010
• Results First Posted: July 15, 2019
• Last Update Posted: June 30, 2022
• Sponsor: Novartis Pharmaceuticals
• Collaborator: GlaxoSmithKline
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: July 1, 2010
• First Posted Date: July 12, 2010
• Results First Submitted Date: January 3, 2019
• Results First Posted Date: July 15, 2019
• Last Update Posted Date: June 30, 2022
• Actual Study Start Date: May 5, 2011
• Actual Primary Completion Date: March 11, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 1, 2019)

• PFS of Lapatinib+Trastuzumab+AI Combination vs. Trastuzumab+AI Combination [ Time Frame: approximately 5 years ]
  Progression free survival (PFS) of lapatinib/trastuzumab/aromatase inhibitor (AI) combination vs. trastuzumab/AI combination. PFS is defined as the time from randomization to the earliest date of disease progression (with radiological evidence) or death from any cause, or to the date of censor.
• Median Kaplan Meier Estimates for PFS of Lapatinib+Trastuzumab+AI Combination vs. Trastuzumab+AI Combination [ Time Frame: approximately 5 years ]
  Progression free survival (PFS) of lapatinib/trastuzumab/aromatase inhibitor (AI) combination vs. trastuzumab/AI combination. PFS is defined as the time from randomization to the earliest date of disease progression (with radiological evidence) or death from any cause, or to the date of censor.

• Original Primary Outcome Measures (submitted: July 8, 2010): To demonstrate superiority of lapatinib/trastuzumab/aromatase inhibitor (AI) combination vs. trastuzumab/AI combination for overall survival (OS) [ Time Frame: approximately 6 years ]

Current Secondary Outcome Measures (submitted: November 7, 2019)

• PFS of Trastuzumab/AI vs. Lapatinib/AI and Trastuzumab/Lapatinib/AI vs. Lapatinib/AI [ Time Frame: approximately 5 years ]
  PFS in the lapatinib arm vs. the trastuzumab arm and in the lapatinib+trastuzumab arm vs. the lapatinib arm.
• Overall Survival (OS) Events of Lapatinib+Trastuzumab+AI vs. Trastuzumab+AI and Lapatinib+AI vs. Trastuzumab+AI [ Time Frame: approximately 5 years ]
  OS was defined as the interval of time (in weeks) between the date of randomization and the date of death due to any cause. For subjects who did not die during the study, death was censored at the date of last contact.
• Overall Response Rate (ORR; Complete or Partial Response) in Lapatinib+Trastuzumab+AI vs. Trastuzumab+AI and Lapatinib+AI vs. Trastuzumab+AI [ Time Frame: approximately 5 years ]
  The best overall response was the best response recorded from the start of the treatment until disease progression/recurrence & was determined programmatically using investigators assessment of responses of target lesion, non-target lesion and new lesions based on RECIST v1.1. CR=disappearance of all target lesion & non-target lesions, if applicable, and no new lesion; PR = ≥30% decrease in the sum of the longest diameter of target lesions & non-target lesion was neither non-CR nor progressive disease (Non-PD) or not evaluable (NE); stable disease (SD) = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (SD should maintain for at least 56 days); PD = ≥20% increase from nadir (smallest sum diameters recorded since treatment start) of the target lesions and/or any status for non-target lesions or appearance of new lesion; NE = cannot be classified by the above definitions. Overall Response (OR) = CR + PR.
• Clinical Benefit Rate (CBR; Complete Response, Partial Response, or Stable Disease for at Least 6 Months) in Lapatinib+Trastuzumab+AI vs. Trastuzumab+AI and Lapatinib+AI vs. Trastuzumab+AI [ Time Frame: approximately 5 years ]
  Clinical Benefit Rate (CBR) was defined as the percentage of patients with evidence of complete response (CR) or partial response (PR) at any time or maintaining SD for at least 24 weeks while on study, according to the investigator assessment of response per RECIST 1.1 criteria.
• Duration of Response in Lapatinib+Trastuzumab+AI vs. Trastuzumab+AI and Lapatinib+AI vs. Trastuzumab+AI [ Time Frame: approximately 5 years ]
  Kaplan-Meier estimates for duration of response in lapatinib+trastuzumab+AI vs. trastuzumab+AI and lapatinib+AI vs. trastuzumab+AI. Duration of response is defined as the time from first documented Complete Response or Partial Response until the first documented sign of Progressive Disease or Death, or to the date of censor.
• Changes in the Quality of Life (QoL) Status Relative to Baseline FACT-B Overall and Subscale Scores at Last On-treatment Assessment [ Time Frame: approximately 5 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 are 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) In the scoring system, negative stated items are reversed by subtracting the response from "4" and after reversing proper items, all subscale items are summed to a total, which is the subscale score. For all the FACIT scales and symptom indices, the higher the score the better cut off
• Time to Response in Lapatinib+Trastuzumab+AI vs. Trastuzumab+AI and Lapatinib+AI vs. Trastuzumab+AI [ Time Frame: approximately 5 years ]
  Time to response in lapatinib+trastuzumab+AI vs. trastuzumab+AI and lapatinib+AI vs. trastuzumab+AI. Time to response is defined as time from randomization to first documented Complete Response or Partial Response.

Original Secondary Outcome Measures (submitted: July 8, 2010)

• To compare OS in trastuzumab/AI vs. lapatinib/AI and trastuzumab/lapatinib/AI vs. lapatinib/AI [ Time Frame: approximately 6 years ]
• To compare progression free survival (PFS) in lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI [ Time Frame: approximately 6 years ]
• To compare overall response rate (complete or partial response), time to response, and duration of response in lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI [ Time Frame: approximately 6 years ]
• To compare clinical benefit (complete response, partial response, or stable disease for at least 6 months) in lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI [ Time Frame: approximately 6 years ]
• To evaluate the safety and tolerability of all three treatment groups (lapatinib/ trastuzumab/ AI, trastuzumab/ AI, or lapatinib/AI) [ Time Frame: approximately 6 years ]
• To compare lapatinib/trastuzumab/AI vs. trastuzumab/AI and lapatinib/AI vs. trastuzumab/AI with respect to change in quality of life (QoL) status relative to baseline [ Time Frame: approximately 6 years ]
• • To identify tumor-derived biomarkers (DNA, RNA and protein) associated with clinical outcome
• To evaluate biomarkers known to predict sensitivity or resistance to lapatinib and trastuzumab (e.g. p95HER2, PIK3CA mutations, PTEN aberrations and other markers associated with these pathways) and determine the relationship with clinical outcome
• To examine pre and post treatment circulating free DNA (cfDNA) to determine whether mutations (e.g., PI3KCA) in cfDNA correlate with that in the tumor tissue from which it is derived
• Dependent on study outcomes, exploratory research may be conducted to identify genetic markers in patient DNA that are associated with response to study drugs.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: A Phase III Trial to Compare the Safety and Efficacy of Lapatinib Plus Trastuzumab Plus an Aromatase Inhibitor (AI) vs. Trastuzumab Plus an AI vs. Lapatinib Plus an AI as 1st- or 2nd- Line Therapy in Postmenopausal Subjects With Hormone Receptor+, HER2-positive Metastatic Breast Cancer (MBC) Who Received Prior Trastuzumab and Endocrine Therapies
• Brief Summary: 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 (MBC).
• Detailed Description: This was a Phase III, randomized, open-label, multi-center, three arm study of lapatinib plus trastuzumab plus an aromatase inhibitor (AI), trastuzumab plus an AI, or lapatinib plus an AI to evaluate the efficacy and safety of these regimens as first- or second-line therapy in postmenopausal subjects with hormone receptor positive (HR+), HER2-positive metastatic breast cancer (MBC) who have received prior trastuzumab and endocrine therapies. Eligible subjects was postmenopausal; had tumors that are ER and/or PgR positive and HER2-positive; had Stage IV metastatic breast cancer. The primary objective was to demonstrate superiority of lapatinib/trastuzumab/AI combination versus (vs.) trastuzumab/AI combination for progression free survival. The secondary objectives were to evaluate progression free survival in trastuzumab/AI vs. lapatinib/AI and trastuzumab/lapatinib/AI vs. lapatinib/AI, overall survival, overall response rate, clinical benefit rate, the safety and tolerability of all three treatment groups (lapatinib plus trastuzumab plus an AI, trastuzumab plus an AI, or lapatinib plus an AI), and quality of life status relative to baseline.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Neoplasms, Breast

Intervention

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

Study Arms

• Experimental: Lapatinib plus trastuzumab plus aromatase inhibitor
  Experimental
  Interventions:

  • Drug: lapatinib
  • Drug: trastuzumab
  • Drug: Aromatase inhibitor
• Active Comparator: trastuzmab plus aromatase inhibitor
  Active Comparator
  Interventions:

  • Drug: trastuzumab
  • Drug: Aromatase inhibitor
• Active Comparator: lapatinib plus aromatase inhibitor
  Active Comparator
  Interventions:

  • Drug: Aromatase inhibitor
  • Drug: lapatinib

Publications *

• 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.
• 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.
  Retraction in:J Clin Oncol. 2021 Jan 1;39(1):95

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 1, 2019): 369
• Original Estimated Enrollment (submitted: July 8, 2010): 525
• Actual Study Completion Date: June 6, 2022
• Actual Primary Completion Date: March 11, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Croatia, France, Germany, Greece, Hong Kong, Hungary, India, Ireland, Israel, Italy, Japan, Korea, Republic of, Lithuania, Norway, Peru, Philippines, Poland, Portugal, Puerto Rico, Romania, Russian Federation, Serbia, Singapore, South Africa, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Mexico

Administrative Information

• NCT Number: NCT01160211
• Other Study ID Numbers: 114299; 2010-019577-16 ( EudraCT Number ); CLAP016A2307 ( Other Identifier: Novartis )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Study Director, GSK
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: GlaxoSmithKline
• Collaborators: GlaxoSmithKline

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: June 2022