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

NCT01160211 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: 1142992010-019577-16CLAP016A2307
• Study Type: interventional
• Target: 369
• Locations: 29 countries
• Sites: 110

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).

Conditions

Neoplasms, Breast

Keywords

1st line MBC; MBC; hormone receptor positive; lapatinib; trastuzumab; HER2 positive; aromatase inhibitor

Outcome Measures

Primary Outcomes (2)

• Progression Free Survival (PFS) Events in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI)

  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.

  From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 5 years

• Median Kaplan Meier Estimates for PFS in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI)

  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.

  From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 5 years

Secondary Outcomes (7)

• 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

• Overall Survival (OS)

  From date of randomization until date of death from any cause, assessed up approximately 11 years

• Overall Response Rate (ORR)

  Up approximately 11 years

• Clinical Benefit Rate (CBR)

  Up approximately 11 years

• Time to Response

  From date of randomization until the earliest date of Complete Response (CR) or Partial Response (PR), assessed up approximately 11 years

Study Arms (3)

Treatment group A

EXPERIMENTAL

Lapatinib 1000 mg PO once daily + Trastuzumab (loading dose of 8 mg/kg) followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks) + an Aromatase Inhibitor (AI) of Investigator's choice PO once daily.

Drug: Lapatinib; Drug: Trastuzumab; Drug: Aromatase Inhibitor

Treatment group B

ACTIVE COMPARATOR

Trastuzumab (loading dose of 8 mg/kg) followed by maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks) + an Aromatase Inhibitor (AI) of Investigator's choice PO once daily.

Drug: Trastuzumab; Drug: Aromatase Inhibitor

Treatment Group C

ACTIVE COMPARATOR

Lapatinib 1500 mg PO once daily + an Aromatase Inhibitor (AI) of Investigator's choice PO once daily.

Drug: Aromatase Inhibitor; Drug: Lapatinib

Interventions

Lapatinib DRUG

1000 mg by mouth once a day

Treatment group A

Trastuzumab DRUG

Loading dose of 8 mg/kg IV followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks)

Treatment group A; Treatment group B

Aromatase Inhibitor DRUG

Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator's choice given by mouth once daily

Treatment Group C; Treatment group A; Treatment group B

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects eligible for enrollment in the study must meet all of the following criteria:
• 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.
• 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
• 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)
• Tumors that are ER+ and/or PgR+ by local laboratory
• Documentation of HER2 overexpression or gene amplification, in the invasive component of either the primary tumor or metastatic disease site as defined as:
• + by Immunohistochemistry (IHC) and/or
• HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization \[FISH, CISH or SISH; \>6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of ≥2.0\]
• 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.

You may not qualify if:

• 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.
• 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)
• 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
• Known history of, or clinical evidence of, central nervous system (CNS) metastases or leptomeningeal carcinomatosis
• 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)
• 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)
• Have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
• 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
• Any prohibited medication.
• Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead
• GlaxoSmithKline: collaborator

Study Sites (110)

Novartis Investigative Site

Hollywood, Florida, 33021, United States

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Augusta, Georgia, 30912, United States

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Germantown, Tennessee, 38138, United States

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Tacoma, Washington, 98405, United States

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Berazategui, Buenos Aires, B1880BBF, Argentina

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Capital Federal, Buenos Aires, C1417DTN, Argentina

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Ciudad Autonoma de Buenos Aires, Buenos Aires, C1050AAK, Argentina

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Ciudad Autonoma de Buenos Aires, Buenos Aires, C1280AEB, Argentina

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La Plata, Buenos Aires, B1920CMK, Argentina

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Viedma, Río Negro Province, R8500ACE, Argentina

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Rosario, Santa Fe Province, S2000KZE, Argentina

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Córdoba, X5004FHP, Argentina

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La Rioja, F5300COE, Argentina

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Quilmes, 1878, Argentina

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San Miguel de Tucumán, T4000IAK, Argentina

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Albury, 2640, Australia

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Douglas, 4814, Australia

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Leuven, 3000, Belgium

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Namur, 5000, Belgium

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Goiânia, Goiás, 74605-070, Brazil

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Porto Alegre, Rio Grande do Sul, 90470-340, Brazil

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Porto Alegre, Rio Grande do Sul, 91350-200, Brazil

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Barretos, São Paulo, 14784-400, Brazil

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São Paulo, São Paulo, 01317-001, Brazil

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São Paulo, São Paulo, 03102-002, Brazil

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São Paulo, São Paulo, 05651-901, Brazil

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Rio de Janeiro, 20560-120, Brazil

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Plovdiv, 4004, Bulgaria

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Sofia, 1330, Bulgaria

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Sofia, 1756, Bulgaria

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Varna, 9010, Bulgaria

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Fuzhou, Fujian, 350001, China

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Guangzhou, Guangdong, 510060, China

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Changchun, Jilin, 130021, China

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Harbin, 150081, China

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Shanghai, 200032, China

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Osijek, 31000, Croatia

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Zagreb, 10000, Croatia

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Besançon, 25030, France

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Montpellier, 34298, France

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Paris, 75970, France

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Munich, Bavaria, 81675, Germany

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Fürstenwalde, Brandenburg, 15517, Germany

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Goslar, Lower Saxony, 38642, Germany

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Troisdorf, North Rhine-Westphalia, 53840, Germany

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Velbert, North Rhine-Westphalia, 42551, Germany

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Alexandroupoli, 68100, Greece

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Chania, 73100, Greece

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Heraklion, 71110, Greece

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Hong Kong, Hong Kong

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Kowloon, Hong Kong

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Tuenmen, Hong Kong

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Győr, H-9024, Hungary

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Gyula, 5700, Hungary

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Kaposvár, 7400, Hungary

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Miskolc, 3526, Hungary

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Nyíregyháza, 4400, Hungary

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Pécs, 7624, Hungary

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Szeged, 6720, Hungary

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Zalaegerszeg, H-8900, Hungary

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Nagpur, 440010, India

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New Delhi, 110 092, India

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Haifa, 31096, Israel

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Jerusalem, 91120, Israel

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Ramat Gan, 52621, Israel

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Rozzano (MI), Lombardy, 20089, Italy

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Aichi, 464-8681, Japan

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Chiba, 277-8577, Japan

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Ehime, 791-0280, Japan

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Osaka, 537-8511, Japan

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Osaka, 540-0006, Japan

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Saitama, 362-0806, Japan

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Tokyo, 104-8560, Japan

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Arequipa, Peru

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Lima, Lima 18, Peru

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Konin, 62-500, Poland

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Warsaw, 04-125, Poland

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Lisbon, 1400-038, Portugal

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Porto, 4200-072, Portugal

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Arkhangelsk, 163045, Russia

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Kazan', 420029, Russia

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Moscow, 115478, Russia

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Ryazan, 390011, Russia

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Saint Petersburg, 197022, Russia

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Saint Petersburg, 197758, Russia

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Belgrade, 11000, Serbia

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Kamenitz, 21204, Serbia

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Singapore, 308433, Singapore

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Gyeonggi-do, 10408, South Korea

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Seoul, 03080, South Korea

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Seoul, 05505, South Korea

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Seoul, 06351, South Korea

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A Coruña, 15009, Spain

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Barcelona, 08036, Spain

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Castellon, 12002, Spain

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Madrid, 28040, Spain

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Changhua, 500, Taiwan

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Kaohsiung City, 833, Taiwan

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Taipei, 11217, Taiwan

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Ankara, 06200, Turkey (Türkiye)

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Izmir, 35100, Turkey (Türkiye)

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Chernivtsi, 58013, Ukraine

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Kharkiv, 61070, Ukraine

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Liutizh, 07352, Ukraine

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Sumy, 40005, Ukraine

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Uzhhorod, 88000, Ukraine

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Vinnitsia, 21029, Ukraine

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London, SW3 6JJ, United Kingdom

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Maidstone, ME16 9QQ, United Kingdom

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Peterborough, PE3 9GZ, United Kingdom

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Related Publications (2)

• 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 BACKGROUND

• 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 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Lapatinib; Trastuzumab; Aromatase Inhibitors

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 1, 2010
• First Posted: July 12, 2010
• Study Start: May 5, 2011
• Primary Completion: March 11, 2016
• Study Completion: June 6, 2022
• Last Updated: March 7, 2025
• Results First Posted: July 15, 2019

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share

Locations

JP (7); BU (4); SG (1); BR (8); PL (2); DE (5); ES (4); UA (6); GR (3); IN (2); US (4); HK (3); IT (1); PE (2); CN (5); PT (2); AU (2); SE (2); TW (3); BE (2); CR (2); FR (3); TU (2); KR (4); IL (3); RU (6); GB (3); AR (11); HU (8)