Evaluation of Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02213042
• Collaborator: (none)
• Enrollment: 42
• Locations: 51
• Arms: 3
• Actual Duration (Months): 67.4
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This was a multicenter, open-label, Phase II study in subjects with Human epidermal growth factor receptor (HER2)-positive metastatic breast cancer who received at least 2 prior lines of anti-HER2-targeted therapies of which at least one included a Trastuzumab-containing regimen. This study was a post-approval commitment with regulatory authorities. It was designed to evaluate whether treatment with Dual blockade promoted changes to biomarkers associated with immunomodulation.

Condition or Disease	Intervention/Treatment	Phase
Neoplasms, Breast	Drug: Lapatinib; Biological: Trastuzumab; Drug: Aromatase Inhibitors (AIs)	Phase 2

Detailed Description

This study was designed to address the post-authorization measures as agreed with the Committee for Medicinal Products for Human Use (CHMP). Recruitment of subjects into this study was challenging, and following agreement with the European Medicines Agency (EMA) enrollment into this study was halted after the enrollment of 42 of the 225 planned subjects.

The primary endpoint of the study evaluated changes in expression of biomarkers associated with immunomodulation between a pre-treatment biopsy and the disease progression biopsy. Secondary efficacy endpoints included overall response rate, clinical benefit rate and progression-free survival (PFS), as well as safety/tolerability. All subjects received study treatment until disease progression, death, unacceptable toxicity, or subject withdrawal. In case of disease progression during the treatment period, the subject was followed-up for 30 days for safety evaluation. In case of study treatment discontinuation for any reasons other than disease progression, the subject was followed-up for safety and efficacy assessments until disease progression, new anticancer therapy, death, withdrawal of consent or end of study, whichever came first.

This study supported a better understanding of the rapidly accumulating evidence for the importance of the immune microenvironment in HER2-positive breast cancer and the observed immunomodulation in the neoadjuvant setting could be confirmed in the advanced setting and supported the putative mechanism of action of HER2 dual blockade and its potential function on the tumor microenvironment. No formal comparisons between treatment arms were undertaken.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants were randomized to Arms A and B but randomized to Arm C.Participants were randomized to Arms A and B but randomized to Arm C.
• Masking: None (Open Label)
• Masking Description: This was a two-cohort, three-arm, open-label Phase II study to evaluate the changes in the expression of biomarkers between pre-treatment and progression biopsy in subjects with Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Subjects were allocated to 1 of 2 cohorts depending on the molecular subtype of their biopsy. Cohort 1 HER2 -enriched included HER2-positive subjects with a HER2-Enriched molecular subtype, and were randomized in a 1:1 ratio to receive either trastuzumab in combination with lapatinib (Arm A) or trastuzumab in combination with chemotherapy (Arm B). Cohort 2 non-HER2-enriched, included HER2-positive subjects with luminal A, luminal B, and basal-like molecular subtypes and were to receive trastuzumab in combination with lapatinib (Arm C). Subjects with hormone receptor (ER and/or PgR)-positive MBC in this arm were required to be treated with an AI of the Investigator's choice.
• Primary Purpose: Treatment
• Official Title: An Open-Label, Phase II, Study to Evaluate Biomarkers Associated With Response to Subsequent Therapies in Subjects With HER2-Positive Metastatic Breast Cancer Receiving Treatment With Trastuzumab in Combination With Lapatinib or Chemotherapy (EGF117165)
• Actual Study Start Date: Oct 24, 2014
• Actual Primary Completion Date: Jun 4, 2020
• Actual Study Completion Date: Jun 4, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.	Drug: Lapatinib; Lapatinib is available as 250-mg orange tablets. Subjects randomized to the Lapatinib plus Trastuzumab arm received 1000 mg per day of Lapatinib, so wre instructed to take 4 x 250 mg tablets per day. Lapatinib was to be taken either 1 hour (or more) before a meal or 1 hour (or more) after a meal; Biological: Trastuzumab; Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for IV administration. Trastuzumab was administered on Day 1 of the start of Lapatinib or in conjunction with the first cycle of chemotherapy, as an 8 mg/kg loading dose. Subsequently, Trastuzumab was administered q3weekly as a 6 mg/kg maintenance dose. At the discretion of the investigator, weekly Trastuzumab could be given in either of the three treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg).; Drug: Aromatase Inhibitors (AIs); Subjects who were hormone receptor-positive were required to receive an aromatase inhibitor as combination treatment; however the choice of the aromatase inhibitor selected for each patient was determined by the patients' investigator. The AIs the Investigator could choose from were anastrozole, exemestane, and letrozole and dosing was per product information.
Active Comparator: Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.	Biological: Trastuzumab; Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for IV administration. Trastuzumab was administered on Day 1 of the start of Lapatinib or in conjunction with the first cycle of chemotherapy, as an 8 mg/kg loading dose. Subsequently, Trastuzumab was administered q3weekly as a 6 mg/kg maintenance dose. At the discretion of the investigator, weekly Trastuzumab could be given in either of the three treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg).; Drug: Aromatase Inhibitors (AIs); Subjects who were hormone receptor-positive were required to receive an aromatase inhibitor as combination treatment; however the choice of the aromatase inhibitor selected for each patient was determined by the patients' investigator. The AIs the Investigator could choose from were anastrozole, exemestane, and letrozole and dosing was per product information.
Active Comparator: Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.	Drug: Lapatinib; Lapatinib is available as 250-mg orange tablets. Subjects randomized to the Lapatinib plus Trastuzumab arm received 1000 mg per day of Lapatinib, so wre instructed to take 4 x 250 mg tablets per day. Lapatinib was to be taken either 1 hour (or more) before a meal or 1 hour (or more) after a meal; Biological: Trastuzumab; Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for IV administration. Trastuzumab was administered on Day 1 of the start of Lapatinib or in conjunction with the first cycle of chemotherapy, as an 8 mg/kg loading dose. Subsequently, Trastuzumab was administered q3weekly as a 6 mg/kg maintenance dose. At the discretion of the investigator, weekly Trastuzumab could be given in either of the three treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg).; Drug: Aromatase Inhibitors (AIs); Subjects who were hormone receptor-positive were required to receive an aromatase inhibitor as combination treatment; however the choice of the aromatase inhibitor selected for each patient was determined by the patients' investigator. The AIs the Investigator could choose from were anastrozole, exemestane, and letrozole and dosing was per product information.

Outcome Measures

Primary Outcome Measures

1. Fold Change in Expression Profile of Genes and/or Proteins for Arm A (LAP+TRAS±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years [At screening and at disease progression, assessed up to approx. 3.5 years]

   Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available. For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.

2. Fold Change in Expression Profile of Genes and /or Proteins for Arm B (TRAS+CHEM±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years [At screening and at disease progression, assessed up to approx. 3.5 years]

   Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available. For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.

3. Fold Change in Expression Profile of Genes and /or Proteins for Arm C (Non-HER2- Enriched) From Screening to Approx. 3.5 Years [At screening and at disease progression, assessed up to approx. 3.5 years]

   Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available. For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.

Secondary Outcome Measures

1. Progression-free Survival (PFS) [From randomization to disease progression or death, up to approx. 5.6 years]

   PFS was defined as the time from the date of randomization (for Arm A and B) / treatment start date (for Arm C) to the date of the first documented disease progression or death due to any cause, whichever was earlier. If a subject had not progressed or died at the analysis cutoff date, PFS was censored at the time of the last adequate tumor assessment. PFS was summarized using Kaplan-Meier estimates.

2. Overall Response Rate (ORR) [From enrollment/randomization to the end of study, approximately 5.6 years]

   Overall response rate was defined as the percentage of subjects achieving either a confirmed complete response (CR) or partial response (PR) and was calculated from the Investigator's assessment of response per RECIST 1.1 criteria. . The confirmed CR or PR was derived using the following rules: confirmed CR - at least two determinations of CR at least 4 weeks apart before disease progression; confirmed PR - at least two determinations of PR or better at least 4 weeks apart before progression.

3. Clinical Benefit Rate (CBR) [From enrollment/randomization the end of study, approximately 5.6 years]

   CBR is defined as percentage of subjects with a complete response (CR), partial response (PR), or maintaining stable disease (SD) for at least 24 weeks while on study according to the investigator assessment of response per RECIST 1.1 criteria. CR and PR are confirmed responses derived using the following rules: Confirmed CR - at least 2 determinations of CR at least 4 weeks apart before disease progression. Confirmed PR - at least 2 determinations of PR or better at least 4 weeks apart before progression.

4. Association Between Biomarkers and PFS [From randomization to disease progression or death, up to approx. 5.6 years]

   Describe if changes of biomarker expression at disease progression from baseline correlate with PFS.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed written informed consent

• Female >=18 years

• Histologically or cytologically confirmed invasive breast cancer with distant metastasis

• Subjects must have at least one measurable lesion per RECIST 1.1

• Note: Biopsied lesions should not be used as target lesions.

• 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 OR HER2/chromosome 17 ratio <=2.0 with average HER2 copy number >=6 signals/cell nucleus]

• Centrally determined HER2-positive, hormone receptor status, breast molecular subtype by Prediction Analysis of Microarray 50 (PAM50) on the pre-treatment biopsy of metastatic lesion obtained during screening

• Note: Biopsied lesions should not be used as target lesions.

• Progression on at least 2 lines of anti-HER2-targeted therapies for metastatic breast cancer (MBC)

• Documented radiological disease progression during the most recent treatment regimen for metastatic disease

• Most recent treatment regimen for metastatic disease must include Trastuzumab and chemotherapy.

• Note: Trastuzumab emtansine (T-DM1) is considered acceptable as prior Trastuzumab/chemotherapy regimen

• Agreement to provide 2 tumor biopsies

• Prior treatment with pertuzumab, Lapatinib, and/or Trastuzumab emtansine is allowed; however, the last treatment for MBC must not include Trastuzumab in combination with pertuzumab.

• Subjects with radiographically stable Central nervous system (CNS) metastases, defined as radiographically stable on the previous 2 brain imaging scans, asymptomatic, and off systemic steroids and anticonvulsants for at least 1 month are eligible; treatment with prophylactic anticonvulsants is permitted unless listed under Prohibited Medications

• Discontinuation of all prior chemotherapy, immunotherapy, or biological therapy at least 3 weeks prior to the first dose of investigational product is required.

• Note: Discontinuation of Trastuzumab is not necessary.

• All treatment related toxicities, except alopecia, must have recovered to Grade 1 or better (Common Terminology Criteria for Adverse Events (CTCAE); version 4.0) prior to administration of the first dose of study treatment.

• Baseline Left ventricular ejection fraction (LVEF) >=50% as measured by Echocardiogram (ECHO) or Multigated acquisition (MUGA) and above the testing institution's lower limit of normal

• QT interval corrected (QTc) <450 millisecond (msec) or QTc <480 msec for patients with bundle branch block.

• The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB)

• Fridericia's formula (QTcF), or another method, machine or manual overread.

• For subject eligibility and withdrawal, QT correction formula QTcB will be used.

• For purposes of this data analysis, Bazett's formula will be used as the primary method of calculating the corrected QT interval. The QTc should be based on either a single Electrocardiogram (ECG) or an average of 3 sequential ECGs obtained within 24 hours of each other.

• The QTc should be based on single or averaged QTc values of triplicate ECGs obtained over a brief recording period.

• Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment and agree to use effective contraception, during the study and for 30 days following the last dose of study treatment.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Completion of screening and baseline assessments

• Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.

• At least 4 weeks must have elapsed since the last surgery and 2 weeks must have elapsed since radiotherapy

• Adequate baseline organ function as defined below

• Screening laboratory values should be used to confirm subject eligibility. Laboratory results may be retested if necessary to confirm eligibility.

• Hematologic(These values must be independent of growth factor support and stable for at least one week post transfusion)

• Absolute neutrophil count >=1.5 x 10^9/litre (L)

• Hemoglobin >=9.0 grams/decilitre(g/dL) (after transfusion if needed)

• Platelets>=100 x 10^9/L

• Hepatic

• Albumin >=2.5 g/dL

• Serum bilirubin <=1.25 x upper limit of normal (ULN)( These values must be independent of growth factor support and stable for at least one week post transfusion)

• Alanine aminotransferase; and, Aspartate aminotransferase AST and ALT<=2.5 x ULN

• Renal

• Calculate creatinine clearance >=40 millilitre/ minute (mL/min) (With the exception of those subjects who have Gilbert's syndrome; the bilirubin in these subjects should be at their baseline)

Exclusion Criteria:

• Lactating female

• Note: Women with potential to have children must be willing to practice acceptable methods of birth control during the study

• Bone-only disease and/or disease that cannot be biopsied.

• Unstable CNS metastases or leptomeningeal carcinomatosis not considered radiographically stable

• Note: Subjects with radiographically stable CNS metastases are defined as radiographically stable on the previous 2 brain imaging studies, asymptomatic, and off systemic steroids and anticonvulsants for at least 1 month; treatment with prophylactic anticonvulsants is permitted unless listed under prohibited medications

• Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions including concurrent disease that could interfere with subject's safety, obtaining informed consent, or compliance with the study procedures.

• Serious cardiac illness or medical condition including but not confined to: Uncontrolled arrhythmias (e.g. ventricular tachycardia, high-grade atrioventricular (AV)-block, supraventricular arrhythmias which are not adequately rate-controlled);

• Angina pectoris requiring antianginal medication

• History of congestive heart failure or systolic dysfunction (LVEF <50%)

• Documented myocardial infarction <6 months from study entry

• Evidence of transmural infarction on ECG

• Poorly controlled hypertension (e.g. systolic >160milimiter (mm) Mercury (Hg) or diastolic >100mm Hg)

• Clinically significant valvular heart disease

• Current active hepatic or biliary disease (with exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease per investigator assessment)

• Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels as well as subjects with ulcerative colitis are also excluded

• Any prohibited medication

• Prior treatment with Trastuzumab in combination with Lapatinib or prior treatment with an irreversible inhibitor of the intracellular domain of the HER2 receptor such as neratinib

• Last treatment for metastatic disease including Trastuzumab in combination with pertuzumab

• Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment

• A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study drugs or their excipients that, in the opinion of the investigator or medical monitor, contraindicates participation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Mobile	Alabama	United States	36608
2	Novartis Investigative Site	Boston	Massachusetts	United States	02114
3	Novartis Investigative Site	Houston	Texas	United States	77030
4	Novartis Investigative Site	Berazategui	Buenos Aires	Argentina	B1880BBF
5	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1125ABD
6	Novartis Investigative Site	Viedma	Río Negro	Argentina	R8500ACE
7	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000KZE
8	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires		Argentina	C1025ABI
9	Novartis Investigative Site	Cordoba		Argentina	X5004FHP
10	Novartis Investigative Site	La Rioja		Argentina	F5300COE
11	Novartis Investigative Site	San Miguel de Tucuman		Argentina	T4000IAK
12	Novartis Investigative Site	Salzburg		Austria	A-5020
13	Novartis Investigative Site	Wien		Austria	1090
14	Novartis Investigative Site	Salvador	Bahía	Brazil	41825-010
15	Novartis Investigative Site	Belo Horizonte	Minas Gerais	Brazil	30130-090
16	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul	Brazil	90430-090
17	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul	Brazil	90470-340
18	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul	Brazil	90610-000
19	Novartis Investigative Site	Itajai	Santa Catarina	Brazil	88301220
20	Novartis Investigative Site	Barretos	São Paulo	Brazil	14784-400
21	Novartis Investigative Site	Sao Paulo	São Paulo	Brazil	01236030
22	Novartis Investigative Site	Sao Paulo	São Paulo	Brazil	01317-001
23	Novartis Investigative Site	Sao Jose do Rio Preto		Brazil	15090-000
24	Novartis Investigative Site	Pok Fu Lam		Hong Kong
25	Novartis Investigative Site	Pokfulam		Hong Kong
26	Novartis Investigative Site	Milano	Lombardia	Italy	20133
27	Novartis Investigative Site	Milano	Lombardia	Italy	20141
28	Novartis Investigative Site	Mexico		Mexico	06760
29	Novartis Investigative Site	Arequipa		Peru
30	Novartis Investigative Site	Lima		Peru	Lima 34
31	Novartis Investigative Site	Cebu		Philippines	6000
32	Novartis Investigative Site	Manila		Philippines	1000
33	Novartis Investigative Site	Kazan		Russian Federation	420029
34	Novartis Investigative Site	Moscow		Russian Federation	115 478
35	Novartis Investigative Site	Ryazan		Russian Federation	390011
36	Novartis Investigative Site	St. Petersburg		Russian Federation	197022
37	Novartis Investigative Site	St. Petersburg		Russian Federation	197758
38	Novartis Investigative Site	Volzhskiy		Russian Federation	404130
39	Novartis Investigative Site	Barcelona		Spain	08035
40	Novartis Investigative Site	Barcelona		Spain	08036
41	Novartis Investigative Site	Donostia		Spain	20014
42	Novartis Investigative Site	Madrid		Spain	28034
43	Novartis Investigative Site	Madrid		Spain	28040
44	Novartis Investigative Site	Madrid		Spain	28041
45	Novartis Investigative Site	Malaga		Spain	29010
46	Novartis Investigative Site	Sevilla		Spain	41013
47	Novartis Investigative Site	Valencia		Spain	46010
48	Novartis Investigative Site	Valencia		Spain	46015
49	Novartis Investigative Site	Bangkok		Thailand	10330
50	Novartis Investigative Site	Chiangmai		Thailand	50200
51	Novartis Investigative Site	Phitsanulok		Thailand	65000

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - May 15, 2017
• Statistical Analysis Plan - Nov 10, 2020

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02213042
• Other Study ID Numbers: 117165; 2014-001220-30; CLAP016A2206
• First Posted: Aug 11, 2014
• Last Update Posted: Oct 13, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: CLAP016A2206; biomarker; Lapatinib; Prosigna; ErbB2; PAM50; HER2; HER2-overexpressing metastatic breast cancer; HER2-enriched; Trastuzumab
• Additional relevant MeSH terms: Breast Neoplasms; Trastuzumab; Lapatinib; Aromatase Inhibitors

Study Results

Participant Flow

Recruitment Details	Overall, 225 subjects were planned and 42 subjects were enrolled in this study
Pre-assignment Detail	This study was designed to address the post-authorization measures as agreed with the Committee for Medicinal Products for Human Use (CHMP). Recruitment of subjects into this study was challenging, and following agreement with the European Medicines Agency (EMA) enrollment into this study was halted after the enrollment of 42 of the 225 planned subjects.

Arm/Group Title	LAP+TRAS±AI (HER2-Enriched) - Arm A	TRAS+CHEM±AI (HER2-Enriched) - Arm B	Non-HER2- Enriched - Arm C
Arm/Group Description	Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.	Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.	Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
Period Title: Overall Study
STARTED	17	15	10
Total Deaths	11	9	6
COMPLETED	0	0	0
NOT COMPLETED	17	15	10

Baseline Characteristics

Arm/Group Title	LAP+TRAS±AI (HER2-Enriched) - Arm A	TRAS+CHEM±AI (HER2-Enriched) - Arm B	Non-HER2- Enriched - Arm C	Total
Arm/Group Description	Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.	Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.	Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.	Total of all reporting groups
Overall Participants	17	15	10	42
Age, Customized (Number) [Number]
< 65 years	14 82.4%	15 100%	6 60%	35 83.3%
>= 65 years	3 17.6%	0 0%	4 40%	7 16.7%
Sex: Female, Male (Count of Participants)
Female	17 100%	15 100%	10 100%	42 100%
Male	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	14 82.4%	11 73.3%	10 100%	35 83.3%
African American	1 5.9%	2 13.3%	0 0%	3 7.1%
Asian	1 5.9%	2 13.3%	0 0%	3 7.1%
Native Hawaiian or Pacific Islander	1 5.9%	0 0%	0 0%	1 2.4%

Outcome Measures

1. Primary Outcome

Title	Fold Change in Expression Profile of Genes and/or Proteins for Arm A (LAP+TRAS±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years
Description	Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available. For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.
Time Frame	At screening and at disease progression, assessed up to approx. 3.5 years

Outcome Measure Data

Analysis Population Description

Evaluable Set: Included all subjects in Arm A who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.

Arm/Group Title	LAP+TRAS±AI (HER2-Enriched) - Arm A
Arm/Group Description	Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
Measure Participants	7
Membrane spanning 4-domains A1	0.25
POU class 2 associating factor 1	0.32
CD19+	0.35
Interleukin 6	0.36
G antigen 1	0.43
ubiquitin specific peptidase 9, Y-linked	0.50
Thy-1 cell surface antigen	0.50
Chemerin chemokine-like receptor 1	0.51
Major histocompatibility complex, class II, DR beta 4	0.51
Collectin subfamily member 12	0.51
Complement C3b/C4b receptor 1 (Knops blood group)	0.51
CD33 molecule	0.56
B-cell linker	0.56
Interleukin 12A	0.57
CD163+	0.57
C-C motif chemokine ligand 8	0.58
Chemokine (C-C motif) receptor 1	0.59
POU class 2 homeobox 2	0.60
Cyclin dependent kinase inhibitor 1A	0.62
CD27 molecule	0.62
Lymphocyte antigen 86	0.63
TNF superfamily member 8	0.64
CD34+	0.67
Integrin subunit alpha 6	0.68
C-type lectin domain containing 7A	0.69
CD180 molecule	0.70
Integrin subunit alpha M	0.72
Toll like receptor 6	0.72
Autophagy related 10	0.73
C-C motif chemokine ligand 3 like 1	0.74
Bone marrow stromal cell antigen 1	0.75
CD22+	0.76
CD37 molecule	0.76
NEG_A	0.77
Sperm auto antigenic protein 17	0.79
CD200 molecule	0.79
TNF receptor associated factor 3	0.82
Interferon alpha and beta receptor subunit 1	1.10
TNF receptor associated factor 6	1.21

2. Primary Outcome

Title	Fold Change in Expression Profile of Genes and /or Proteins for Arm B (TRAS+CHEM±AI (HER2-Enriched)) From Screening to Approx. 3.5 Years
Description	Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available. For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.
Time Frame	At screening and at disease progression, assessed up to approx. 3.5 years

Outcome Measure Data

Analysis Population Description

Evaluable Set: Included all subjects in Arm B who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.

Arm/Group Title	TRAS+CHEM±AI (HER2-Enriched) - Arm B
Arm/Group Description	Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.
Measure Participants	6
C-type lectin domain containing 5A	0.16
Interferon induced transmembrane protein 1	0.25
Fibronectin 1	0.27
C-C motif chemokine ligand 7	0.27
Triggering receptor expressed on myeloid cells 1	0.27
Plasminogen activator, urokinase	0.27
Interleukin 22 receptor subunit alpha 2	0.28
C-C motif chemokine ligand 8	0.28
Tumor necrosis factor (ligand) superfamily member 4 gene	0.31
Major histocompatibility complex, Class I-related	0.32
Cathepsin L	0.32
SPP-1 (Osteopontin)	0.33
Thy-1 cell surface antigen	0.34
Transforming growth factor beta 2	0.35
Hepatitis A virus cellular receptor 2	0.36
Bone marrow stromal cell antigen 1	0.37
C-type lectin domain containing 7A	0.37
C-X-C motif chemokine ligand 5	0.38
Collagen type III alpha 1 chain	0.40
Complement C1s	0.41
IFIT1 gene	0.41
Major histocompatibility complex, class I, G	0.41
Tumour necrosis factor gene	0.42
Integrin subunit beta 1	0.43
Pro-melanin concentrating hormone	0.43
CD86+	0.44
FCGR3A SNP rs396991	0.44
TNF receptor superfamily member 10c	0.44
Integrin subunit alpha M	0.45
TNF receptor superfamily member 11b	0.45
Platelet derived growth factor C	0.45
Mannan binding lectin serine peptidase 1	0.46
Recombination activating 1	0.46
Interleukin 22	0.47
Tumor necrosis factor (ligand) superfamily member 13b gene	0.47
BMI1 proto-oncogene, polycomb ring finger	0.47
CXCL10 gene	0.48
Leukocyte immunoglobulin like receptor B1	0.48
MX1 gene	0.48
Tumor necrosis factor (ligand) superfamily member 11 gene	0.48
Cathepsin S	0.49
Interferon induced transmembrane protein 2	0.49
LYN proto-oncogene, Src family tyrosine kinase	0.50
Platelet derived growth factor receptor beta	0.50
OAS3 gene	0.50
CD58 molecule	0.50
complement C3a receptor 1	0.51
Chemokine (C-C motif) receptor 1	0.52
Interleukin 24 gene	0.52
Chemokine (C-X-C motif) receptor 2	0.53
Strawberry notch homolog 2	1.13
Zinc finger protein 205	1.42
Fas associated via death domain	1.58
CD3e molecule associated protein	1.67
Baculoviral IAP repeat containing 5	1.73
Interleukin 17 receptor B	2.01

3. Primary Outcome

Title	Fold Change in Expression Profile of Genes and /or Proteins for Arm C (Non-HER2- Enriched) From Screening to Approx. 3.5 Years
Description	Evaluate changes in biomarkers associated with immunomodulation between pre-treatment biopsy and disease progression biopsy within each arm. Biomarker analysis was performed using an mRNA gene expression panel derived from Nanostring platform in a total of 20 subjects who received the study treatment as per the study design and with baseline tumor biopsies available. For the selected biomarkers associated with immunomodulation, the median fold changes of gene expression level and 95% confidence interval are presented. The fold change was calculated as the ratio of the expression level of a biomarker at disease progression over the baseline.
Time Frame	At screening and at disease progression, assessed up to approx. 3.5 years

Outcome Measure Data

Analysis Population Description

Evaluable Set: Included all subjects in Arm C who received the study treatment and had both baseline and progression tumor biopsies available, with evaluable data for at least 1 biomarker.

Arm/Group Title	Non-HER2- Enriched - Arm C
Arm/Group Description	Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
Measure Participants	7
Triggering receptor expressed on myeloid cells 1	0.50
Interleukin 1 receptor, type 1 gene	1.58
Complement component 2	2.13
Coagulation factor XII	2.69

4. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS was defined as the time from the date of randomization (for Arm A and B) / treatment start date (for Arm C) to the date of the first documented disease progression or death due to any cause, whichever was earlier. If a subject had not progressed or died at the analysis cutoff date, PFS was censored at the time of the last adequate tumor assessment. PFS was summarized using Kaplan-Meier estimates.
Time Frame	From randomization to disease progression or death, up to approx. 5.6 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): Consisted of all subjects who were randomized to study Arm A or Arm B or assigned to study Arm C, irrespective of whether they actually received study treatment.

Arm/Group Title	LAP+TRAS±AI (HER2-Enriched) - Arm A	TRAS+CHEM±AI (HER2-Enriched) - Arm B	Non-HER2- Enriched - Arm C
Arm/Group Description	Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.	Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.	Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
Measure Participants	17	15	10
Median (95% Confidence Interval) [Months]	6.0	7.2	6.0

5. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	Overall response rate was defined as the percentage of subjects achieving either a confirmed complete response (CR) or partial response (PR) and was calculated from the Investigator's assessment of response per RECIST 1.1 criteria. . The confirmed CR or PR was derived using the following rules: confirmed CR - at least two determinations of CR at least 4 weeks apart before disease progression; confirmed PR - at least two determinations of PR or better at least 4 weeks apart before progression.
Time Frame	From enrollment/randomization to the end of study, approximately 5.6 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): Consisted of all subjects who were randomized to study Arm A or Arm B or assigned to study Arm C, irrespective of whether they actually received study treatment.

Arm/Group Title	LAP+TRAS±AI (HER2-Enriched) - Arm A	TRAS+CHEM±AI (HER2-Enriched) - Arm B	Non-HER2- Enriched - Arm C
Arm/Group Description	Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.	Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.	Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
Measure Participants	17	15	10
Number (95% Confidence Interval) [Percentage of participants]	35.3 207.6%	33.3 222%	30.0 300%

6. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	CBR is defined as percentage of subjects with a complete response (CR), partial response (PR), or maintaining stable disease (SD) for at least 24 weeks while on study according to the investigator assessment of response per RECIST 1.1 criteria. CR and PR are confirmed responses derived using the following rules: Confirmed CR - at least 2 determinations of CR at least 4 weeks apart before disease progression. Confirmed PR - at least 2 determinations of PR or better at least 4 weeks apart before progression.
Time Frame	From enrollment/randomization the end of study, approximately 5.6 years

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): Consisted of all subjects who were randomized to study Arm A or Arm B or assigned to study Arm C, irrespective of whether they actually received study treatment.

Arm/Group Title	LAP+TRAS±AI (HER2-Enriched) - Arm A	TRAS+CHEM±AI (HER2-Enriched) - Arm B	Non-HER2- Enriched - Arm C
Arm/Group Description	Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.	Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.	Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
Measure Participants	17	15	10
Number (95% Confidence Interval) [Percentage of participants]	35.3 207.6%	46.7 311.3%	30.0 300%

7. Secondary Outcome

Title	Association Between Biomarkers and PFS
Description	Describe if changes of biomarker expression at disease progression from baseline correlate with PFS.
Time Frame	From randomization to disease progression or death, up to approx. 5.6 years

Outcome Measure Data

Analysis Population Description

The number of patients with available biomarker data at both baseline and at progression is very small within each treatment arm (Arm A: n=7, Arm B: n=5, Arm C: n=5). This number of subjects is insufficient for an analysis to establish a relationship between the changes in biomarker at disease progression and progression free survival and would be statistically inappropriate to fit a model correlating changes in biomarkers with progression free survival with so few patients.

Arm/Group Title	LAP+TRAS±AI (HER2-Enriched) - Arm A	TRAS+CHEM±AI (HER2-Enriched) - Arm B	Non-HER2- Enriched - Arm C
Arm/Group Description	Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.	Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.	Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
Measure Participants	0	0	0

8. Post-Hoc Outcome

Title	All-Collected Deaths
Description	On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 168 weeks for Lapatinib, (treatment duration ranged from 151 to 164 weeks), 164 weeks for Trastuzumab (treatment duration ranged from 0 to 160 weeks), 168 weeks for Aromatase Inhibitors (treatment duration ranged from 9 to 164 weeks). Deaths post treatment survival follow up were collected after the on- treatment period, up to approx. 5.6 years.
Time Frame	On-treatment deaths: up to approx. 168 weeks, Total deaths: up to approx. 5.6 years

Outcome Measure Data

Analysis Population Description

Clinical Database Population: All treated participants.

Arm/Group Title	LAP+TRAS±AI (HER2-Enriched) - Arm A	TRAS+CHEM±AI (HER2-Enriched) - Arm B	Non-HER2- Enriched - Arm C
Arm/Group Description	Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.	Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.	Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
Measure Participants	17	15	10
Total Deaths	11 64.7%	9 60%	6 60%
On-treatment deaths	3 17.6%	1 6.7%	0 0%

Adverse Events

Time Frame	On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 168 weeks for lapatinib, for a maximum duration of 164 weeks for trastuzumab and for a maximum duration of 168 weeks for aromatase inhibitors (anastrozole, letrozole and exemestane.)
Adverse Event Reporting Description	Adverse Event: Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Arm/Group Title	LAP+TRAS±AI (HER2-Enriched) - Arm A		TRAS+CHEM±AI (HER2-Enriched) • ArmB		Non-HER2-Enriched - Arm C
Arm/Group Description	Lapatinib 1000mg + Trastuzumab in HER2 Enriched In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.		Trastuzumab in HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator.		Lapatinib 1000mg + Trastuzumab in Non- HER2 Enriched: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
All Cause Mortality
	LAP+TRAS±AI (HER2-Enriched) - Arm A		TRAS+CHEM±AI (HER2-Enriched) • ArmB		Non-HER2-Enriched - Arm C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/17 (17.6%)		1/15 (6.7%)		0/10 (0%)
Serious Adverse Events
	LAP+TRAS±AI (HER2-Enriched) - Arm A		TRAS+CHEM±AI (HER2-Enriched) • ArmB		Non-HER2-Enriched - Arm C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/17 (5.9%)		1/15 (6.7%)		2/10 (20%)
Cardiac disorders
Cardiac arrest	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Infections and infestations
Escherichia sepsis	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Sepsis	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Urinary tract infection	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Metabolism and nutrition disorders
Hypoalbuminaemia	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Hypoglycaemia	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Hypokalaemia	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Hypomagnesaemia	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Hyponatraemia	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Metabolic disorder	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast neoplasm	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Nervous system disorders
Seizure	0/17 (0%)		0/15 (0%)		1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/17 (0%)		0/15 (0%)		1/10 (10%)
Hypoxia	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	LAP+TRAS±AI (HER2-Enriched) - Arm A		TRAS+CHEM±AI (HER2-Enriched) • ArmB		Non-HER2-Enriched - Arm C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/17 (88.2%)		14/15 (93.3%)		10/10 (100%)
Blood and lymphatic system disorders
Anaemia	2/17 (11.8%)		3/15 (20%)		2/10 (20%)
Leukopenia	1/17 (5.9%)		1/15 (6.7%)		0/10 (0%)
Lymphopenia	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Neutropenia	1/17 (5.9%)		4/15 (26.7%)		0/10 (0%)
Cardiac disorders
Left ventricular dysfunction	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Sinus tachycardia	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Ventricular extrasystoles	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Eye disorders
Eyelid oedema	0/17 (0%)		0/15 (0%)		1/10 (10%)
Visual impairment	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Gastrointestinal disorders
Abdominal pain	0/17 (0%)		0/15 (0%)		1/10 (10%)
Abdominal pain upper	3/17 (17.6%)		2/15 (13.3%)		0/10 (0%)
Constipation	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Diarrhoea	9/17 (52.9%)		1/15 (6.7%)		6/10 (60%)
Nausea	1/17 (5.9%)		5/15 (33.3%)		3/10 (30%)
Stomatitis	0/17 (0%)		2/15 (13.3%)		0/10 (0%)
Vomiting	1/17 (5.9%)		1/15 (6.7%)		4/10 (40%)
General disorders
Asthenia	3/17 (17.6%)		4/15 (26.7%)		2/10 (20%)
Face oedema	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Fatigue	2/17 (11.8%)		2/15 (13.3%)		0/10 (0%)
Influenza like illness	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Mucosal inflammation	0/17 (0%)		2/15 (13.3%)		1/10 (10%)
Pain	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Infections and infestations
Bronchitis	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Cellulitis	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Nasopharyngitis	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Paronychia	4/17 (23.5%)		0/15 (0%)		0/10 (0%)
Pharyngitis	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Respiratory tract infection	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Upper respiratory tract infection	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Urinary tract infection	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Injury, poisoning and procedural complications
Incision site pain	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Rib fracture	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Investigations
Alanine aminotransferase increased	0/17 (0%)		5/15 (33.3%)		0/10 (0%)
Aspartate aminotransferase increased	2/17 (11.8%)		2/15 (13.3%)		0/10 (0%)
Blood alkaline phosphatase increased	1/17 (5.9%)		2/15 (13.3%)		2/10 (20%)
Blood sodium decreased	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Ejection fraction decreased	2/17 (11.8%)		0/15 (0%)		0/10 (0%)
Neutrophil count decreased	1/17 (5.9%)		1/15 (6.7%)		0/10 (0%)
Weight decreased	2/17 (11.8%)		0/15 (0%)		2/10 (20%)
Weight increased	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/17 (11.8%)		0/15 (0%)		3/10 (30%)
Hyperglycaemia	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Hyperkalaemia	0/17 (0%)		2/15 (13.3%)		0/10 (0%)
Hypermagnesaemia	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Hypoalbuminaemia	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Hypocalcaemia	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Hypokalaemia	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Back pain	2/17 (11.8%)		1/15 (6.7%)		0/10 (0%)
Muscle spasms	1/17 (5.9%)		1/15 (6.7%)		0/10 (0%)
Musculoskeletal chest pain	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Myalgia	1/17 (5.9%)		3/15 (20%)		0/10 (0%)
Pain in extremity	0/17 (0%)		1/15 (6.7%)		1/10 (10%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Tumour pain	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Nervous system disorders
Dizziness	0/17 (0%)		3/15 (20%)		0/10 (0%)
Headache	1/17 (5.9%)		2/15 (13.3%)		0/10 (0%)
Neuropathy peripheral	0/17 (0%)		2/15 (13.3%)		0/10 (0%)
Neurotoxicity	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Paraesthesia	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Somnolence	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Psychiatric disorders
Depression	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Catarrh	0/17 (0%)		0/15 (0%)		1/10 (10%)
Cough	2/17 (11.8%)		0/15 (0%)		0/10 (0%)
Dyspnoea	0/17 (0%)		0/15 (0%)		1/10 (10%)
Pleurisy	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Skin and subcutaneous tissue disorders
Alopecia	0/17 (0%)		5/15 (33.3%)		0/10 (0%)
Dermatitis acneiform	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Dry skin	2/17 (11.8%)		0/15 (0%)		0/10 (0%)
Nail discolouration	0/17 (0%)		0/15 (0%)		1/10 (10%)
Nail disorder	2/17 (11.8%)		1/15 (6.7%)		1/10 (10%)
Nail dystrophy	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Palmar-plantar erythrodysaesthesia syndrome	3/17 (17.6%)		1/15 (6.7%)		1/10 (10%)
Pruritus	2/17 (11.8%)		0/15 (0%)		0/10 (0%)
Rash	3/17 (17.6%)		2/15 (13.3%)		0/10 (0%)
Rash maculo-papular	0/17 (0%)		0/15 (0%)		1/10 (10%)
Skin toxicity	1/17 (5.9%)		0/15 (0%)		0/10 (0%)
Vascular disorders
Hypertension	0/17 (0%)		1/15 (6.7%)		0/10 (0%)
Lymphoedema	0/17 (0%)		2/15 (13.3%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.