Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00553358
• Collaborator: Breast International Group (Other), SOLTI Breast Cancer Research Group (Other)
• Enrollment: 455
• Locations: 122
• Arms: 3
• Actual Duration (Months): 143.6
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a randomised, open label multicenter Phase III study comparing the efficacy of neoadjuvant lapatinib plus paclitaxel, versus trastuzumab plus paclitaxel, versus concomitant lapatinib and trastuzumab plus paclitaxel given as neoadjuvant treatment in HER2/ErbB2 over-expressing and/or amplified primary breast cancer.

Patients will be randomised to receive either: lapatinib 1500 mg daily, trastuzumab 4 mg/kg intravenous (IV) load followed by 2 mg/kg IV weekly, or lapatinib 1000 mg daily with trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for a total of 6 weeks. After this biological window, patients on monotherapy arms will continue on the same targeted therapy plus weekly paclitaxel 80 mg/m^{2 for a further 12 weeks, up to definitive surgery. In the combination arm, patients will receive lapatinib 750 mg daily in combination with trastuzumab 2 mg/kg IV plus weekly paclitaxel 80mg/m}2 IV for a further 12 weeks, up to definitive surgery. After surgery, patients will receive three courses of adjuvant chemotherapy with 5-Fluorouracil Epirubicin Cyclophosphamide (FEC) followed by the same targeted therapy as in the biological window of the neoadjuvant setting for a further 34 weeks (in the combination arm, lapatinib dose will be 1000 mg daily in combination with trastuzumab). The planned total duration of the anti-HER2 therapy one year.

Primary objective is to evaluate and compare the rate of pathological complete response (pCR) at the time of surgery in patients with HER2/ErbB2 overexpressing or amplified operable breast cancer randomised to lapatinib followed by lapatinib plus paclitaxel versus trastuzumab followed by trastuzumab plus paclitaxel versus lapatinib in combination with trastuzumab followed by lapatinib, trastuzumab plus paclitaxel.

Condition or Disease	Intervention/Treatment	Phase
Neoplasms, Breast	Drug: Lapatinib; Biological: Trastuzumab; Drug: Paclitaxel	Phase 3

Detailed Description

This was a parallel group, three-arm, randomized, multicenter, open-label phase III study. The study compared the efficacy and tolerability of neoadjuvant lapatinib and paclitaxel, versus trastuzumab and paclitaxel, versus the combination of lapatinib with trastuzumab and paclitaxel given as neoadjuvant treatment in HER2/ErbB2 over-expressing and/or amplified primary breast cancer. Subjects were randomized to receive lapatinib, trastuzumab or lapatinib plus trastuzumab for a total of 6 weeks. After this biological window, subjects continued on the same targeted therapy plus weekly paclitaxel for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). Paclitaxel could be initiated at Week 4 if there is evidence of progressive disease (PD) at that time. Within 6 weeks after surgery, subjects received 3 cycles of adjuvant 5-flourouracil, epirubicin and cyclophosphamide (FEC) followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy).

After completing 52 weeks of (neo-)/adjuvant anti-HER2 therapy, subjects were scheduled to attend post-treatment follow-up every 3 months during the first year (months 12, 15, 18, 21, and 24), every 6months in Years 3 to 5 inclusive, and annually thereafter up to Year 10. Each subject was to be followed for 10 Years. All subjects were to be followed for EFS and OS up to 10 years from last subject randomized.

Study Design

• Study Type: Interventional
• Actual Enrollment: 455 participants
• Allocation: Randomized
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study: A Randomised, Multicenter Open-label Phase III Study of Neoadjuvant Lapatinib, Trastuzumab and Their Combination Plus Paclitaxel in Women With HER2/ErbB2 Positive Primary Breast Cancer
• Actual Study Start Date: Jan 5, 2008
• Actual Primary Completion Date: May 27, 2010
• Actual Study Completion Date: Dec 23, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Lapatinib 1500 mg lapatinib for 6 weeks followed by lapatinib plus weekly paclitaxel for an additional 12 weeks. After definitive surgery, 3 cycles of adjuvant FEC followed by 34 weeks of adjuvant lapatinib.	Drug: Lapatinib; Small molecule receptor tyrosine kinase inhibitor; Drug: Paclitaxel; antimicrotubule agent
Active Comparator: Arm 2 Trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly trastuzumab for 6 weeks followed by 2 mg/kg trastuzumab plus weekly paclitaxel for an additional 12 weeks. After definitive surgery, 3 cycles of adjuvant FEC followed by 34 weeks of adjuvant trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks).	Biological: Trastuzumab; Therapeutic Monoclonal Antibody; Drug: Paclitaxel; antimicrotubule agent
Experimental: Arm 3 Lapatinib plus Trastuzumab 1000 mg lapatinib plus 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly trastuzumab for 6 weeks, followed by 750 mg lapatinib plus 2 mg/kg IV weekly trastuzumab plus weekly paclitaxel for an additional 12 weeks. After definitive surgery, 3 cycles of adjuvant FEC followed by 34 weeks of adjuvant lapatinib (1000 mg) in combination with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks).	Drug: Lapatinib; Small molecule receptor tyrosine kinase inhibitor; Biological: Trastuzumab; Therapeutic Monoclonal Antibody; Drug: Paclitaxel; antimicrotubule agent

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Pathological Complete Response (pCR) at the Time of Surgery [Weeks 20 to 22]

   Pathological complete response is defined as no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. Surgical breast and axillary node resection specimens were evaluated for pathologic tumor response according to National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines, which do not take into account the histological nodal status.

Secondary Outcome Measures

1. Number of Participants With Overall Response at Week 6 [Week 6]

   The number of participants with overall response (complete response and/or partial response) was evaluated using World Health Organization (WHO) criteria by clinical examination and by mammography and breast echography with bi-dimensional measurements at Week 6. As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.

2. Overall Response at the Time of Surgery [Time of surgery (Weeks 20 to 22)]

   The number of participants with overall response (complete response and/or partial response) was evaluated using WHO criteria by clinical examination and mammography and breast echography with bi-dimensional measurements at the time of surgery (Weeks 20 to 22). As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.

3. Number of Participants With Negative Lymph Nodes at the Time of Surgery [Time of surgery (Weeks 20 to 22)]

   Participants were assessed for node-negative lymph nodes at the time of surgery. As per the pathological TNM (Tumor, Node, Metastases) classification (pTNM) of malignant tumors: pN, absence or presence and extent of regional lymph node metastasis. Node-negative (pN0) participants had no regional lymph node metastasis. Although not assessed in this measure, pT is the extent of primary tumor, and pM is the absence or presence of distant metastasis.

4. Number of Participants With Actual Indicated Surgery [At surgery (Weeks 20 to 22)]

   Participants were assessed for the type of surgery they underwent for breast cancer. Non-conservative surgery is defined as a radical or modified radical mastectomy. Conservative surgery is comprised of a lumpectomy, a quadrantectomy/segmentectomy, or a partial mastectomy. Participants who were not assessed as being candidates for non-conservative or conservative surgery were classified as non-operable.

5. Mean Change From Baseline in Tumor Size at Week 6 and at Surgery [Week 6 and surgery (Weeks 20 to 22)]

   Mean change from baseline in tumor in tumor size. Change from baseline in tumor size was defined as tumor size at Week 6/ surgery (Weeks 20 to 22) minus tumor size at baseline. The difference in treatment arms was estimated for Lapatinib 1500 mg versus Trastuzumab 2 mg/kg and for Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg versus Trastuzumab 2 mg/kg.

6. Number of Participants Starting Paclitaxel Before Completing 6 Weeks of Treatment With Either Lapatinib or Trastuzumab [Week 6]

   Participants with progressive disease at 4 week assessment that were permitted to commence treatment with paclitaxel.

7. Event-free Survival (EFS) - Median Clinical Follow-up [From randomization up to approximately year 10]

   Event free survival (EFS) is defined as the time from randomization to first EFS event. For subjects who had breast cancer surgery, EFS events were post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For subjects who did not have breast cancer surgery, EFS events were death during clinical follow-up or non-completion of any neoadjuvant investigational product due to disease progression.

8. Event-free Survival (EFS) - Events and Censoring [From randomization up to approximately year 10]

   Event free survival (EFS) is defined as the time from randomization to first EFS event. For subjects who had breast cancer surgery, EFS events were post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For subjects who did not have breast cancer surgery, EFS events were death during clinical follow-up or non-completion of any neoadjuvant investigational product due to disease progression.

9. Overall Survival (OS) - Median Survival Follow-up [From randomization up to approximately year 10]

   Overall survival is defined as the period from randomization until death (from any cause). OS was assessed annually for up to 10 years after the randomization of the last participant into the study.

10. Overall Survival (OS) - Deaths and Censoring [From randomization up to approximately year 10]

    Overall survival is defined as the period from randomization until death (from any cause). OS was assessed annually for up to 10 years after the randomization of the last participant into the study.

11. Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Median Clinical Follow-up (EFS Landmark Population) [up to year 10]

    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Clinical follow-up is the period during which the patient is monitored such that all recurrence or second primary malignancy (SPM) or contralateral breast cancer (CBC) events would be reported. Patients are considered in clinical follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death.

12. Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Number of Participants With EFS Events (EFS Landmark Population) [up to year 10]

    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. For patients who had breast cancer surgery, EFS events are post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For patients who do not undergo breast cancer surgery, EFS events are death during clinical follow-up or non-completion of any neo-adjuvant investigational product due to disease progression or second primary malignancy or contralateral breast cancer.

13. Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Median Clinical Follow-up (OS Landmark Population) [up to year 10]

    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Patients are considered in survival follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death. For subjects with no death recorded in the database, time to death is censored.

14. Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Number of Participants Who Died (OS Landmark Population) [up to year 10]

    The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Includes deaths due to any cause.

15. To Assess Safety Via a Comparison of the Three Treatment Arms - to Measure On-treatment Primary Cardiac Endpoints [Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 31 weeks.]

16. Metabolic Response Rate Determined by Positron Emission Tomography/Computed Tomography (PET/CT) [Week 2 and Week 6]

    Metabolic Response Rate determined by Positron Emission Tomography/Computed Tomography (PET/CT)

17. Percentage of Participants With the Indicated Biomarker Expression - PIK3CA. [Baseline]

    Biomarker levels of phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) were assessed in participants at baseline.

18. Percentage of Participants With the Indicated Biomarker Expression - PTEN. [Baseline]

    Biomarker levels of phosphate and tensin homolog deleted from chromosome 10 (PTEN) were assessed in participants at baseline.

19. Ratio (95% CI) of Geometric Means in p95HER2 Expression in HR Positive Patients With pCR vs no pCR [Baseline]

    Ratio (95% CI) of geometric means in p95 human epidermal growth factor receptor (p95HER2) expression in hormone-receptor (HR) positive patients with pathological complete response (pCR) vs no pCR

20. Percentage of Participants With Circulating Tumor Cells (CTC) in the Bloodstream [Measurement performed at one or more of the time points: baseline, week 2 or week 18]

    Circulating tumor cells (CTCs) are cells that have detached from a primary tumor and circulate in the bloodstream. In the adjuvant phase, after surgery all participants received 3 courses of adjuvant 5-fluorouracil, epirubicin and cyclophosphamide, followed by lapatinib 1500 mg or trastuzumab 2 mg/kg or lapatinib 1000/750 mg plus trastuzumab 2 mg/kg given prior to surgery in the neoadjuvant setting for an additional 34 weeks.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Female gender;

• Age ≥18 years;

• Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1

• Histologically confirmed invasive breast cancer:

• Primary tumour greater than 2 cm diameter, measured by clinical examination and mammography or echography,

• Any N,

• No evidence of metastasis (M0) (isolated supraclavicular node involvement allowed);

• Over expression and/or amplification of HER2 in the invasive component of the primary tumour [Wolff et al 2006] and confirmed by a certified laboratory prior to randomisation

• Known hormone receptor status.

• Haematopoietic status:

• Absolute neutrophil count ≥ 1,5 x 10^9/L,

• Platelet count ≥ 100 x 10^9/L,

• Hemoglobin at least 9 g/dl,

• Hepatic status:

• Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (< 2 x ULN) is allowed,

• Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times ULN,

• Alkaline phosphatase ≤ 2.5 times ULN,

• Renal status:

• Creatinine ≤ 2.0 mg/dL,

• Cardiovascular:

• Baseline left ventricular ejection fraction (LVEF) ³ 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan,

• Negative serum pregnancy test, within 2-weeks (preferably 7 days) prior to randomization (For women of childbearing potential)

• Fertile patients must use effective contraception (barrier method - condoms, diaphragm

• also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed)

• Signed informed consent form (ICF)

• Patient accepts to make available tumour samples for submission to central laboratory to conduct translational studies as part of this protocol

Exclusion Criteria:

• Received any prior treatment for primary invasive breast cancer;

• Previous (less than 10 years) or current history of malignant neoplasms, except for curatively treated:

• Basal and squamous cell carcinoma of the skin;

• Carcinoma in situ of the cervix.

• Patients with a prior malignancy diagnosed more than 10 years prior to randomisation may enter the study. Patients must have been curatively treated with surgery alone. Radiation therapy or systemic therapy (chemotherapy or endocrine) are NOT permitted. Prior diagnoses of breast cancer or melanoma are excluded.

• Diagnosis of inflammatory breast cancer;

• Bilateral cancer;

• This criterion has been deleted from the protocol Version 1. Patients with multi-focal cancer are no longer excluded.

• Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnoea at rest, or chronic therapy with oxygen;

• Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety;

• Unresolved or unstable, serious adverse events from prior administration of another investigational drug;

• Active or uncontrolled infection;

• Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF;

• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded;

• Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies);

• Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial;

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab or lapatinib or their excipients;

• Pregnant or lactating women;

• Concomitant use of CYP3A4 inhibitors or inducers

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Berazategui	Buenos Aires	Argentina	B1880BBF
2	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1125ABD
3	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1185AAT
4	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000KZE
5	Novartis Investigative Site	Quilmes		Argentina	1878
6	Novartis Investigative Site	Santa Fe		Argentina	3000
7	Novartis Investigative Site	Tucuman		Argentina	4000
8	Novartis Investigative Site	Brussels		Belgium	1000
9	Novartis Investigative Site	Brussel		Belgium	1090
10	Novartis Investigative Site	Bruxelles		Belgium	1070
11	Novartis Investigative Site	Gent		Belgium	9000
12	Novartis Investigative Site	Leuven		Belgium	3000
13	Novartis Investigative Site	Namur		Belgium	5000
14	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul	Brazil	90430-090
15	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul	Brazil	90560-030
16	Novartis Investigative Site	Santo Andre	São Paulo	Brazil	09060-650
17	Novartis Investigative Site	Sao Paulo	São Paulo	Brazil	03102-002
18	Novartis Investigative Site	Montreal	Quebec	Canada	H4J 1C5
19	Novartis Investigative Site	Brno		Czechia	656 53
20	Novartis Investigative Site	Novy Jicin		Czechia	741 01
21	Novartis Investigative Site	Praha 10		Czechia	100 34
22	Novartis Investigative Site	Bayonne		France	64100
23	Novartis Investigative Site	Bordeaux		France	33077
24	Novartis Investigative Site	Le Mans		France	72015
25	Novartis Investigative Site	Levallois-Perret		France	92300
26	Novartis Investigative Site	Paris		France	75010
27	Novartis Investigative Site	Reims		France	51100
28	Novartis Investigative Site	Strasbourg		France	67000
29	Novartis Investigative Site	Strasbourg		France	67085
30	Novartis Investigative Site	Toulouse		France	31076
31	Novartis Investigative Site	Villejuif Cedex		France	94805
32	Novartis Investigative Site	Freiburg	Baden-Wuerttemberg	Germany	79106
33	Novartis Investigative Site	Karlsruhe	Baden-Wuerttemberg	Germany	76135
34	Novartis Investigative Site	Fuerth	Bayern	Germany	90766
35	Novartis Investigative Site	Nuernberg	Bayern	Germany	90340
36	Novartis Investigative Site	Fuerstenwalde	Brandenburg	Germany	15517
37	Novartis Investigative Site	Frankfurt am Main	Hessen	Germany	60590
38	Novartis Investigative Site	Rostock	Mecklenburg-Vorpommern	Germany	18059
39	Novartis Investigative Site	Stralsund	Mecklenburg-Vorpommern	Germany	18435
40	Novartis Investigative Site	Celle	Niedersachsen	Germany	29223
41	Novartis Investigative Site	Hannover	Niedersachsen	Germany	30625
42	Novartis Investigative Site	Dortmund	Nordrhein-Westfalen	Germany	44137
43	Novartis Investigative Site	Essen	Nordrhein-Westfalen	Germany	45122
44	Novartis Investigative Site	Koeln	Nordrhein-Westfalen	Germany	50937
45	Novartis Investigative Site	Witten	Nordrhein-Westfalen	Germany	58452
46	Novartis Investigative Site	Halle	Sachsen-Anhalt	Germany	06120
47	Novartis Investigative Site	Kiel	Schleswig-Holstein	Germany	24105
48	Novartis Investigative Site	Berlin		Germany	13125
49	Novartis Investigative Site	Berlin		Germany	13589
50	Novartis Investigative Site	Hong Kong		Hong Kong
51	Novartis Investigative Site	Kowloon		Hong Kong
52	Novartis Investigative Site	Wanchai		Hong Kong
53	Novartis Investigative Site	Budapest		Hungary	H-1122
54	Novartis Investigative Site	Bangalore		India	560029
55	Novartis Investigative Site	Hyderabad		India	500082
56	Novartis Investigative Site	Mumbai		India	400012
57	Novartis Investigative Site	Nagpur		India	440010
58	Novartis Investigative Site	New Delhi		India	110060
59	Novartis Investigative Site	New Delhi		India	110076
60	Novartis Investigative Site	Pune		India	411001
61	Novartis Investigative Site	Roma	Lazio	Italy	00144
62	Novartis Investigative Site	Genova	Liguria	Italy	16132
63	Novartis Investigative Site	Lecco	Lombardia	Italy	23900
64	Novartis Investigative Site	Milano	Lombardia	Italy	20132
65	Novartis Investigative Site	Milano	Lombardia	Italy	20141
66	Novartis Investigative Site	Monza	Lombardia	Italy	20052
67	Novartis Investigative Site	Sondrio	Lombardia	Italy	23100
68	Novartis Investigative Site	Trento	Trentino-Alto Adige	Italy	38100
69	Novartis Investigative Site	Seoul		Korea, Republic of	003722
70	Novartis Investigative Site	Seoul		Korea, Republic of	06351
71	Novartis Investigative Site	Seoul		Korea, Republic of	135-710
72	Novartis Investigative Site	Seoul		Korea, Republic of	138-736
73	Novartis Investigative Site	Songpa-gu, Seoul		Korea, Republic of	138-736
74	Novartis Investigative Site	Vilnius		Lithuania	LT-08660
75	Novartis Investigative Site	Oslo		Norway	0310
76	Novartis Investigative Site	Oslo		Norway	0407
77	Novartis Investigative Site	Karachi		Pakistan	74800
78	Novartis Investigative Site	Lima		Peru	Lima 11
79	Novartis Investigative Site	Lima		Peru	Lima 34
80	Novartis Investigative Site	Bucharest		Romania	022328
81	Novartis Investigative Site	Bucharest		Romania	050098
82	Novartis Investigative Site	Bucuresti		Romania	022328
83	Novartis Investigative Site	Cluj-Napoca		Romania	400015
84	Novartis Investigative Site	Moscow		Russian Federation	115 478
85	Novartis Investigative Site	Ryazan		Russian Federation	390011
86	Novartis Investigative Site	St. Petersburg		Russian Federation	197022
87	Novartis Investigative Site	St. Petersburg		Russian Federation	197758
88	Novartis Investigative Site	Pretoria	Gauteng	South Africa	0181
89	Novartis Investigative Site	Athlone Park, Amanzimtoti		South Africa	4126
90	Novartis Investigative Site	Capital Park		South Africa	0002
91	Novartis Investigative Site	Parktown		South Africa	2193
92	Novartis Investigative Site	Barcelona		Spain	08035
93	Novartis Investigative Site	Girona		Spain	17007
94	Novartis Investigative Site	Lerida		Spain	25198
95	Novartis Investigative Site	Madrid		Spain	28033
96	Novartis Investigative Site	Madrid		Spain	28041
97	Novartis Investigative Site	Mataro		Spain	08304
98	Novartis Investigative Site	Santiago de Compostela		Spain	15706
99	Novartis Investigative Site	Sevilla		Spain	41013
100	Novartis Investigative Site	Toledo		Spain	45004
101	Novartis Investigative Site	Torrevieja (Alicante)		Spain	03186
102	Novartis Investigative Site	Valencia		Spain	46014
103	Novartis Investigative Site	Goteborg		Sweden	SE-413 45
104	Novartis Investigative Site	Changhua		Taiwan	500
105	Novartis Investigative Site	Tainan		Taiwan	704
106	Novartis Investigative Site	Taipei		Taiwan	100
107	Novartis Investigative Site	Taipei		Taiwan	104
108	Novartis Investigative Site	Taipei		Taiwan	112
109	Novartis Investigative Site	Chernivtsi		Ukraine	58013
110	Novartis Investigative Site	Dnipropetrovsk		Ukraine	49100
111	Novartis Investigative Site	Kharkiv		Ukraine	61070
112	Novartis Investigative Site	Kiev		Ukraine	03115
113	Novartis Investigative Site	Krivoy Rog		Ukraine	50048
114	Novartis Investigative Site	Kyiv		Ukraine	03022
115	Novartis Investigative Site	Lviv		Ukraine	79031
116	Novartis Investigative Site	Odessa		Ukraine	65055
117	Novartis Investigative Site	Simferopol		Ukraine	95023
118	Novartis Investigative Site	Epping	Essex	United Kingdom	CM16 6TN
119	Novartis Investigative Site	Bournemouth		United Kingdom	BH7 7DW
120	Novartis Investigative Site	London		United Kingdom	EC1A 7BE
121	Novartis Investigative Site	London		United Kingdom	SE1 9RT
122	Novartis Investigative Site	Nottingham		United Kingdom	NG5 1PB

Sponsors and Collaborators

• Novartis Pharmaceuticals
• Breast International Group
• SOLTI Breast Cancer Research Group

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

• Baselga J, Piccart M, Gelber R, di CosimoS, Viale G, Koehler M, Rojo F. Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study [BIG 1-06 /solti/EGF106903]: a phase III translational study for HER2-overexpressing early breast cancer. [Lancet]. 2012;S140-6736(11):

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00553358
• Other Study ID Numbers: EGF106903; 2006-000564-81; CLAP016B2302
• First Posted: Nov 4, 2007
• Last Update Posted: Sep 21, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Lapatinib; ErbB2+; Early Breast Cancer; Neoadjuvant; breast carcinoma; breast cancer; breast lump; HER2 positive metastatic breast cancer; breast cancer positive for human epidermal growth factor receptor 2 (HER2) HER2 positive metastatic breast cancer; breast cancer progression; estrogen-receptor (ER) positive(+) breast cancer; Paget's disease
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Trastuzumab; Lapatinib

Study Results

Participant Flow

Arm/Group Title	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg	Lapatinib 1500 mg	Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Period Title: Overall Study
STARTED	152	154	149
COMPLETED	73	58	61
NOT COMPLETED	79	96	88

Baseline Characteristics

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg	Total
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Total of all reporting groups
Overall Participants	154	149	152	455
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	50.0	49.0	50.0	50.0
Sex: Female, Male (Count of Participants)
Female	154 100%	149 100%	152 100%	455 100%
Male	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	13 8.4%	14 9.4%	15 9.9%	42 9.2%
Asian - Central/South	7 4.5%	5 3.4%	5 3.3%	17 3.7%
Asian - East	30 19.5%	28 18.8%	31 20.4%	89 19.6%
Asian - South East	0 0%	0 0%	2 1.3%	2 0.4%
Black or African American/African Heritage	0 0%	4 2.7%	4 2.6%	8 1.8%
White - Arabic/North African Heritage	6 3.9%	5 3.4%	3 2%	14 3.1%
White - Caucasian European Heritage	97 63%	93 62.4%	92 60.5%	282 62%
Missing	1 0.6%	0 0%	0 0%	1 0.2%
Number of participants with tumor cells of the indicated histologic grade (Count of Participants)
Well differentiated	2 1.3%	5 3.4%	5 3.3%	12 2.6%
Moderately differentiated	56 36.4%	53 35.6%	63 41.4%	172 37.8%
Poorly differentiated	73 47.4%	68 45.6%	64 42.1%	205 45.1%
Differentiation cannot be assessed	22 14.3%	23 15.4%	20 13.2%	65 14.3%
Missing	1 0.6%	0 0%	0 0%	1 0.2%
Number of participants with lymph nodes (LNs) of the indicated clinical N stage (Count of Participants)
N0	34 22.1%	41 27.5%	48 31.6%	123 27%
N1	95 61.7%	85 57%	80 52.6%	260 57.1%
N2 (including N2a and N2b)	19 12.3%	13 8.7%	15 9.9%	47 10.3%
N3 (including N3a, N3b, and N3c)	6 3.9%	7 4.7%	6 3.9%	19 4.2%
Nx	0 0%	3 2%	3 2%	6 1.3%
Number of participants with the indicated IHC results (Count of Participants)
Not applicable	60 39%	53 35.6%	61 40.1%	174 38.2%
Equivocal: Score of 2+	9 5.8%	5 3.4%	8 5.3%	22 4.8%
Positive: Score of 3+	81 52.6%	89 59.7%	76 50%	246 54.1%
Negative: Score of 0-1+	0 0%	1 0.7%	3 2%	4 0.9%
Non interpretable	4 2.6%	1 0.7%	4 2.6%	9 2%
Number of participants with the indicated FISH results (Count of Participants)
Not applicable	38 24.7%	42 28.2%	41 27%	121 26.6%
Amplified	115 74.7%	105 70.5%	109 71.7%	329 72.3%
Not amplified	1 0.6%	2 1.3%	1 0.7%	4 0.9%
Not interpretable	0 0%	0 0%	1 0.7%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Pathological Complete Response (pCR) at the Time of Surgery
Description	Pathological complete response is defined as no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen. Surgical breast and axillary node resection specimens were evaluated for pathologic tumor response according to National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines, which do not take into account the histological nodal status.
Time Frame	Weeks 20 to 22

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all participants randomized to treatment, except for those who withdrew their consent to use any of their data (permitted by law in certain countries) prior to receiving any study medication

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	154	149	152
Number [participants]	38 24.7%	44 29.5%	78 51.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Trastuzumab 2 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3416
	Comments
	Method	Binomial
	Comments	Binomial p-value for Trastuzumab 2 mg/kg versus Lapatinib 1500 mg
Method of Estimation	Estimation Parameter	Percentage of participants with pCR
	Estimated Value	-4.85
	Confidence Interval	(2-Sided) 97.5%; -17.6 to 8.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimation Comments: Estimated value is the difference in the percentage of participants with pCR: Arm1 (Lapatinib 1500 mg) minus Arm2 (Trastuzumab 2 mg/kg).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab 2 mg/kg, Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Binomial
	Comments	Binomial p-value for Trastuzumab 2 mg/kg versus Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Method of Estimation	Estimation Parameter	Percentage of participants with pCR
	Estimated Value	21.79
	Confidence Interval	(2-Sided) 97.5%; 9.08 to 34.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimation Comments: Estimated value is the difference in the percentage of participants with pCR: Arm3 (Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg) minus Arm2 (Trastuzumab 2 mg/kg)

2. Secondary Outcome

Title	Number of Participants With Overall Response at Week 6
Description	The number of participants with overall response (complete response and/or partial response) was evaluated using World Health Organization (WHO) criteria by clinical examination and by mammography and breast echography with bi-dimensional measurements at Week 6. As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	154	149	152
Overall Response	81 52.6%	45 30.2%	102 67.1%
No Change	57 37%	81 54.4%	33 21.7%
Progressive Disease	5 3.2%	11 7.4%	2 1.3%
Not Evaluated	7 4.5%	9 6%	12 7.9%
Missing Data	4 2.6%	3 2%	3 2%

3. Secondary Outcome

Title	Overall Response at the Time of Surgery
Description	The number of participants with overall response (complete response and/or partial response) was evaluated using WHO criteria by clinical examination and mammography and breast echography with bi-dimensional measurements at the time of surgery (Weeks 20 to 22). As per WHO criteria: complete response is defined as the disappearance of all lesions; partial response is defined as a greater than 50% decrease in the sum of products of the greatest length and width of the largest lesion; progressive disease is defined as a greater than 25% increase in the sum of products of all measurable lesions.
Time Frame	Time of surgery (Weeks 20 to 22)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	154	149	152
Overall Response	114 74%	105 70.5%	122 80.3%
No Change	8 5.2%	16 10.7%	7 4.6%
Progressive Disease	0 0%	2 1.3%	1 0.7%
Not Evaluated	19 12.3%	20 13.4%	14 9.2%
Missing Data	13 8.4%	6 4%	8 5.3%

4. Secondary Outcome

Title	Number of Participants With Negative Lymph Nodes at the Time of Surgery
Description	Participants were assessed for node-negative lymph nodes at the time of surgery. As per the pathological TNM (Tumor, Node, Metastases) classification (pTNM) of malignant tumors: pN, absence or presence and extent of regional lymph node metastasis. Node-negative (pN0) participants had no regional lymph node metastasis. Although not assessed in this measure, pT is the extent of primary tumor, and pM is the absence or presence of distant metastasis.
Time Frame	Time of surgery (Weeks 20 to 22)

Outcome Measure Data

Analysis Population Description

ITT Population. Participants with a lymph node status of pNX (i.e., regional lymph nodes cannot be assessed) were omitted from the analysis of node-negative participants.

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	139	140	137
Number [participants]	72 46.8%	82 55%	100 65.8%

5. Secondary Outcome

Title	Number of Participants With Actual Indicated Surgery
Description	Participants were assessed for the type of surgery they underwent for breast cancer. Non-conservative surgery is defined as a radical or modified radical mastectomy. Conservative surgery is comprised of a lumpectomy, a quadrantectomy/segmentectomy, or a partial mastectomy. Participants who were not assessed as being candidates for non-conservative or conservative surgery were classified as non-operable.
Time Frame	At surgery (Weeks 20 to 22)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	154	149	152
Conservative	66 42.9%	58 38.9%	63 41.4%
Non-conservative	77 50%	85 57%	80 52.6%
Non-operable	11 7.1%	6 4%	9 5.9%

6. Secondary Outcome

Title	Mean Change From Baseline in Tumor Size at Week 6 and at Surgery
Description	Mean change from baseline in tumor in tumor size. Change from baseline in tumor size was defined as tumor size at Week 6/ surgery (Weeks 20 to 22) minus tumor size at baseline. The difference in treatment arms was estimated for Lapatinib 1500 mg versus Trastuzumab 2 mg/kg and for Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg versus Trastuzumab 2 mg/kg.
Time Frame	Week 6 and surgery (Weeks 20 to 22)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	154	149	152
Week 6	-20.45 (18.43)	-13.42 (16.44)	-25.77 (19.91)
Surgery (Weeks 20 to 22)	-41.01 (23.81)	-35.47 (22.95)	-43.59 (26.88)

7. Secondary Outcome

Title	Number of Participants Starting Paclitaxel Before Completing 6 Weeks of Treatment With Either Lapatinib or Trastuzumab
Description	Participants with progressive disease at 4 week assessment that were permitted to commence treatment with paclitaxel.
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

ITT Population. Participants who did not start any treatment were excluded from analysis.

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	149	146	149
Number [participants]	8 5.2%	12 8.1%	6 3.9%

8. Secondary Outcome

Title	Event-free Survival (EFS) - Median Clinical Follow-up
Description	Event free survival (EFS) is defined as the time from randomization to first EFS event. For subjects who had breast cancer surgery, EFS events were post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For subjects who did not have breast cancer surgery, EFS events were death during clinical follow-up or non-completion of any neoadjuvant investigational product due to disease progression.
Time Frame	From randomization up to approximately year 10

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all participants randomized to treatment, except for those who withdrew their consent to use any of their data (permitted by law in certain countries) prior to receiving any study medication

Arm/Group Title	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg	Lapatinib 1500 mg	Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	152	154	149
Median (95% Confidence Interval) [years]	9.69	9.60	9.66

9. Secondary Outcome

Title	Event-free Survival (EFS) - Events and Censoring
Description	Event free survival (EFS) is defined as the time from randomization to first EFS event. For subjects who had breast cancer surgery, EFS events were post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For subjects who did not have breast cancer surgery, EFS events were death during clinical follow-up or non-completion of any neoadjuvant investigational product due to disease progression.
Time Frame	From randomization up to approximately year 10

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all participants randomized to treatment, except for those who withdrew their consent to use any of their data (permitted by law in certain countries) prior to receiving any study medication

Arm/Group Title	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg	Lapatinib 1500 mg	Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	152	154	149
Number of subjects with EFS events	43 27.9%	47 31.5%	47 30.9%
Number of subjects censored - total	109 70.8%	107 71.8%	102 67.1%
Number of subjects censored - Clinical follow-up ongoing	0 0%	0 0%	0 0%
Number of subjects censored - Clinical follow-up ended - total	103 66.9%	105 70.5%	99 65.1%
Number of subjects censored -Clinical follow-up ended - Completed study follow-up	61 39.6%	49 32.9%	58 38.2%
Number of subjects censored - Clinical follow-up ended - Lost to follow-up	17 11%	20 13.4%	10 6.6%
Number of subjects censored - Clinical follow-up ended - Withdrew (but consent for survival f/u)	3 1.9%	6 4%	4 2.6%
Number of subjects censored - Clinical follow-up ended - Withdrew	22 14.3%	30 20.1%	27 17.8%
Number of subjects censored - Other	6 3.9%	2 1.3%	3 2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.548
	Comments	The two-sided stratified log-rank test was implemented as the score test from the Cox model.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.878
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate hazard ratios and corresponding confidence intervals for the pairwise comparisons of individual treatment arms with the trastuzumab alone arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab 2 mg/kg, Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.981
	Comments	The two-sided stratified log-rank test was implemented as the score test from the Cox model.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.005
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate hazard ratios and corresponding confidence intervals for the pairwise comparisons of individual treatment arms with the trastuzumab alone arm.

10. Secondary Outcome

Title	Overall Survival (OS) - Median Survival Follow-up
Description	Overall survival is defined as the period from randomization until death (from any cause). OS was assessed annually for up to 10 years after the randomization of the last participant into the study.
Time Frame	From randomization up to approximately year 10

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all participants randomized to treatment, except for those who withdrew their consent to use any of their data (permitted by law in certain countries) prior to receiving any study medication

Arm/Group Title	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg	Lapatinib 1500 mg	Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	152	154	149
Median (95% Confidence Interval) [years]	9.70	9.62	9.64

11. Secondary Outcome

Title	Overall Survival (OS) - Deaths and Censoring
Description	Overall survival is defined as the period from randomization until death (from any cause). OS was assessed annually for up to 10 years after the randomization of the last participant into the study.
Time Frame	From randomization up to approximately year 10

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all participants randomized to treatment, except for those who withdrew their consent to use any of their data (permitted by law in certain countries) prior to receiving any study medication

Arm/Group Title	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg	Lapatinib 1500 mg	Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	152	154	149
Number of deaths due to any cause	26 16.9%	31 20.8%	32 21.1%
Number of subjects censored - total	126 81.8%	123 82.6%	117 77%
Number of subjects censored - Survival follow-up ongoing	0 0%	0 0%	0 0%
Number of subjects censored - Survival follow-up ended - total	120 77.9%	121 81.2%	114 75%
Number of subjects censored -Survival follow-up ended - Completed study follow-up	74 48.1%	59 39.6%	62 40.8%
Number of subjects censored - Survival follow-up ended - Lost to follow-up	22 14.3%	27 18.1%	18 11.8%
Number of subjects censored - Survival follow-up ended - Withdrew	24 15.6%	35 23.5%	34 22.4%
Number of subjects censored - Other	6 3.9%	2 1.3%	3 2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.379
	Comments	The two-sided stratified log-rank test was implemented as the score test from the Cox model.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.788
	Confidence Interval	(2-Sided) 95%; 0.46 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate hazard ratios and corresponding confidence intervals for the pairwise comparisons of individual treatment arms with the trastuzumab alone arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab 2 mg/kg, Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.880
	Comments	The two-sided stratified log-rank test was implemented as the score test from the Cox model.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.962
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate hazard ratios and corresponding confidence intervals for the pairwise comparisons of individual treatment arms with the trastuzumab alone arm.

12. Secondary Outcome

Title	Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Median Clinical Follow-up (EFS Landmark Population)
Description	The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Clinical follow-up is the period during which the patient is monitored such that all recurrence or second primary malignancy (SPM) or contralateral breast cancer (CBC) events would be reported. Patients are considered in clinical follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death.
Time Frame	up to year 10

Outcome Measure Data

Analysis Population Description

For EFS, the landmark population was the subset of the ITT population who have not had an EFS event within 30 weeks after randomization and were still in clinical follow-up.

Arm/Group Title	Pathological Complete Response (pCR)	No Pathological Complete Response (pCR)	Overall
Arm/Group Description	locoregional pathological Complete Response (pCR)	no locoregional pathological Complete Response (pCR)	Overall - of the 3 arms
Measure Participants	136	274	410
Median clinical follow-up - all subjects in the EFS landmark analysis	9.05	9.11	9.09
Median clinical follow-up- EFS landmark analysis - lapatinib + trastuzumab arm (n=67,71,138)	9.13	9.10	9.12
Median clinical follow-up - subjects in the EFS landmark analysis - lapatinib arm (n=30,104,134)	8.08	9.09	9.05
Median clinical follow-up - subjects in the EFS landmark analysis - trastuzumab arm (n=39,99,138)	8.98	9.12	9.11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Trastuzumab 2 mg/kg
	Comments	Overall - All subjects in the EFS landmark analysis
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.00079
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.481
	Confidence Interval	(2-Sided) 95%; 0.31 to 0.73
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate a hazard ratio and corresponding confidence interval comparing pCR and no pCR.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Trastuzumab 2 mg/kg
	Comments	Subjects in the EFS landmark analysis in the lapatinib + trastuzumab arm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.350
	Confidence Interval	(2-Sided) 95%; 0.16 to 0.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate a hazard ratio and corresponding confidence interval comparing pCR and no pCR.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Trastuzumab 2 mg/kg
	Comments	Subjects in the EFS landmark analysis in the lapatinib arm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.134
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.532
	Confidence Interval	(2-Sided) 95%; 0.21 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate a hazard ratio and corresponding confidence interval comparing pCR and no pCR.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Trastuzumab 2 mg/kg
	Comments	Subjects in the EFS landmark analysis in the trastuzumab arm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.163
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.601
	Confidence Interval	(2-Sided) 95%; 0.28 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate a hazard ratio and corresponding confidence interval comparing pCR and no pCR.

13. Secondary Outcome

Title	Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Number of Participants With EFS Events (EFS Landmark Population)
Description	The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. For patients who had breast cancer surgery, EFS events are post-surgery breast cancer relapse, second primary malignancy or death without recurrence. For patients who do not undergo breast cancer surgery, EFS events are death during clinical follow-up or non-completion of any neo-adjuvant investigational product due to disease progression or second primary malignancy or contralateral breast cancer.
Time Frame	up to year 10

Outcome Measure Data

Analysis Population Description

For EFS, the landmark population was the subset of the ITT population who have not had an EFS event within 30 weeks after randomization and were still in clinical follow-up.

Arm/Group Title	Pathological Complete Response (pCR)	No Pathological Complete Response (pCR)	Overall
Arm/Group Description	locoregional pathological Complete Response (pCR)	no locoregional pathological Complete Response (pCR)	Overall - of the 3 arms
Measure Participants	136	274	410
All subjects in the EFS landmark analysis with EFS events	29 18.8%	98 65.8%	127 83.6%
Subjects in the EFS landmark analysis - lapatinib + trastuzumab arm with EFS events (n=67,71,138)	11 7.1%	28 18.8%	39 25.7%
Subjects in the EFS landmark analysis in the lapatinib arm with EFS events (n=30,104,134)	7 4.5%	36 24.2%	43 28.3%
Subjects in the EFS landmark analysis in the trastuzumab arm with EFS events (n=39,99,138)	11 7.1%	34 22.8%	45 29.6%

14. Secondary Outcome

Title	Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Median Clinical Follow-up (OS Landmark Population)
Description	The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Patients are considered in survival follow-up from randomisation until one of the following occurs: lost to follow-up, withdrawal of consent, end of follow-up due to completion of year 10 visit, termination of study follow-up, or death. For subjects with no death recorded in the database, time to death is censored.
Time Frame	up to year 10

Outcome Measure Data

Analysis Population Description

For OS, the landmark population was the subset of the ITT population who were alive and were followed up for overall survival 30 weeks after randomization.

Arm/Group Title	Pathological Complete Response (pCR)	No Pathological Complete Response (pCR)	Overall
Arm/Group Description	locoregional pathological Complete Response (pCR)	no locoregional pathological Complete Response (pCR)	Overall - of the 3 arms
Measure Participants	137	283	420
Median survival follow-up - All subjects in the OS landmark analysis	9.10	9.09	9.09
Median survival follow-up - OS landmark analysis in the lapatinib + trastuzumab arm (n=67,72,139)	9.14	9.09	9.12
Median survival follow-up - OS landmark analysis in the lapatinib (n=30,109,139)	8.31	9.08	9.07
Median survival follow-up - OS landmark analysis in the trastuzumab arm (n=40,102,142)	8.98	9.09	9.07

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Trastuzumab 2 mg/kg
	Comments	Overall - All subjects in the OS landmark analysis
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.00041
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.366
	Confidence Interval	(2-Sided) 95%; 0.20 to 0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate a hazard ratio and corresponding confidence interval comparing pCR and no pCR.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Trastuzumab 2 mg/kg
	Comments	Subjects in the OS landmark analysis in the lapatinib + trastuzumab arm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.223
	Confidence Interval	(2-Sided) 95%; 0.07 to 0.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate a hazard ratio and corresponding confidence interval comparing pCR and no pCR.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Trastuzumab 2 mg/kg
	Comments	Subjects in the OS landmark analysis in the lapatinib arm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.125
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.433
	Confidence Interval	(2-Sided) 95%; 0.12 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate a hazard ratio and corresponding confidence interval comparing pCR and no pCR.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Lapatinib 1500 mg, Trastuzumab 2 mg/kg
	Comments	Subjects in the OS landmark analysis in the trastuzumab arm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.414
	Confidence Interval	(2-Sided) 95%; 0.15 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox models (Cox, 1972), with the stratification factors entered as strata variables, were used to calculate a hazard ratio and corresponding confidence interval comparing pCR and no pCR.

15. Secondary Outcome

Title	Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Number of Participants Who Died (OS Landmark Population)
Description	The landmark date is 30 weeks after a subject's randomization. Subjects with missing pCR status were not included in the landmark analysis. Includes deaths due to any cause.
Time Frame	up to year 10

Outcome Measure Data

Analysis Population Description

For OS, the landmark population was the subset of the ITT population who were alive and were followed up for overall survival 30 weeks after randomization.

Arm/Group Title	Pathological Complete Response (pCR)	No Pathological Complete Response (pCR)	Overall
Arm/Group Description	locoregional pathological Complete Response (pCR)	no locoregional pathological Complete Response (pCR)	Overall - of the 3 arms
Measure Participants	137	283	420
All participants in the OS landmark analysis who died	15 9.7%	70 47%	85 55.9%
Participants in the OS landmark analysis in the lapatinib + trastuzumab arm who died (n=67,72,139)	5 3.2%	19 12.8%	24 15.8%
Participants in the OS landmark analysis in the lapatinib arm who died (n=30,109,139)	4 2.6%	26 17.4%	30 19.7%
Participants in the OS landmark analysis in the trastuzumab arm who died (n=40,102,142)	6 3.9%	25 16.8%	31 20.4%

16. Secondary Outcome

Title	To Assess Safety Via a Comparison of the Three Treatment Arms - to Measure On-treatment Primary Cardiac Endpoints
Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 31 weeks.

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg	Lapatinib 1500 mg	Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	149	151	148
Count of Participants [Participants]	2 1.3%	0 0%	1 0.7%

17. Secondary Outcome

Title	Metabolic Response Rate Determined by Positron Emission Tomography/Computed Tomography (PET/CT)
Description	Metabolic Response Rate determined by Positron Emission Tomography/Computed Tomography (PET/CT)
Time Frame	Week 2 and Week 6

Outcome Measure Data

Analysis Population Description

Translational Data Set. Note that evaluable samples were not available for all participants.

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	26	26	25
Metabolic Response Rate (%) Determined by PET/CT at week 2	66.7 43.3%	56.5 37.9%	95.0 62.5%
Metabolic Response Rate (%) Determined by PET/CT at week 6	60.9 39.5%	43.5 29.2%	78.9 51.9%

18. Secondary Outcome

Title	Percentage of Participants With the Indicated Biomarker Expression - PIK3CA.
Description	Biomarker levels of phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) were assessed in participants at baseline.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Translational Data Set. Note that evaluable samples were not available for all participants.

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	124	112	119
Number [Percentage of participants]	23 14.9%	19 12.8%	25 16.4%

19. Secondary Outcome

Title	Percentage of Participants With the Indicated Biomarker Expression - PTEN.
Description	Biomarker levels of phosphate and tensin homolog deleted from chromosome 10 (PTEN) were assessed in participants at baseline.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Translational Data Set. Note that evaluable samples were not available for all participants.

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	123	114	112
Biomarker: PTEN by Cell Signalling Technology - PTEN Normal (%)	74 48.1%	70 47%	75 49.3%
Biomarker: PTEN by Cell Signalling Technology - PTEN Loss (%)	26 16.9%	30 20.1%	25 16.4%

20. Secondary Outcome

Title	Ratio (95% CI) of Geometric Means in p95HER2 Expression in HR Positive Patients With pCR vs no pCR
Description	Ratio (95% CI) of geometric means in p95 human epidermal growth factor receptor (p95HER2) expression in hormone-receptor (HR) positive patients with pathological complete response (pCR) vs no pCR
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Translational Data Set. Note that evaluable samples were not available for all participants.

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	97	93	91
Geometric Mean (95% Confidence Interval) [Ratio]	1.0	1.6	2.1

21. Secondary Outcome

Title	Percentage of Participants With Circulating Tumor Cells (CTC) in the Bloodstream
Description	Circulating tumor cells (CTCs) are cells that have detached from a primary tumor and circulate in the bloodstream. In the adjuvant phase, after surgery all participants received 3 courses of adjuvant 5-fluorouracil, epirubicin and cyclophosphamide, followed by lapatinib 1500 mg or trastuzumab 2 mg/kg or lapatinib 1000/750 mg plus trastuzumab 2 mg/kg given prior to surgery in the neoadjuvant setting for an additional 34 weeks.
Time Frame	Measurement performed at one or more of the time points: baseline, week 2 or week 18

Outcome Measure Data

Analysis Population Description

Translational Data Set. Note that evaluable samples were not available for all participants.

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	19	12	20
Number [Percentage of Participants]	21 13.6%	17 11.4%	25 16.4%

22. Post-Hoc Outcome

Title	All Collected Deaths
Description	On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, which was approximately 31 weeks. Deaths post treatment survival follow up were collected after the on treatment period, up to 10 years.
Time Frame	on-treatment: up to week 31; post-treatment: up to year 10

Outcome Measure Data

Analysis Population Description

Safety population (for on-treatment deaths) and ITT (for total deaths)

Arm/Group Title	Lapatinib 1500 mg	Trastuzumab 2 mg/kg	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks	Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
Measure Participants	154	149	152
Total Deaths	31 20.1%	32 21.5%	26 17.1%
On-Treatment Deaths (n=151,148,149)	2 1.3%	0 0%	1 0.7%

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 31 weeks.
Arm/Group Title	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg		Lapatinib 1500 mg		Trastuzumab 2 mg/kg
Arm/Group Description	Oral lapatinib 1000 mg daily plus trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for 6 weeks, followed by lapatinib 750 mg daily plus trastuzumab (2 mg/kg IV weekly) plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks		Oral lapatinib (1500 milligrams [mg] daily) for 6 weeks, followed by lapatinib plus weekly paclitaxel (80 mg per meters squared [mg/m^2]) intravenous (IV) for an additional 12 weeks		Trastuzumab (4 mg/kilograms [kg] IV load followed by 2 mg/kg IV weekly) for 6 weeks, followed by trastuzumab plus weekly paclitaxel (80 mg/m^2 IV) for an additional 12 weeks
All Cause Mortality
	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg		Lapatinib 1500 mg		Trastuzumab 2 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/149 (0.7%)		2/151 (1.3%)		0/148 (0%)
Serious Adverse Events
	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg		Lapatinib 1500 mg		Trastuzumab 2 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/149 (40.9%)		58/151 (38.4%)		36/148 (24.3%)
Blood and lymphatic system disorders
AGRANULOCYTOSIS	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
ANAEMIA	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
FEBRILE NEUTROPENIA	3/149 (2%)		2/151 (1.3%)		8/148 (5.4%)
LEUKOPENIA	2/149 (1.3%)		0/151 (0%)		1/148 (0.7%)
NEUTROPENIA	14/149 (9.4%)		13/151 (8.6%)		16/148 (10.8%)
PANCYTOPENIA	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
Cardiac disorders
CARDIAC FAILURE CONGESTIVE	3/149 (2%)		0/151 (0%)		1/148 (0.7%)
CARDIO-RESPIRATORY ARREST	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
MYOCARDIAL INFARCTION	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
Gastrointestinal disorders
DIARRHOEA	9/149 (6%)		9/151 (6%)		0/148 (0%)
DUODENITIS	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
ENTERITIS	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
GASTRITIS EROSIVE	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
GASTROINTESTINAL HAEMORRHAGE	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
INGUINAL HERNIA	0/149 (0%)		0/151 (0%)		1/148 (0.7%)
NAUSEA	2/149 (1.3%)		1/151 (0.7%)		1/148 (0.7%)
PANCREATITIS	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
VOMITING	3/149 (2%)		1/151 (0.7%)		2/148 (1.4%)
General disorders
ASTHENIA	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
CHEST DISCOMFORT	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
CHEST PAIN	1/149 (0.7%)		1/151 (0.7%)		0/148 (0%)
GENERAL PHYSICAL HEALTH DETERIORATION	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
PYREXIA	5/149 (3.4%)		2/151 (1.3%)		2/148 (1.4%)
Hepatobiliary disorders
CHOLECYSTITIS ACUTE	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
HEPATITIS ACUTE	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
HYPERBILIRUBINAEMIA	4/149 (2.7%)		4/151 (2.6%)		0/148 (0%)
HYPERTRANSAMINASAEMIA	15/149 (10.1%)		23/151 (15.2%)		3/148 (2%)
Infections and infestations
APPENDICITIS	0/149 (0%)		0/151 (0%)		1/148 (0.7%)
BACTERIAL SEPSIS	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
BREAST CELLULITIS	1/149 (0.7%)		0/151 (0%)		1/148 (0.7%)
CELLULITIS	2/149 (1.3%)		1/151 (0.7%)		2/148 (1.4%)
CELLULITIS STAPHYLOCOCCAL	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
DEVICE RELATED INFECTION	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
DEVICE RELATED SEPSIS	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
ERYSIPELAS	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
HEPATITIS B	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
HERPES SIMPLEX	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
HERPES ZOSTER	0/149 (0%)		1/151 (0.7%)		1/148 (0.7%)
MASTITIS	1/149 (0.7%)		2/151 (1.3%)		0/148 (0%)
PHARYNGITIS	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
PNEUMONIA	2/149 (1.3%)		0/151 (0%)		2/148 (1.4%)
SKIN INFECTION	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
URINARY TRACT INFECTION	0/149 (0%)		3/151 (2%)		0/148 (0%)
VASCULAR DEVICE INFECTION	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
WOUND INFECTION	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
Injury, poisoning and procedural complications
ACCIDENTAL OVERDOSE	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
INFUSION RELATED REACTION	0/149 (0%)		0/151 (0%)		1/148 (0.7%)
LUMBAR VERTEBRAL FRACTURE	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
POISONING	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
SEROMA	1/149 (0.7%)		1/151 (0.7%)		1/148 (0.7%)
SPINAL FRACTURE	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
TOXICITY TO VARIOUS AGENTS	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
TRANSFUSION REACTION	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
Investigations
GAMMA-GLUTAMYLTRANSFERASE INCREASED	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
Metabolism and nutrition disorders
DEHYDRATION	0/149 (0%)		2/151 (1.3%)		0/148 (0%)
DIABETES MELLITUS	0/149 (0%)		0/151 (0%)		1/148 (0.7%)
HYPERPHOSPHATASAEMIA	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
HYPOGLYCAEMIA	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
HYPOKALAEMIA	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
Musculoskeletal and connective tissue disorders
OSTEOPOROTIC FRACTURE	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
ROTATOR CUFF SYNDROME	0/149 (0%)		0/151 (0%)		1/148 (0.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
LOBULAR BREAST CARCINOMA IN SITU	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
UTERINE LEIOMYOMA	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
Nervous system disorders
HEADACHE	0/149 (0%)		0/151 (0%)		1/148 (0.7%)
NEUROPATHY PERIPHERAL	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
SCIATICA	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
Renal and urinary disorders
ACUTE KIDNEY INJURY	2/149 (1.3%)		1/151 (0.7%)		0/148 (0%)
NEPHRECTASIA	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
NEPHROLITHIASIS	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
Reproductive system and breast disorders
METRORRHAGIA	0/149 (0%)		0/151 (0%)		1/148 (0.7%)
VULVOVAGINAL PRURITUS	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
Respiratory, thoracic and mediastinal disorders
ASTHMA	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
INTERSTITIAL LUNG DISEASE	2/149 (1.3%)		0/151 (0%)		0/148 (0%)
ORGANISING PNEUMONIA	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
PNEUMONITIS	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
PNEUMOTHORAX	0/149 (0%)		1/151 (0.7%)		0/148 (0%)
PULMONARY EMBOLISM	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
Skin and subcutaneous tissue disorders
BLISTER	1/149 (0.7%)		0/151 (0%)		0/148 (0%)
Vascular disorders
JUGULAR VEIN THROMBOSIS	0/149 (0%)		0/151 (0%)		1/148 (0.7%)
Other (Not Including Serious) Adverse Events
	Lapatinib 1000/750 mg + Trastuzumab 2 mg/kg		Lapatinib 1500 mg		Trastuzumab 2 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	147/149 (98.7%)		148/151 (98%)		141/148 (95.3%)
Blood and lymphatic system disorders
ANAEMIA	36/149 (24.2%)		33/151 (21.9%)		27/148 (18.2%)
FEBRILE NEUTROPENIA	3/149 (2%)		0/151 (0%)		1/148 (0.7%)
LEUKOPENIA	21/149 (14.1%)		18/151 (11.9%)		10/148 (6.8%)
LYMPHOPENIA	5/149 (3.4%)		2/151 (1.3%)		6/148 (4.1%)
NEUTROPENIA	47/149 (31.5%)		51/151 (33.8%)		37/148 (25%)
THROMBOCYTOPENIA	4/149 (2.7%)		2/151 (1.3%)		1/148 (0.7%)
Cardiac disorders
CARDIAC FAILURE CONGESTIVE	3/149 (2%)		0/151 (0%)		1/148 (0.7%)
LEFT VENTRICULAR DYSFUNCTION	4/149 (2.7%)		0/151 (0%)		2/148 (1.4%)
PALPITATIONS	6/149 (4%)		6/151 (4%)		3/148 (2%)
TACHYCARDIA	4/149 (2.7%)		2/151 (1.3%)		4/148 (2.7%)
Ear and labyrinth disorders
EAR PAIN	3/149 (2%)		1/151 (0.7%)		1/148 (0.7%)
TINNITUS	6/149 (4%)		1/151 (0.7%)		3/148 (2%)
VERTIGO	11/149 (7.4%)		7/151 (4.6%)		6/148 (4.1%)
Eye disorders
DRY EYE	4/149 (2.7%)		1/151 (0.7%)		2/148 (1.4%)
LACRIMATION INCREASED	3/149 (2%)		3/151 (2%)		1/148 (0.7%)
VISUAL IMPAIRMENT	2/149 (1.3%)		2/151 (1.3%)		3/148 (2%)
Gastrointestinal disorders
ABDOMINAL DISCOMFORT	3/149 (2%)		1/151 (0.7%)		4/148 (2.7%)
ABDOMINAL DISTENSION	10/149 (6.7%)		8/151 (5.3%)		5/148 (3.4%)
ABDOMINAL PAIN	21/149 (14.1%)		28/151 (18.5%)		13/148 (8.8%)
ABDOMINAL PAIN UPPER	23/149 (15.4%)		27/151 (17.9%)		16/148 (10.8%)
ANAL INFLAMMATION	4/149 (2.7%)		2/151 (1.3%)		1/148 (0.7%)
CONSTIPATION	18/149 (12.1%)		15/151 (9.9%)		15/148 (10.1%)
DIARRHOEA	128/149 (85.9%)		123/151 (81.5%)		52/148 (35.1%)
DRY MOUTH	9/149 (6%)		5/151 (3.3%)		3/148 (2%)
DYSPEPSIA	17/149 (11.4%)		26/151 (17.2%)		10/148 (6.8%)
DYSPHAGIA	3/149 (2%)		0/151 (0%)		3/148 (2%)
EPIGASTRIC DISCOMFORT	3/149 (2%)		2/151 (1.3%)		2/148 (1.4%)
FLATULENCE	3/149 (2%)		5/151 (3.3%)		2/148 (1.4%)
GASTRITIS	2/149 (1.3%)		8/151 (5.3%)		3/148 (2%)
GASTROOESOPHAGEAL REFLUX DISEASE	5/149 (3.4%)		2/151 (1.3%)		0/148 (0%)
HAEMORRHOIDS	13/149 (8.7%)		10/151 (6.6%)		10/148 (6.8%)
MOUTH ULCERATION	12/149 (8.1%)		4/151 (2.6%)		1/148 (0.7%)
NAUSEA	75/149 (50.3%)		81/151 (53.6%)		76/148 (51.4%)
RECTAL HAEMORRHAGE	4/149 (2.7%)		2/151 (1.3%)		0/148 (0%)
STOMATITIS	27/149 (18.1%)		18/151 (11.9%)		23/148 (15.5%)
TOOTHACHE	4/149 (2.7%)		1/151 (0.7%)		2/148 (1.4%)
VOMITING	54/149 (36.2%)		57/151 (37.7%)		38/148 (25.7%)
General disorders
ASTHENIA	39/149 (26.2%)		47/151 (31.1%)		35/148 (23.6%)
AXILLARY PAIN	5/149 (3.4%)		0/151 (0%)		3/148 (2%)
CHEST DISCOMFORT	0/149 (0%)		3/151 (2%)		6/148 (4.1%)
CHEST PAIN	5/149 (3.4%)		5/151 (3.3%)		6/148 (4.1%)
CHILLS	11/149 (7.4%)		3/151 (2%)		6/148 (4.1%)
FACE OEDEMA	3/149 (2%)		5/151 (3.3%)		4/148 (2.7%)
FATIGUE	52/149 (34.9%)		45/151 (29.8%)		38/148 (25.7%)
FEELING COLD	0/149 (0%)		1/151 (0.7%)		3/148 (2%)
GENERALISED OEDEMA	1/149 (0.7%)		3/151 (2%)		3/148 (2%)
INFLUENZA LIKE ILLNESS	3/149 (2%)		2/151 (1.3%)		2/148 (1.4%)
MUCOSAL DRYNESS	3/149 (2%)		2/151 (1.3%)		2/148 (1.4%)
MUCOSAL EROSION	3/149 (2%)		0/151 (0%)		0/148 (0%)
MUCOSAL INFLAMMATION	36/149 (24.2%)		34/151 (22.5%)		22/148 (14.9%)
OEDEMA	4/149 (2.7%)		0/151 (0%)		11/148 (7.4%)
OEDEMA PERIPHERAL	8/149 (5.4%)		9/151 (6%)		13/148 (8.8%)
PAIN	3/149 (2%)		6/151 (4%)		2/148 (1.4%)
PERIPHERAL SWELLING	4/149 (2.7%)		2/151 (1.3%)		3/148 (2%)
PYREXIA	34/149 (22.8%)		23/151 (15.2%)		23/148 (15.5%)
Hepatobiliary disorders
HYPERBILIRUBINAEMIA	21/149 (14.1%)		26/151 (17.2%)		7/148 (4.7%)
HYPERTRANSAMINASAEMIA	55/149 (36.9%)		55/151 (36.4%)		39/148 (26.4%)
Immune system disorders
HYPERSENSITIVITY	6/149 (4%)		6/151 (4%)		7/148 (4.7%)
SEASONAL ALLERGY	3/149 (2%)		1/151 (0.7%)		0/148 (0%)
Infections and infestations
BRONCHITIS	2/149 (1.3%)		5/151 (3.3%)		3/148 (2%)
CONJUNCTIVITIS	11/149 (7.4%)		8/151 (5.3%)		5/148 (3.4%)
CYSTITIS	8/149 (5.4%)		6/151 (4%)		3/148 (2%)
HERPES SIMPLEX	3/149 (2%)		0/151 (0%)		2/148 (1.4%)
INFLUENZA	8/149 (5.4%)		8/151 (5.3%)		9/148 (6.1%)
LOCALISED INFECTION	3/149 (2%)		3/151 (2%)		0/148 (0%)
LOWER RESPIRATORY TRACT INFECTION	3/149 (2%)		1/151 (0.7%)		1/148 (0.7%)
MASTITIS	2/149 (1.3%)		1/151 (0.7%)		3/148 (2%)
NAIL INFECTION	8/149 (5.4%)		1/151 (0.7%)		0/148 (0%)
NASOPHARYNGITIS	11/149 (7.4%)		12/151 (7.9%)		11/148 (7.4%)
ORAL HERPES	2/149 (1.3%)		0/151 (0%)		3/148 (2%)
PARONYCHIA	17/149 (11.4%)		14/151 (9.3%)		2/148 (1.4%)
PHARYNGITIS	4/149 (2.7%)		7/151 (4.6%)		5/148 (3.4%)
PUSTULE	3/149 (2%)		1/151 (0.7%)		1/148 (0.7%)
RHINITIS	6/149 (4%)		4/151 (2.6%)		5/148 (3.4%)
SINUSITIS	3/149 (2%)		5/151 (3.3%)		2/148 (1.4%)
SKIN INFECTION	4/149 (2.7%)		1/151 (0.7%)		2/148 (1.4%)
TONSILLITIS	0/149 (0%)		3/151 (2%)		4/148 (2.7%)
UPPER RESPIRATORY TRACT INFECTION	10/149 (6.7%)		9/151 (6%)		14/148 (9.5%)
URINARY TRACT INFECTION	11/149 (7.4%)		14/151 (9.3%)		6/148 (4.1%)
VAGINAL INFECTION	5/149 (3.4%)		1/151 (0.7%)		2/148 (1.4%)
VIRAL INFECTION	0/149 (0%)		0/151 (0%)		3/148 (2%)
Injury, poisoning and procedural complications
RADIATION SKIN INJURY	16/149 (10.7%)		11/151 (7.3%)		18/148 (12.2%)
SEROMA	2/149 (1.3%)		0/151 (0%)		6/148 (4.1%)
THERMAL BURN	3/149 (2%)		0/151 (0%)		1/148 (0.7%)
WOUND COMPLICATION	4/149 (2.7%)		4/151 (2.6%)		6/148 (4.1%)
Investigations
EJECTION FRACTION DECREASED	6/149 (4%)		2/151 (1.3%)		4/148 (2.7%)
GAMMA-GLUTAMYLTRANSFERASE	3/149 (2%)		2/151 (1.3%)		0/148 (0%)
GAMMA-GLUTAMYLTRANSFERASE INCREASED	3/149 (2%)		7/151 (4.6%)		1/148 (0.7%)
NEUTROPHIL COUNT INCREASED	3/149 (2%)		1/151 (0.7%)		2/148 (1.4%)
WEIGHT DECREASED	8/149 (5.4%)		10/151 (6.6%)		1/148 (0.7%)
WEIGHT INCREASED	2/149 (1.3%)		2/151 (1.3%)		3/148 (2%)
Metabolism and nutrition disorders
DECREASED APPETITE	35/149 (23.5%)		39/151 (25.8%)		17/148 (11.5%)
DEHYDRATION	1/149 (0.7%)		5/151 (3.3%)		0/148 (0%)
HYPERCHOLESTEROLAEMIA	0/149 (0%)		1/151 (0.7%)		3/148 (2%)
HYPERGLYCAEMIA	3/149 (2%)		0/151 (0%)		4/148 (2.7%)
HYPERPHOSPHATASAEMIA	22/149 (14.8%)		22/151 (14.6%)		12/148 (8.1%)
HYPOKALAEMIA	4/149 (2.7%)		3/151 (2%)		0/148 (0%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	27/149 (18.1%)		26/151 (17.2%)		32/148 (21.6%)
BACK PAIN	22/149 (14.8%)		10/151 (6.6%)		14/148 (9.5%)
BONE PAIN	10/149 (6.7%)		12/151 (7.9%)		18/148 (12.2%)
JOINT STIFFNESS	2/149 (1.3%)		1/151 (0.7%)		4/148 (2.7%)
MUSCLE SPASMS	6/149 (4%)		4/151 (2.6%)		3/148 (2%)
MUSCULOSKELETAL CHEST PAIN	4/149 (2.7%)		2/151 (1.3%)		1/148 (0.7%)
MUSCULOSKELETAL PAIN	8/149 (5.4%)		16/151 (10.6%)		11/148 (7.4%)
MUSCULOSKELETAL STIFFNESS	1/149 (0.7%)		1/151 (0.7%)		3/148 (2%)
MYALGIA	31/149 (20.8%)		33/151 (21.9%)		34/148 (23%)
NECK PAIN	7/149 (4.7%)		5/151 (3.3%)		5/148 (3.4%)
OSTEOPOROSIS	0/149 (0%)		1/151 (0.7%)		3/148 (2%)
PAIN IN EXTREMITY	13/149 (8.7%)		20/151 (13.2%)		13/148 (8.8%)
Nervous system disorders
AGEUSIA	4/149 (2.7%)		3/151 (2%)		0/148 (0%)
DIZZINESS	13/149 (8.7%)		13/151 (8.6%)		15/148 (10.1%)
DYSGEUSIA	6/149 (4%)		6/151 (4%)		1/148 (0.7%)
HEADACHE	31/149 (20.8%)		27/151 (17.9%)		26/148 (17.6%)
HYPOAESTHESIA	9/149 (6%)		7/151 (4.6%)		12/148 (8.1%)
MEMORY IMPAIRMENT	2/149 (1.3%)		4/151 (2.6%)		2/148 (1.4%)
NEUROPATHY PERIPHERAL	19/149 (12.8%)		21/151 (13.9%)		19/148 (12.8%)
NEUROTOXICITY	3/149 (2%)		6/151 (4%)		3/148 (2%)
PARAESTHESIA	24/149 (16.1%)		15/151 (9.9%)		22/148 (14.9%)
PERIPHERAL SENSORY NEUROPATHY	13/149 (8.7%)		19/151 (12.6%)		14/148 (9.5%)
POLYNEUROPATHY	5/149 (3.4%)		1/151 (0.7%)		3/148 (2%)
TASTE DISORDER	9/149 (6%)		6/151 (4%)		1/148 (0.7%)
Psychiatric disorders
ANXIETY	7/149 (4.7%)		9/151 (6%)		11/148 (7.4%)
DEPRESSION	7/149 (4.7%)		5/151 (3.3%)		9/148 (6.1%)
INSOMNIA	34/149 (22.8%)		23/151 (15.2%)		24/148 (16.2%)
SLEEP DISORDER	5/149 (3.4%)		4/151 (2.6%)		2/148 (1.4%)
Renal and urinary disorders
DYSURIA	11/149 (7.4%)		6/151 (4%)		5/148 (3.4%)
HAEMATURIA	4/149 (2.7%)		0/151 (0%)		0/148 (0%)
Reproductive system and breast disorders
AMENORRHOEA	6/149 (4%)		3/151 (2%)		1/148 (0.7%)
BREAST DISCHARGE	3/149 (2%)		0/151 (0%)		0/148 (0%)
BREAST PAIN	6/149 (4%)		5/151 (3.3%)		15/148 (10.1%)
MENSTRUATION IRREGULAR	1/149 (0.7%)		2/151 (1.3%)		3/148 (2%)
PELVIC PAIN	0/149 (0%)		0/151 (0%)		4/148 (2.7%)
VULVOVAGINAL DRYNESS	2/149 (1.3%)		2/151 (1.3%)		3/148 (2%)
VULVOVAGINAL INFLAMMATION	0/149 (0%)		4/151 (2.6%)		0/148 (0%)
VULVOVAGINAL PRURITUS	2/149 (1.3%)		2/151 (1.3%)		4/148 (2.7%)
Respiratory, thoracic and mediastinal disorders
COUGH	25/149 (16.8%)		17/151 (11.3%)		26/148 (17.6%)
DYSPHONIA	1/149 (0.7%)		5/151 (3.3%)		2/148 (1.4%)
DYSPNOEA	16/149 (10.7%)		11/151 (7.3%)		13/148 (8.8%)
DYSPNOEA EXERTIONAL	6/149 (4%)		2/151 (1.3%)		6/148 (4.1%)
EPISTAXIS	37/149 (24.8%)		30/151 (19.9%)		22/148 (14.9%)
HAEMOPTYSIS	0/149 (0%)		0/151 (0%)		3/148 (2%)
NASAL DRYNESS	6/149 (4%)		6/151 (4%)		2/148 (1.4%)
NASAL INFLAMMATION	5/149 (3.4%)		3/151 (2%)		1/148 (0.7%)
OROPHARYNGEAL PAIN	16/149 (10.7%)		20/151 (13.2%)		15/148 (10.1%)
PRODUCTIVE COUGH	3/149 (2%)		0/151 (0%)		0/148 (0%)
RHINORRHOEA	13/149 (8.7%)		6/151 (4%)		10/148 (6.8%)
Skin and subcutaneous tissue disorders
ACNE	22/149 (14.8%)		20/151 (13.2%)		5/148 (3.4%)
ALOPECIA	95/149 (63.8%)		90/151 (59.6%)		96/148 (64.9%)
DERMATITIS	13/149 (8.7%)		13/151 (8.6%)		8/148 (5.4%)
DERMATITIS ACNEIFORM	14/149 (9.4%)		12/151 (7.9%)		4/148 (2.7%)
DRY SKIN	28/149 (18.8%)		29/151 (19.2%)		8/148 (5.4%)
ECZEMA	6/149 (4%)		4/151 (2.6%)		2/148 (1.4%)
ERYTHEMA	14/149 (9.4%)		14/151 (9.3%)		15/148 (10.1%)
EXFOLIATIVE RASH	8/149 (5.4%)		4/151 (2.6%)		0/148 (0%)
HYPERHIDROSIS	2/149 (1.3%)		1/151 (0.7%)		3/148 (2%)
NAIL DISORDER	36/149 (24.2%)		26/151 (17.2%)		18/148 (12.2%)
NAIL DYSTROPHY	3/149 (2%)		2/151 (1.3%)		1/148 (0.7%)
ONYCHALGIA	3/149 (2%)		3/151 (2%)		1/148 (0.7%)
ONYCHOLYSIS	7/149 (4.7%)		0/151 (0%)		2/148 (1.4%)
PAIN OF SKIN	1/149 (0.7%)		4/151 (2.6%)		2/148 (1.4%)
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	14/149 (9.4%)		14/151 (9.3%)		3/148 (2%)
PRURITUS	24/149 (16.1%)		29/151 (19.2%)		9/148 (6.1%)
RASH	67/149 (45%)		68/151 (45%)		28/148 (18.9%)
RASH PRURITIC	4/149 (2.7%)		3/151 (2%)		3/148 (2%)
SCAR PAIN	1/149 (0.7%)		3/151 (2%)		4/148 (2.7%)
SKIN EXFOLIATION	4/149 (2.7%)		0/151 (0%)		1/148 (0.7%)
SKIN FISSURES	13/149 (8.7%)		4/151 (2.6%)		4/148 (2.7%)
SKIN HYPERPIGMENTATION	6/149 (4%)		6/151 (4%)		2/148 (1.4%)
SKIN IRRITATION	3/149 (2%)		1/151 (0.7%)		1/148 (0.7%)
SKIN LESION	5/149 (3.4%)		1/151 (0.7%)		0/148 (0%)
SKIN REACTION	2/149 (1.3%)		4/151 (2.6%)		0/148 (0%)
Vascular disorders
FLUSHING	1/149 (0.7%)		3/151 (2%)		6/148 (4.1%)
HAEMATOMA	3/149 (2%)		1/151 (0.7%)		1/148 (0.7%)
HOT FLUSH	22/149 (14.8%)		15/151 (9.9%)		21/148 (14.2%)
HYPERTENSION	5/149 (3.4%)		5/151 (3.3%)		8/148 (5.4%)
HYPOTENSION	8/149 (5.4%)		5/151 (3.3%)		2/148 (1.4%)
LYMPHOEDEMA	3/149 (2%)		5/151 (3.3%)		3/148 (2%)
PHLEBITIS	2/149 (1.3%)		3/151 (2%)		5/148 (3.4%)

Limitations/Caveats

[Not Specified]

More Information

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 the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety