The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: Lapatinib Study Number: EGF30008 Title: A Randomized, Double-Blind, -Controlled, Multicenter, Phase III Study Comparing Lapatinib and Letrozole versus Letrozole in Subjects with Estrogen/Progesterone Receptor-Positive Advanced or Metastatic Breast Cancer. Rationale: This study investigated whether an ErbB-targeted agent added to standard therapy with an aromatase inhibitor (AI) increased time without tumor progression. EGF30008 compared the efficacy and tolerability of lapatinib plus letrozole compared with letrozole plus placebo in post-menopausal women with hormone receptor positive (estrogen receptor [ER] positive and/or progesterone receptor [PgR] positive) advanced or metastatic breast cancer, who had not received prior therapy for advanced or metastatic disease. Patient eligibility was not dependent on the HER2 status of the primary tumor. The HER2-positive subject population was the primary population of interest for the evaluation of efficacy. The ITT population was the secondary population of interest. A closed hierarchical testing procedure was use to examine the HER2-positive population first followed by the ITT population. Phase: III Study Period: The study was initiated on 09 December The study is currently ongoing (subjects are either still on study treatment or are in follow-up for survival). This synopsis presents results of study data analyses as of the clinical data cut-off date of 03 June Subject accountability and results from a post hoc survival analysis as of the clinical data cut-off date of 07 August 2013 are also presented. Study Design: A Phase III, randomized, double-blind, placebo-controlled, parallel-group, multicenter, 2-arm study. Centres: 212 centers in 29 countries: Argentina (3), Australia (4), Brazil (2), Bulgaria (3), Canada (9), Chile (2), Colombia (1), Croatia (3), Czech Republic (2), Denmark (4), France (8), Germany (26), Hungary (7), Ireland (6), Italy (6), Mexico (4), Netherlands (9), New Zealand (1), Pakistan (3), Peru (2), Poland (5), Russia (5), South Africa (3), South Korea (3), Spain (16), Tunisia (3), Turkey (1), United Kingdom (10), and United States (61). Indication: Advanced or metastatic breast cancer. Treatment: Subjects were randomized (1:1) to receive either lapatinib (1500 mg once daily orally) plus letrozole (2.5 mg once daily orally), or placebo (visually matching lapatinib tablets; once daily orally) plus letrozole (2.5 mg once daily orally). Randomization was stratified by site of disease and time since prior adjuvant endocrine therapy. Study therapy was administered daily until disease progression (objective or symptomatic) or withdrawal from therapy (e.g., due to unacceptable toxicity, withdrawal of consent). Objectives: The primary objective was to evaluate and compare investigator-evaluated progression free survival (PFS) with letrozole and lapatinib versus letrozole and placebo in subjects with HER2-positive hormone receptor positive, advanced or metastatic breast cancer. Primary Outcome/Efficacy: The primary efficacy variable was investigator-evaluated PFS in the HER2-positive population. PFS was defined as the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. Secondary Outcomes/Efficacy: The secondary efficacy endpoints were all based on investigator assessment (except for overall survival [OS] and overall death rate) and were assessed in the HER2-positive, and intent to treat (ITT) populations. The secondary efficacy variables were: PFS in the ITT population; OS (defined as the time from randomization until death due to any cause; the overall death rate was the percentage of subjects who died due to any cause); overall tumor response rate (ORR) (the percentage of subjects achieving either a confirmed complete response [CR] or a partial response [PR] as a best overall tumor response [using Response Evaluation Criteria in Solid Tumors; RECIST], where best overall tumor response was the best response recorded from the start of treatment until disease progression/recurrence); clinical benefit rate (CBR) (defined as the percentage of subjects with evidence of confirmed CR or PR or stable disease [SD] for at least 6 months); time to response (defined as the time from randomization until first documented evidence of confirmed PR or CR [whichever status was recorded first], for subjects that responded); duration of response (for the subset of subjects who show a confirmed CR or PR, duration of response was defined as the time from first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause); evidence of brain metastases (defined as the incidence of lesions occurring within any part of the central nervous system [CNS] as evidenced by radiological scans); time to progression (TTP) (defined as the interval between the date of randomization and the earliest date of disease progression or death due to breast cancer). To assess qualitative and quantitative toxicities associated with oral lapatinib when administered with letrozole. Serum extracellular domain (ECD) samples were collected for HER2 determination. Health outcomes 1

2 were assessed using the Functional Assessment of Cancer Therapy Breast (FACT-B) questionnaire and Qualityadjusted Time Without Symptoms or Toxicity (Q-TWiST) analysis. Statistical Methods: The HER2-positive population was the primary population of interest for the evaluation of efficacy. The HER2-positive population comprised all randomized subjects who had retrospectively documented amplification of baseline HER2 by fluorescence in situ hybridization (FISH) ( 2.0) or 3+ immunohistochemistry (IHC) (or 2+ IHC and FISH +) in archived, tumor tissue regardless of whether or not study treatment had been received. The ITT population was the secondary population of interest and comprised all randomized subjects regardless of whether or not study treatment had been received. The HER2-positive and ITT populations were used for all efficacy displays and for selected baseline displays. The Safety population comprised all randomized subjects who had received at least 1 dose of study treatment and was based on actual treatment received, if this differed from that to which the subject was randomized. This population was used for the analysis of safety data. PFS for the HER2-positive and then the ITT population was summarized using Kaplan-Meier curves and compared between the 2 treatment groups using a stratified log-rank test, stratifying for site of disease and time since prior endocrine adjuvant therapy. The Pike estimator of the treatment HR based on the log-rank test was provided, together with a 95% confidence interval (CI). To ensure that the pre-defined Type 1 alpha error rate was preserved since PFS was examined in 2 populations with HER2-positive as primary and ITT as secondary, a closed hierarchical testing procedure was employed, i.e., the effect of PFS was first to be tested in the HER2-positive population as the primary analysis at an alpha level of Testing was performed in the ITT population at the alpha 0.05 level as a secondary analysis only if statistical significance was achieved in the HER2 positive population. OS was analyzed first using a Cox regression model with 5 known prognostic baseline covariates without model selection. Adjusted HR estimates and 95% CIs were examined. OS was also summarized using Kaplan-Meier curves and compared between the 2 treatment groups using a stratified log-rank test. The Pike estimator of the treatment HR based on the log-rank test was provided. Approximate 95% CIs were calculated, based on Greenwood s formula for the standard error of the Kaplan-Meier estimates. ORRs were compared between the 2 treatment groups using stratified Fisher s exact tests. An exact CI for the assumed common odds ratio was calculated. CBR was analyzed in the same way as ORR. For time to response, a summary of crude cumulative response rates was produced by nominal visit time. Additionally, Kaplan-Meier curves were provided for time to response. Kaplan-Meier curves were provided for duration of response from which the median durations were calculated. The number of subjects with evidence of brain metastasis recorded at any assessment was summarized for each treatment group. An estimate for the incidence of brain metastases occurring on study with a corresponding 95% CI for this estimate was provided. A Fisher s exact test was used to test if there are any significant differences between the 2 treatment groups with respect to incidence of brain metastasis. TTP was analyzed using a competing risk approach. Median times were calculated from the curves and treatment arms compared using a stratified log rank as described for PFS. For biomarker variables, the percentage of subjects with elevated serum HER2 ECD at baseline (>15 ng/ml) were summarized. In addition, PFS, TTP and ORR, as assessed by investigator, were summarized by serum HER2 ECD status at baseline. For health outcome variables, changes from baseline in the FACT-B total score, Functional Assessment of Cancer Therapy General (FACT-G) score, and trial outcome index (TOI) score were analyzed by parametric analysis of covariance (ANCOVA) using the baseline score as a covariate. These analyses were repeated using the last-observation carried-forward (LOCF) approach. The overall Q-TWiST difference between treatment groups was calculated for each combination of selected utility weights. Study Population: Post-menopausal female subjects 18 years of age who had: histologically confirmed invasive breast cancer with Stage IIIB/C (prior to Protocol Amendment 3, 27 October 2005) and Stage IV disease; measurable or non-measurable disease per RECIST; tumors that were ER positive and/or PgR positive by local laboratory (subjects were considered ER positive or PgR positive if any assay [cytochemical, immunochemical, IHC, or radioimmunoassay] of primary or secondary tumor tissue was positive); Eastern Cooperative Oncology Group performance status of 0 or 1; archived tumor tissue available to compare tumor response with intra tumoral expression of epidermal growth factor receptor (EGFR) and HER2 (archived tumor tissue was also used to confirm ER and/or PgR positivity. Results were not used to determine subject eligibility for the study). Adjuvant therapy with an aromatase inhibitor or trastuzumab was allowed; however, treatment must have ended more than 1 year prior (>12 months) to the first dose of study therapy. Subjects were to have: no prior chemotherapy, endocrine therapy, immunotherapy, biologic therapy, or anti-egfr/her2 therapy for advanced or metastatic disease; no history of other malignancy; no 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; no extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumor, or the disease was considered by the investigator to be rapidly progressing or life threatening were not eligible for study entry; no known history of uncontrolled or symptomatic angina, arrhythmias, congestive heart failure, CNS metastases or leptomeningeal carcinomatosis; or no concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, or tumor embolization) other than letrozole. 2

3 Subject Accountability as of 03 June 2008 Number of Subjects (HER2-Positive Population): Planned, N NA NA Randomized, N Ongoing a, n (%) 42 (39) 48 (43) Total Number Subjects Withdrawn b, n (%) 66 (61) 63 (57) Withdrawn due to death, n (%) 53 (49) 50 (45) Withdrawn due to adverse events, n (%) 0 0 Withdrawn due to lack of efficacy, n (%) 0 0 Withdrawn for other reasons c, n (%) 13 (12) 13 (12) Number of Subjects (ITT Population): Planned, N Randomized, N Ongoing a, n (%) 349 (54) 344 (54) Total Number Subjects Withdrawn b, n (%) 295 (46) 298 (46) Withdrawn due to death, n (%) 229 (36) 238 (37) Withdrawn due to adverse events, n (%) 0 0 Withdrawn due to lack of efficacy, n (%) 0 0 Withdrawn for other reasons d, n (%) 66 (10) 60 (9) a Included subjects who were still on study treatment or in follow-up for survival as of the clinical cut-off date of 03 June Primary data analyses for EGF30008 were conducted at this time. b Permanent discontinuation from study. c Other included consent withdrawn, lost to follow-up, and protocol violation. d Other included consent withdrawn, lost to follow-up, protocol violation, and Other. Subject Accountability as of 07 August 2013 Number of Subjects (HER2-Positive Population): Planned, N NA NA Randomized, N Ongoing a, n (%) 13 (12) 8 (7) Total Number Subjects Withdrawn b, n (%) 95 (88) 103 (93) Withdrawn due to death, n (%) 78 (72) 86 (77) Withdrawn due to withdrawal of consent, n (%) 7 (6) 10 (9) Withdrawn due to being lost to follow-up, n (%) 9 (8) 5 (5) Withdrawn due to protocol violation, n (%) 1 (<1) 0 Withdrawn for other reasons, n (%) 0 2 (2) Number of Subjects (ITT Population): Planned, N Randomized, N Ongoing a, n (%) 66 (10) 93 (14) Total Number Subjects Withdrawn b, n (%) 578 (90) 549 (86) Withdrawn due to death, n (%) 474 (74) 456 (71) Withdrawn due to withdrawal of consent, n (%) 45 (7) 37 (6) Withdrawn due to being lost to follow-up, n (%) 48 (7) 41 (6) Withdrawn due to protocol violation, n (%) 3 (<1) 5 (<1) Withdrawn for other reasons, n (%) 8 (1) 10 (2) a Included subjects who were still on study treatment or in follow-up for survival as of the clinical cut-off date of 07 August Post hoc final survival analyses for EGF30008 were conducted at this time. b Permanent discontinuation from study. 3

4 Demographics N (HER2-positive population) Females, n Mean age, years (standard deviation) 60.9 (9.18) 61.0 (9.41) White, n (%) 91 (84) 82 (74) N (ITT population) Females, n Mean age, years (standard deviation) 63.3 (9.95) 62.8 (9.70) White, n (%) 557 (86) 529 (82) Primary Efficacy Result: Investigator-Evaluated PFS in the HER2-Positive Population (N=108) (N=111) Progressed or died due to any cause (event), n (%) 89 (82) 88 (79) PFS (weeks), median (95% CI) 13.0 (12.0, 23.7) 35.4 (24.1, 39.4) HR (95% CI) 0.71 (0.53, 0.96) Log-rank p-value Secondary Outcome Results in the HER2-Positive Population: OS (as of 03 June 2008) n (%) of subjects who died 54 (50) 50 (45) OS (weeks), median (95% CI) (92.1, 159.4) (95.6, NE) Kaplan-Meier HR (95% CI) 0.74 (0.5, 1.1) Cox HR (95% CI) 0.77 (0.52, 1.14) Note: The HER2-positive population OS dataset was not mature at the time of database freeze (clinical cut-off date 03 June 2008); only 104 (47%) of subjects had died and 90 (41%) of subjects were still being followed for survival. OS Final Analysis (as of 07 August 2013) n (%) of subjects who died 78 (72) 86 (77) OS (weeks), median (95% CI) (92.6, 169.3) (105.3, 179.7) Kaplan-Meier HR (95% CI) 0.97 (0.7, 1.3) Cox HR (95% CI) 0.97 (0.70, 1.33) Note: The HER2-positive population OS dataset was mature at the time of the post hoc final analysis (clinical cut-off date 07 August 2013); 164 (75%) of subjects had died and 21 (10%) of subjects were still being followed for survival. ORR Complete response (CR), n (%) 4 (4) 5 (5) Partial response (PR), n (%) 12 (11) 26 (23) Response rate (CR or PR), % (95% CI) 14.8 (8.7, 22.9) 27.9 (19.8, 37.2 Difference of common odds ratio for response rate estimate (95% CI) 0.4 (0.2, 0.9) CBR Percent response rate (95% CI) 28.7 (20.4,38.2) 47.7 (38.2, 57.4) Estimate of common odds ratio for clinical benefit (95% CI) 0.4 (0.2, 0.8) Time to Response (where assessments of CR or PR required confirmation using bone scans) Number of subjects with response, n (%) 16 (15) 31 (28) CR or PR by Week (10) 23 (21) CR or PR by Week 16 1 (<1) 3 (3) CR or PR by Week 24 or longer 4 (4) 5 (5) Duration of Response (where assessments of CR or PR required confirmation using bone scans) Subjects with response, n Progressed or died due to any cause (event), n (%) 9 (56) 20 (65) Duration of tumor response (weeks), median Evidence of Brain Metastases CNS relapse (with or without baseline CNS), n 2 1 CNS relapse rate, % (95% CI) 1.9 (0.2, 6.5) 0.9 (0.0, 4.9) 4

5 TTP Only 1 subject (in the letrozole plus lapatinib group) of the HER2-positive population died from a cause other than breast cancer. Thus, the TTP results were nearly identical to the PFS results and, therefore, are not presented in this summary. Secondary Outcome Results in the ITT Population: (N=644) (N=642) PFS (Investigator-evaluated) Progressed or died, n (%) 476 (74) 413 (64) PFS (weeks), median (95% CI) 47.0 (36.9, 50.9) 51.7 (47.6, 59.6) HR (95% CI) 0.86 (0.76, 0.98) Log-rank p-value OS n (%) of subjects who died 234 (36) 240 (37) OS (weeks), median (95% CI) (156.1, 189.7) (157.7, 196.3) Kaplan-Meier HR (95% CI) 1.01 (0.8, 1.2) Cox HR (95% CI) 0.99 (0.82, 1.18) Note: The ITT population OS dataset was not mature at the time of database freeze (clinical cut-off date 03 June 2008); only 474 (37%) of subjects had died and 693 (54%) were still being followed for survival. ORR Complete response (CR), n (%) 26 (4) 28 (5) Partial response (PR), n (%) 153 (24) 168 (26) Response rate, % (95% CI) 27.8 (24.4, 31.4) 30.5 (27.0, 34.3) Difference of common odds ratio for response rate estimate (95% CI) 0. 9 (0.7,1.1) CBR Percent response rate (95% CI) 50.6 (46.7, 54.5) 55.8 (51.8, 59.6) Estimate of common odds ratio for clinical benefit (95% CI) 0.8 (0.7, 1.0) Time to Response (where assessments of CR or PR required confirmation using bone scans) Number of subjects with response, n (%) 179 (28) 196 (31) CR or PR by Week (12) 94 (15) CR or PR by Week (3) 18 (3) CR or PR by Week (4) 28 (4) CR or PR by Week (3) 14 (2) CR or PR by Week 36 or longer 37 (6) 42 (7) Duration of Response (where assessments of CR or PR required confirmation using bone scans) Subjects with response, n Progressed or died due to any cause (event), n (%) 104 (58) 106 (54) Duration of tumor response (weeks), median Evidence of Brain Metastases CNS relapse (with or without baseline CNS), n 4 6 CNS relapse rate, % (95% CI) 0.6 (0.2, 1.6) 0.9 (0.3, 2.0) TTP Only 11 subjects in the ITT population died due to causes other than breast cancer. Thus, the TTP results were nearly identical to the PFS results and, therefore, are not presented in this summary. Biomarker Data (HER2-Positive Population): In the HER2-positive population, regardless of treatment, the subjects with higher serum HER2 levels at baseline (>15 ng/ml) had shorter PFS compared with those subjects who had low baseline serum HER2 levels ( 15 ng/ml). For subjects with low serum HER2 levels at baseline ( 15 ng/ml), PFS was similar between the 2 treatment groups. However, for subjects with high baseline serum HER2 levels (>15 ng/ml), PFS was statistically significantly lower in the letrozole plus placebo group compared with the letrozole plus lapatinib group with a HR of 0.44 (95% CI: 0.29, 0.69). 5

6 Health Outcomes Data (HER2-Positive Population): In the HER2-positive population, mean subscale and total QOL scores were generally stable over time in both treatment groups for subjects who stayed in the study suggesting QOL was maintained. The Q-TWiST difference between treatment groups for the HER2-positive population ranged from 8 to 9.5 weeks, favoring letrozole plus lapatinib over letrozole plus placebo for all hypothetical utility levels, although none of the comparisons were statistically significant. Safety Results (Safety Population): On-therapy AEs and serious adverse events (SAEs) were defined as those collected from the first dose of study therapy to 30 days after the last dose of study therapy. (N=624) (N=654) Most Frequent Adverse Events On-Therapy e n (%) n (%) Subjects with any AE(s), n (%) 536 (86) 628 (96) Diarrhea 124 (20) 419 (64) Rash f 83 (13) 293 (45) Nausea 129 (21) 200 (31) Arthralgia 145 (23) 128 (20) Fatigue 108 (17) 134 (20) Vomiting 68 (11) 109 (17) Back pain 97 (16) 105 (16) Headache 83 (13) 91 (14) Dry skin 27 (4) 87 (13) Cough 90 (14) 80 (12) Asthenia 69 (11) 80 (12) Hot flush 92 (15) 69 (11) e Defined as the most frequent 10 events in each group. f In addition to the rash reported under Skin and subcutaneous tissue disorders, 3 additional subjects in each treatment group had a rash under Infections and infestations. Serious Adverse Events On-Therapy n (%) [n considered by the investigator to be related to study medication] (N=624) (N=654) Subjects with any SAE (fatal and non-fatal), n (%) 94 (15) 144 (22) n (%) [related] n (%) [related] Ejection fraction decreased 8 (1) [7] 17 (3) [14] Diarrhea 2 (<1) [1] 15 (2) [10] Vomiting 7 (1) [3] 10 (2) [4] Dehydration 2 (<1) [1] 7 (1) [3] Urinary tract infection 1 (<1) [1] 6 (<1) Dyspnea 4 (<1) [1] 5 (<1) Nausea 4 (<1) [1] 5 (<1) [3] Anemia 2 (<1) [2] 5 (<1) Left ventricular dysfunction 1 (<1) 5 (<1) [5] Cellulitis 0 5 (<1) Pyrexia 4 (<1) [1] 4 (<1) Abdominal pain 2 (<1) 4 (<1) Erysipelas 2 (<1) [1] 4 (<1) [1] Chest pain 3 (<1) 3 (<1) Pulmonary embolism 3 (<1) 3 (<1) [1] Asthenia 1 (<1) 3 (<1) [2] Femur fracture 1 (<1) 3 (<1) Back pain 5 (<1) 2 (<1) [1] Pneumonia 3 (<1) 2 (<1) Deep vein thrombosis 2 (<1) 2 (<1) [1] Atrial fibrillation 1 (<1) [1] 2 (<1) [1] 6

7 Lung infection 1 (<1) 2 (<1) Pleural effusion 1 (<1) 2 (<1) Renal failure 1 (<1) 2 (<1) Syncope 1 (<1) 2 (<1) [1] Arthralgia 0 2 (<1) Ascites 0 2 (<1) Febrile neutropenia 0 2 (<1) Gastrointestinal hemorrhage 0 2 (<1) Hematemesis 0 2 (<1) Hemoptysis 0 2 (<1) [1] Hepatic function abnormal 0 2 (<1) [2] Hyperuricemia 0 2 (<1) Hypoxia 0 2 (<1) Lower respiratory tract infection 0 2 (<1) Neck pain 0 2 (<1) Paronychia 0 2 (<1) [2] Rash 0 2 (<1) [2] Rectal hemorrhage 0 2 (<1) [1] Septic shock 0 2 (<1) Thrombocytopenia 0 2 (<1) Anorexia 2 (<1) [2] 1 (<1) [1] Hepatotoxicity 2 (<1) [1] 1 (<1) [1] Pyelonephritis 2 (<1) 1 (<1) Supraventricular tachycardia 2 (<1) [1] 1 (<1) Blood alkaline phosphatase increased 1 (<1) 1 (<1) [1] Bone pain 1 (<1) 1 (<1) Breast cellulitis 1 (<1) 1 (<1) Cardiac failure 1 (<1) [1] 1 (<1) [1] Cerebrovascular accident 1 (<1) 1 (<1) Colitis 1 (<1) 1 (<1) [1] Confusional state 1 (<1) 1 (<1) General physical health deterioration 1 (<1) 1 (<1) Hydronephrosis 1 (<1) 1 (<1) Hyperglycemia 1 (<1) 1 (<1) Intestinal obstruction 1 (<1) 1 (<1) Myocardial infarction 1 (<1) [1] 1 (<1) [1] Pathological fracture 1 (<1) 1 (<1) Pericardial effusion 1 (<1) 1 (<1) Pneumothorax 1 (<1) 1 (<1) Sepsis 1 (<1) 1 (<1) Small intestinal obstruction 1 (<1) 1 (<1) Acute leukemia 0 1 (<1) Acute pulmonary edema 0 1 (<1) Alanine aminotransferase increased 0 1 (<1) [1] Angina unstable 0 1 (<1) Ankle fracture 0 1 (<1) Anxiety 0 1 (<1) Blood urea increased 0 1 (<1) Breast abscess 0 1 (<1) Breast cancer metastatic 0 1 (<1) Carcinoid tumor 0 1 (<1) Cerebrovascular disorder 0 1 (<1) Cholecystitis 0 1 (<1) Cholecystitis acute 0 1 (<1) Colon cancer 0 1 (<1) 7

8 Colonic obstruction 0 1 (<1) Depressed level of consciousness 0 1 (<1) Dermatomyositis 0 1 (<1) [1] Diverticulitis 0 1 (<1) Electrolyte imbalance 0 1 (<1) Excessive granulation tissue 0 1 (<1) [1] Facial palsy 0 1 (<1) Fall 0 1 (<1) Fatigue 0 1 (<1) Femoral neck fracture 0 1 (<1) Furuncle 0 1 (<1) Gallbladder disorder 0 1 (<1) Gallbladder pain 0 1 (<1) Gamma-glutamyltransferase increased 0 1 (<1) [1] Gastric ulcer 0 1 (<1) [1] Hematoma 0 1 (<1) Hemothorax 0 1 (<1) Hepatic enzyme increased 0 1 (<1) [1] Hepatorenal failure 0 1 (<1) Hernia obstructive 0 1 (<1) Herpes zoster 0 1 (<1) Humerus fracture 0 1 (<1) Hypercreatinemia 0 1 (<1) Hyponatremia 0 1 (<1) [1] Idiopathic pulmonary fibrosis 0 1 (<1) Inappropriate anti-diuretic hormone secretion 0 1 (<1) [1] Incision site cellulitis 0 1 (<1) Infection 0 1 (<1) Interstitial lung disease 0 1 (<1) [1] Intestinal ischemia 0 1 (<1) Intraocular lens dislocation 0 1 (<1) Jaundice 0 1 (<1) Leukocytosis 0 1 (<1) Lobar pneumonia 0 1 (<1) Melena 0 1 (<1) Multi-organ failure 0 1 (<1) Musculoskeletal pain 0 1 (<1) Nephrolithiasis 0 1 (<1) Non-cardiac chest pain 0 1 (<1) Oral infection 0 1 (<1) Osteoarthritis 0 1 (<1) Ovarian cyst 0 1 (<1) Ovarian enlargement 0 1 (<1) Overdose 0 1 (<1) Pain in extremity 0 1 (<1) Pancreatitis 0 1 (<1) [1] Pelvic fracture 0 1 (<1) Peritonitis bacterial 0 1 (<1) Pleuritic pain 0 1 (<1) Post procedural infection 0 1 (<1) Pruritus 0 1 (<1) [1] Pulmonary hypertension 0 1 (<1) Renal cell carcinoma 0 1 (<1) Renal failure acute 0 1 (<1) Rhabdomyolysis 0 1 (<1) 8

9 Sinus tachycardia 0 1 (<1) Spinal compression fracture 0 1 (<1) Superior vena caval occlusion 0 1 (<1) Tachypnea 0 1 (<1) Therapeutic agent toxicity 0 1 (<1) Thrombophlebitis 0 1 (<1) [1] Tibia fracture 0 1 (<1) Toxic skin eruption 0 1 (<1) [1] Transitional cell carcinoma 0 1 (<1) Urosepsis 0 1 (<1) Uterine hemorrhage 0 1 (<1) [1] Vulval abscess 0 1 (<1) Wound infection 0 1 (<1) Wrist fracture 0 1 (<1) Constipation 2 (<1) 0 Headache 2 (<1) 0 Hemiparesis 2 (<1) 0 Hip fracture 2 (<1) 0 Hypercalcemia 2 (<1) [1] 0 Hypokalemia 2 (<1) 0 Acute myocardial infarction 1 (<1) 0 Arrhythmia 1 (<1) 0 Aspartate aminotransferase increased 1 (<1) 0 Ataxia 1 (<1) 0 Bronchopneumonia 1 (<1) 0 Cardio-respiratory arrest 1 (<1) 0 Catheter related complication 1 (<1) 0 Catheter site infection 1 (<1) 0 Cervical vertebral fracture 1 (<1) 0 Cognitive disorder 1 (<1) 0 Compression fracture 1 (<1) 0 Crohn s disease 1 (<1) [1] 0 Deafness 1 (<1) 0 Dementia Alzheimer s type 1 (<1) 0 Device breakage 1 (<1) 0 Diabetes mellitus 1 (<1) 0 Dizziness 1 (<1) 0 Edema peripheral 1 (<1) [1] 0 Encephalopathy 1 (<1) 0 Epistaxis 1 (<1) 0 Eye injury 1 (<1) 0 Facial paresis 1 (<1) [1] 0 Flank pain 1 (<1) 0 Gait disturbance 1 (<1) 0 Gastric ulcer perforation 1 (<1) [1] 0 Gastroenteritis 1 (<1) [1] 0 Hallucination, visual 1 (<1) 0 Hemorrhoids 1 (<1) 0 Hypercreatininemia 1 (<1) 0 Hypertension 1 (<1) [1] 0 Hypocalcemia 1 (<1) 0 Hypoglycemia 1 (<1) 0 Hypotension 1 (<1) 0 Ileus 1 (<1) 0 Infected skin ulcer 1 (<1) 0 9

10 Ischemic stroke 1 (<1) 0 Left ventricular failure 1 (<1) 0 Localized infection 1 (<1) 0 Lymphedema 1 (<1) 0 Lymphoma 1 (<1) 0 Malaise 1 (<1) 0 Musculoskeletal chest pain 1 (<1) 0 Palpitations 1 (<1) 0 Pancreatitis hemorrhagic 1 (<1) 0 Paraparesis 1 (<1) 0 Pelvic pain 1 (<1) 0 Pelvi-ureteric obstruction 1 (<1) 0 Pericarditis 1 (<1) 0 Post procedural complication 1 (<1) 0 Renal impairment 1 (<1) [1] 0 Respiratory tract infection 1 (<1) 0 Road traffic accident 1 (<1) 0 Synovial rupture 1 (<1) 0 Thrombosis 1 (<1) 0 Tooth abscess 1 (<1) 0 Upper limb fracture 1 (<1) 0 Visual disturbance 1 (<1) 0 Subjects with fatal SAEs, n (%) [related] 8 (1) [2] 8 (1) [1] Septic shock 0 2 (<1) Cerebrovascular accident 1 (<1) 1 (<1) Breast cancer metastatic 0 1 (<1) Hepatic function abnormal 0 1 (<1) [1] Intestinal ischemia 0 1 (<1) Lung infection 0 1 (<1) Multi-organ failure 0 1 (<1) Rhabdomyolysis 0 1 (<1) Renal failure 0 1 (<1) Renal failure acute 0 1 (<1) Sepsis 0 1 (<1) Acute myocardial infarction 1 (<1) 0 Cardio-respiratory arrest 1 (<1) 0 Dyspnea 1 (<1) [1] 0 Hypotension 1 (<1) 0 Lymphoma 1 (<1) 0 Myocardial infarction 1 (<1) [1] 0 Pancreatitis hemorrhagic 1 (<1) 0 Road traffic accident 1 (<1) 0 Small intestinal obstruction 1 (<1) 0 10

11 Conclusion: This study showed that for the primary endpoint of investigator-evaluated PFS in the HER2-positive population, PFS was statistically significantly longer in the letrozole plus lapatinib group compared with the letrozole plus placebo group. The HR was 0.71 (95% CI: 0.53, 0.96; stratified log rank p=0.019). Median PFS was 35.4 weeks in the letrozole plus lapatinib group compared with 13.0 weeks in the letrozole plus placebo group. As statistical significance was achieved in the HER2-positive population, testing was performed in the ITT population at the alpha 0.05 level as a secondary analysis. Investigator-evaluated PFS in the ITT population was also statistically significantly longer in the letrozole plus lapatinib group compared with the letrozole plus placebo group. The HR was 0.86 (95% CI: 0.76, 0.98; stratified log rank p=0.026). The median PFS was 47.0 weeks in the letrozole plus placebo group compared with 51.7 weeks in the letrozole plus lapatinib group. In the Safety population, 536 (86%) and 628 (96%) subjects reported AEs in the letrozole plus placebo and letrozole plus lapatinib groups, respectively. The most frequently reported AEs were arthralgia, nausea, and diarrhea in the letrozole plus placebo group, and diarrhea, rash, and nausea in the letrozole plus lapatinib group. A total of 94 (15%) and 144 (22%) subjects had SAEs in the letrozole plus placebo and letrozole plus lapatinib groups, respectively. The most frequently reported SAEs were ejection fraction decreased, and vomiting in the letrozole plus placebo group, and ejection fraction decreased, diarrhea, and vomiting in the letrozole plus lapatinib. A total of 8 subjects in each treatment group had fatal SAEs. Three subjects had fatal events which were assessed as related to study medication, two subjects in the letrozole-placebo group (dyspnoea and myocardial infarction), and one subject in the letrozole-lapatinib group (hepatic function abnormal). 11