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1 TITLE PAGE STUDY REPORT NO From Final Study Report: RO F. Hoffmann-L a Roche Ltd Protocol BO20652 Report Number PASS INFORMATION TITLE: AN OBSERVATIONAL STUDY OF CARDIAC EVENTS IN PATIENTS WITH HER2 POSITIVE EARLY BREAST CANCER TREATED WITH HERCEPTIN PROTOCOL NUMBER: BO20652 (OHERA) VERSION NUMBER: Version 1.0 EU PAS REGISTER NUMBER: EUPAS9914 LINK TO STUDY RECORD IN EU PAS REGISTER: STUDIED MEDICINAL PRODUCT: Herceptin AUTHOR: DATE FINAL: See electronic date stamp below GCP Compliance: This study was conducted in accordance with the principles of GCP. Reason for Signing STUDY REPORT APPROVAL Date and Time (UTC) 27-Apr :20:12

2 ACTIVE SUBSTANCE PRODUCT REFERENCE NUMBER: PROCEDURE NUMBER: JOINT PASS: RESEARCH QUESTION AND OBJECTIVES: COUNTRIES OF STUDY POPULATION: L01XC03: trastuzumab EMEA/H/C/ Not applicable No The primary objective of the study is to observe the incidence of symptomatic congestive heart failure (CHF) reported and classified according to the New York Heart Association criteria (NYHA class II, III and IV) and cardiac death of patients diagnosed with HER2 positive early breast cancer who receive Herceptin as per the approved EU SmPC in a routine clinical practice setting. The secondary objectives of the study are: to explore risk factors for symptomatic CHF and cardiac death, to observe the time to onset and the time to recovery of symptomatic CHF, and to observe the incidence of asymptomatic left ventricular dysfunction (LVD) and other significant cardiac conditions Austria, Sweden, Hungary, Poland, Italy, Belgium, Spain, Germany, and the United Kingdom MARKETING AUTORISATION HOLDER(S) MARKETING AUTHORIZATION HOLDER (MAH): MAH CONTACT PERSON: Roche Registration Ltd 6 Falcon Way Shire Park Welwyn Garden City AL7 1TW United Kingdom Roche Products Limited 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW United Kingdom

3 1. SYNOPSIS/ABSTRACT Title An Observational Study Of Cardiac Events In Patients With HER2 Positive Early Breast Cancer Treated With Herceptin (OHERA) Keywords Non-interventional observational study, cardiac events, HER2 positive breast cancer, trastuzumab Rationale and Background Study BO20652 (OHERA) designed to observe the incidence of symptomatic congestive heart failure (CHF) and cardiac death in patients with HER2 positive early breast cancer (EBC) treated with Herceptin IV as adjuvant therapy in a real-world setting. Research Question and Objectives Primary objective: To observe, the incidence of symptomatic CHF (NYHA class II, III and IV) and cardiac death of patients diagnosed with HER2-positive EBC who received Herceptin IV as per the approved European (EU) Summary of Product Characteristics (SmPC). Secondary objectives: 1) To explore potential risk factors for symptomatic CHF and cardiac death and other significant cardiac conditions. 2) To observe the time to onset and the time to recovery of symptomatic CHF. 3) To observe the incidence of asymptomatic left ventricular dysfunction. Amendment and Updates to Protocol None Study Design Study BO20652 was an observational, non-interventional single arm cohort safety study designed to observe the incidence of symptomatic congestive heart failure and cardiac death in patients with HER2-positive EBC treated with Herceptin in routine clinical practice. All patients were treated and monitored according to the local clinical practice. No additional procedures/patient visits in comparison with the usual clinical practice were performed during the study. The study enrolled 3938 patients with an extensive follow-up period of approximately 5 years. Setting Clinical practice in a real-world setting. Subject and Study Size, Including Dropouts 3938 patients enrolled from 199 centers in 9 countries (i.e., Austria, Belgium, Germany, Hungary, Italy, Poland, Spain, Sweden, and United Kingdom).

4 Variables and Data Sources Primary safety outcome measure: Incidence of symptomatic CHF (New York Heart Association [NYHA] class II, III, IV) and cardiac death of patients Secondary safety outcome measures: Time to onset of symptomatic CHF and cardiac death Time to recovery of CHF Absolute values and change from baselines in left ventricular ejection fraction (LVEF) over time including incidence of LVEF drops/significant LVEF drops, time to onset and time to recovery of significant LVEF drop. Results In total, 3938 patients were enrolled within the study. Within this population, 3733 patients with EBC (Stage I-IIIB) received at least one valid Herceptin administration and comprised the safety population (SP). Of 3733 patients within the SP, 106 patients developed symptomatic CHF (NYHA Class II IV) prior to any disease recurrence, which translates into a cumulative incidence of 2.8% (95% CI: %) and an incidence rate of 690 per 100,000 person years (95% CI ). The majority of symptomatic CHF events were classified as NYHA Class II (68 patients [1.8%]). Thirtyeight patients [1.0%]) were reported to have severe symptomatic CHF (NYHA Class III/IV), and one patient died due to symptomatic CHF. The incidence of symptomatic CHF was higher in patients with the following baseline characteristics; pre-existing cardiac condition, use of cardiovascular medications at study entry, hypertension or high blood pressure, baseline LVEF 55%, overweight/obese (i.e., BMI 25 kg/m 2 ), age 65 years, and history of cardiac failure or active cardiac failure at study entry. The median time to onset of symptomatic CHF (NYHA II IV) was 174 days (95% CI: days) (i.e., approximately 6 months). The majority of patients (83%) that developed symptomatic CHF had time to onset within 12 months of first Herceptin administration with 50% of these events occurring between approximately 3 to 9 months from first Herceptin administration. Most patients who experienced symptomatic CHF recovered from their CHF event (77 of 106 CHF patients [72.6%]) as per the treating physician s assessment. The median time from onset to resolution of the first symptomatic CHF event prior to disease recurrence was 302 days (95% CI: days) (i.e, approximately 10 months). Of 3733 patients, 11 patients died due to a cardiac event. In the SP, 6 patients had a cardiac-related death without prior disease recurrence translating into an incidence of 0.2% (95% CI: %) and an incidence rate of 37 cardiac deaths per 100,000 person years (95% CI 14 80). The median time to cardiac death in these 6 patients

5 was 1555 days (approximately 4.3 years) (range: days). Five patients experienced a cardiac-related death after disease recurrence. Discussion Data from Study BO20652 provide an understanding of the incidence of symptomatic CHF and cardiac death in the real-world setting, and the potential risk factors that contribute to these outcomes in HER2-positive EBC patients treated with Herceptin adjuvant therapy. Identified risk factors for symptomatic CHF are consistent with those currently specified within the Herceptin EU SmPC (i.e., advanced age [ 50 years], low LVEF [55%] at baseline, prior to or following the initiation of paclitaxel treatment, decline in LVEF by percentage points, and prior or concurrent use of antihypertensive medicinal products, higher cumulative dose of anthracycline given prior to initiation of Herceptin and a body mass index [BMI] >25 kg/m 2 ). Most patients who had experienced symptomatic CHF were reported to have recovered from their CHF event (77 of 106 CHF patients [72.6%]) as per the treating physician s assessment. This finding therefore suggests that these events may in general be reversible and that standard heart failure therapy may lead to resolution. The treating investigator determined resolution of the symptomatic CHF event (i.e., criteria and timing) and the definition of resolution may have slightly differed between investigators. At baseline, of the patients that developed symptomatic CHF, the majority ( 90%), had a baseline LVEF assessment, and when evaluating LVEF assessments separately at 3 month intervals, more than half of patients ( 55%) had a LVEF assessment during the first 9 months of treatment with Herceptin and aligned with the recommendations within the Herceptin EU SmPC (i.e., every 3 months). In these patients, decreases in LVEF occurred in the first 3 months after Herceptin initiation, dropping to its lowest median value during months 4 through 6, before stabilizing in the time period of months at above 50%. However due to small sample size per assessment period there is considerable variability in LVEF values over time for these patients. In patients with symptomatic CHF, more frequent LVEF monitoring was conducted in most patients as per recommendations within the Herceptin EU SmPC (i.e., every 6 8 weeks). Within the SP, 264 patients died within the per-protocol data collection period of 5 years from first administration of Herceptin. Overall, the number of patients that died due to cardiac-related deaths was low (11 patients), with the majority of patients deaths (205 patients [77.5%]) related to metastases or progression of disease. Conclusion Study BO20652 is the largest Herceptin IV adjuvant EBC study to investigate cardiac safety in a real-world setting. The results from the Study BO20652 (OHERA) final analysis are consistent with prior cardiac safety results reported from Herceptin adjuvant EBC studies, such as the HERceptin Adjuvant (HERA) (Study BO16348).

6 Marketing Authorisation Holder(s) Roche Registration Ltd 6 Falcon Way Shire Park Welwyn Garden City AL7 1TW United Kingdom Names and affiliations of principal study physicians No principal investigator was assigned