CTCAE reported as ‘left ventricular systolic dysfunction’ (LVSD) and graded according to NCI-CTCAE. Symptomatic LVSD (that is, Grade 3 or greater LVD) Reportable as a SAE, using the term congestive heart failure (CHF). Reportable as a SAE using the term ‘left ventricular systolic dysfunction’ (LVSD) As for TRYPHAENA Reportable as a single diagnosis rather than symptoms or signs and graded according to and NYHA classification As for NEOSPHERE As for NEOSPHERE CHF occurring during the study and up to 24 months after the last dose of study medications was to be reported regardless of causality graded according to and NYHA classification As for NEOSPHERE (except using the term symptomatic LVSD rather than CHF) Symptomatic LVSD occurring during and up to 36 months after last dose of study medications was to be reported, regardless of causality and graded according to NCI-CTCAE and NYHA classification Specific signs and symptoms of LVSD were entered into the comments section of the AE eForm A cardiac questionnaire was completed by investigators prior to each treatment cycle. Cardiac symptom and physical findings of symptomatic LVSD were entered into the cardiac Cardiac symptoms and signs were reported on a ‘Symptomatic LVSD’ eCRF page for patients with LVSD
questionnaire eForm LVEF schedule of assessments Between Days 15 and 21 of Cycles 2, 4, 8, 11 and 15, and after surgery, and < 7 days prior to Cycle 5, and after Cycle 17 and 21 (Ptz + D arm only) (that is, every 6 weeks during neoadjuvant and adjuvant therapy). Subsequent LVEF assessments every 6 months for 2 years Between Days 15 and 21 of Cycles 2, 4 and 6, surgery and ≤ 7 days prior to Cycle 7, and between Days 15 and 21 of Cycles 10, 12 and 15 and 18 (FEC/Ptz + T + D arm only) (that is, every 6 weeks during the neoadjuvant period and every 6 to 9 weeks during the adjuvant period), at the post-treatment visit, then every 6 months for 2 years, then annually for 2 years 9 weeks during study treatment, at the treatment discontinuation visit, then every 6 months for the first year, then annually for up to 3 years after the treatment discontinuation visit Central review of cardiac data Safety data (in general) reviewed by steering committee Copies of MUGA and ECHO recordings were sent to a central laboratory for independent assessment An independent Cardiac Review Committee (CRC) reviewed data for all potential cardiac events CHF= congestive heart failure; LVEF = left ventricular ejection fraction; LVSD = left ventricular systolic dysfunction; NCI-CTCAE= National Cancer Institute Common Terminology Criteria for Adverse Events; NYHA = New York Heart Association Comment: There was some variability in the terminology used to describe significant cardiac dysfunction, with symptomatic left ventricular systolic dysfunction (Grade 3 and above) being used in the TRYPHAENA (BO22280) and CLEOPATRA (WO20698) studies and symptomatic LVSD being classified as congestive heart failure in the NEOSPHERE (WO20697) study. This is considered in reviewing the aggregate data across the studies. Several other parameters were specifically followed as per Table 4. Table 4: Other events to monitor in the NEOSPHERE (WO20697), TRYPHAENA (BO22280) and CLEOPATRA (WO20698) studies (17, 22 and 23) Adverse events to monitor Safety analysis strategy
NEOSPHERE (WO20697) Neoadjuvant treatment period (%) Arm A Arm B Arm C Arm D TRYPHAENA (BO22280) Neoadjuvant treatment period (%) Arm A Arm B Arm C CLEOPATRA (WO20698) Overall treatment period (%) T+D Ptz + T+D N=107 Ptz + T N=108 Ptz + D N=94 Ptz + T + + T+D +T+D N=75 Ptz +TCH N=76 Pla +T + D Ptz + T + D Any AE 98.1 97.2 70.4 98.9 96.0 100 98.7 100.0 Grade > 3 74.8 60.7 11.1 71.3 69.4 60.0 73.7 76.2 Related AE 97.2 95.3% 66.7 97.9 94.7 100.0 97.3 AE disc 0 1.9 2.8 2.1 5.6 6.7 7.9 28.8 30.6 AE i/m 34.6 32.7 14.8 43.6 36.1 29.3 50.0 54.3 61.8 SAE 16.8 11.2 3.7 17.0 27.8 20.0 35.5 29.0 36.3 AE death 0 0.9 0 0 0 0 0 3.0 2.0 Death, PD 0 0 0 0 0 0 0 34.3 24.5 0 0.9 0 0 0 0 0 4.0 3.2 AE disc =any AE leading to discontinuation of one or more study drugs; AE i/m= any AE leading to interruption or modification; SAE=any SAE; AEdeath=AE with outcome of death (i.e. Grade 5); Death, PD=death due to progressive disease; Death, other=death due to causes other than progressive disease Risk management plan The RMP evaluator identified that there were still outstanding issues: The Delegate does not consider the data currently support a contraindication for concomitant use of pertuzumab with anthracyclines; however, there are insufficient data presented to support its use and it is not currently proposed in the Clinical Trials