Abstract P1-18-26: Risk of reduction of left ventricular ejection fraction with trastuzumab emtansine: A systematic review and meta-analysis of randomized controlled trials
Authors: Jahan Nusrat , Ball Somedeb , Tijani Lukman , Hardwicke Fred , Jones Catherine 
Published: March 2020

Abstract
Background: HER2 targeted therapies have significantly improved the prognosis of HER2 overexpressing cancers, in particular HER2-positive breast cancer. However, type-II cancer therapeutics-related cardiac dysfunction (CTRCD) characterized by a drop in left ventricular ejection fraction (LVEF) remains a significant adverse event for trastuszumab and other HER2 targeted therapies. Trastuzumab Emtansine (T-DM1) is a HER2 targeted antibody-drug conjugate consisting of anti-HER2 IgG1 antibody trastuzumab and a maytansine derivative microtubule inhibitor DM-1. Currently T-DM1 is approved for HER2-positive breast cancer both in the metastatic and in the adjuvant settings. We conducted a systematic review and meta-analysis of published phase 3 randomized controlled trials (RCTs) to determine the relative risk of reduction of LVEF with T-DM1 in comparison to other therapies in HER2-postive cancers.
Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and professional societies meeting abstracts as per PRISMA guidelines from inception until March 31st, 2019. Published phase 3 RCTs comparing T-DM1 with other therapies in patients with HER2-positive cancers and reporting the number of events of reduction in LVEF in both intervention and control arms were included in the final analysis. The primary meta-analytic approach was a random effects model using the Mantel-Haenszel (MH) method, and it was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q-test.
Results: Five RCTs (EMILIA, GATSBY, KATHERINE, KRISTINE, and TH3RESA) randomizing 3802 patients (2080 in intervention arms and 1722 in control arms) with HER2-positive cancers were included in the final analysis. Four studies (EMILIA, KATHERINE, KRISTINE, and TH3RESA) were conducted in breast cancer patients, and one (GATSBY) was done in gastric/gastro-esophageal adenocarcinoma patients. GATSBY was a phase 2/3 study and rest were phase 3 RCTs. Patients in control arms received variable systemic therapies across trials, most of the studies used conventional HER2 targeting drugs (e.g. trastuzumab, lapatinib etc) with exception of GATSBY trial which only used taxanes. Dose of T-DM1 was usually 3.6 mg/kg every 3 weeks, except for GATSBY study where dose was 2.4 mg/kg every week. The pooled RR of any-grade reduction of LVEF was significantly lower in the T-DM1 group as compared to control at 0.58 (95% CI: 0.36-0.95, p = 0.03, I2 = 0). No publication bias was appreciated across all studies included in the final analysis.
Conclusion: In our meta-analysis, the relative risk of reduction of LVEF was significantly lower in the T-DM1 containing regimens compared to other therapies in patients with HER2-positive cancers. It could be an area of research to identify the mechanism and to determine the clinical utility of this finding.
Citation Format: Nusrat Jahan, Somedeb Ball, Lukman Tijani, Fred Hardwicke, Catherine Jones. Risk of reduction of left ventricular ejection fraction with trastuzumab emtansine: A systematic review and meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-26.