Abstract P5-14-15: Risk of peripheral neuropathy with trastuzumab emtansine: A systematic review and meta-analysis of published phase 3 randomized controlled trials
Authors: Jahan Nusrat , Hardwicke Fred 
Published: March 2020

Abstract
Background: Trastuzumab Emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate consisting of anti-HER2 IgG1 antibody trastuzumab and maytansine derivative DM-1. Trastuzumab component of T-DM1 inhibits HER2 receptor signaling and mediates antibody-dependent cell-mediated cytotoxicity. It also ensures selective intracellular delivery of DM-1 into the HER2 overexpressing cells. DM-1 is a microtubule inhibitor causing cell cycle arrest and apoptosis. Currently T-DM1 is approved for HER2-positive breast cancer at both the metastatic and the adjuvant settings. In different studies, peripheral neuropathy has been reported as a significant adverse effect of T-DM1. We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of peripheral neuropathy associated with T-DM1 compare to other regimens in HER2-positive cancers.
Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE databases 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 peripheral neuropathy 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, KRISTINE, MARIANNE, and TH3RESA) randomizing 3,422 participants (2067 in the T-DM1 arms and 1355 in the control arms) were included in the final analysis. Four studies (EMILIA, KRISTINE, MARIANNE, and TH3RESA) were conducted in breast cancer patients, and one (GATSBY) was done in gastric/gastro-esophageal junction adenocarcinoma patients. GATSBY was a phase 2/3 RCT and rest were phase 3 RCTs. Patients in the control arms received variable systemic therapies across trials: a taxane based regimen was used in GATSBY, KRISTINE, and MARIANNE trials; a capecitabine and lapatinib combination was used in EMILIA trial; and a treatment of physician’s choice was used in TH3RESA trial. Dose of T-DM1 was usually 3.6 mg/kg every 3 weeks, except for GATSBY study where it was used as 2.4 mg/kg weekly dose. The pooled RR of any grade peripheral neuropathy was not significantly different in the T-DM1 group compared to the control group (pooled RR:0.83, 95%CI: 0.45-1.55, P= 0.57, I2=87%). No publication bias was appreciated across all the studies included in the final analysis.
Conclusion: Our meta-analysis demonstrated the relative risk of any grade peripheral neuropathy was not significantly higher in the T-DM1 containing regimens compared to other therapies in patients with HER2-positive cancers.
Citation Format: Nusrat Jahan, Fred Hardwicke. Risk of peripheral neuropathy with trastuzumab emtansine: A systematic review and meta-analysis of published phase 3 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 P5-14-15.