Abstract P3-11-24: Relative risk of peripheral neuropathy with trastuzumab emtansine compared to taxane-based regimens in HER2-positive cancers: A systematic review and meta-analysis of published phase 3 randomized controlled trials
Authors: Jahan Nusrat , Tijani Lukman , Mogollon-Duffo Francis , Khan Rafiullah , Ball Somedeb , Rehman Shabnam , Jones Catherine 
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. The trastuzumab part of T-DM1 inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity, and ensures selective delivery of DM-1 into HER2 overexpressing cells. DM-1 inhibits microtubules causing cell cycle arrest and apoptosis. Currently, T-DM1 is approved for HER2-positive breast cancer in the both metastatic and adjuvant settings. In different studies, peripheral neuropathy, in particular sensory 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) using T-DM1 in the experimental arm and a taxane-based regimen in the control arm to determine the relative risk of peripheral neuropathy and peripheral sensory neuropathy associated with T-DM1 comparing to taxane-based regimens.
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 taxane-based regimens in patients with HER2-positive cancers and reporting number of events of peripheral neuropathy and peripheral sensory neuropathy in both the intervention and the 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: Three RCTs (MARIANNE, GATSBY, and KRISTINE) randomizing 1857 participants (1174 in the T-DM1 arms and 683 in the control arms) were included in the final analysis. MARIANNE and KRISTINE were conducted in breast cancer patients, and GATSBY was done in gastric/gastro-esophageal junction adenocarcinoma patients. GATSBY was a phase 2/3 study and the rest were phase 3 RCTs. Trastuzumab was used along with taxanes in the control arm of MARIANNE and KRISTINE trials. Dose of T-DM1 was 3.6 mg/kg every 3 weeks in MARIANNE and KRISTINE trials; and 2.4 mg/kg every week in GATSBY trial. The characteristics of these trial are summarized in Table 1. The pooled RR of any grade peripheral neuropathy was significantly lower in the T-DM1 group compared to the taxane group (pooled RR:0.59, 95% CI: 0.39-0.89, P = 0.01, I2= 45%). The pooled RR for any grade sensory peripheral neuropathy was also significantly lower in the T-DM1 group compared to the taxane group (pooled RR:0.58, 95% CI: 0.46-0.74, P &lt; 0.0001, I2=0%).
Conclusion: Our meta-analysis demonstrated the pooled relative risk of any grade peripheral neuropathy and peripheral sensory neuropathy was significantly lower with the T-DM1 containing regimens compared to the taxane-based regimens for HER2-positive cancers. This could be an area of consideration when choosing therapy for the patients who are at higher risk of developing or have pre-existing peripheral neuropathy.
Table 1TrialAuthorYearDiseaseT-DM1ControlTotal No. of PatientsT-DM1ControlMARIANNEPerez et al.2016Advanced BCT-DM1; andT-DM1+ PTaxane + trastuzumab727353GATSBYThuss-Patience et al.2017Advanced gastric cancerT-DM1Taxane224111KRISTINEHurvitz et al.2018Stage II-III BCT-DM1+ PDocetaxel+carboplatin+trastuzumab+ P223219P: PertuzumabBC: Breast Cancer
Citation Format: Nusrat Jahan, Lukman Tijani, Francis Mogollon-Duffo MD, Rafiullah Khan, Somedeb Ball, Shabnam Rehman, Catherine Jones. Relative risk of peripheral neuropathy with trastuzumab emtansine compared to taxane-based regimens in HER2-positive cancers: 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 P3-11-24.