Abstract P5-14-10: Relative risk of grade 3 and higher hematological toxicities with trastuzumab emtansine: A systematic review and meta-analysis of published phase 3 randomized controlled trials
Authors: Jahan Nusrat , Khan Rafiullah , Rehman Shabnam , Hardwicke Fred , Mogollon-Duffo Francis , Tijani Lukman 
Published: March 2020

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 inhibits HER2 receptor signaling and mediates antibody-dependent cell-mediated cytotoxicity; and DM-1 is a microtubule inhibitor causing cell cycle arrest and apoptosis. In addition, the former ensures selective intracellular delivery of the latter into the HER2 overexpressing cells. 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 phase 3 randomized controlled trials (RCTs) using T-DM1 to determine the relative risk of grade 3 and higher hematological toxicities associated with T-DM1.

Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE and 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 grade 3 and higher hematological toxicities 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: Six RCTs (EMILIA, GATSBY, KRISTINE, KATHERINE, MARIANNE, and TH3RESA) randomizing 4882 participants (2807 in the T-DM1 arms and 2075 in the control arms) were included in the final analysis for grade 3 and higher anemia and thrombocytopenia. KATHERINE trial did not report the number of grade 3 and higher neutropenia. Five RCTs (EMILIA, GATSBY, KRISTINE, MARIANNE and TH3RESA) including 3422 (2067 in the T-DM1 arms and 1355 in the control arms) were included in the final analysis for grade 3 and higher neutropenia. Five studies (EMILIA, KATHERINE, 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 study and rest were phase 3 RCTs. Patients in the control arms received variable systemic therapies across trials: taxane based regimens were used in GATSBY, KRISTINE, and MARIANNE trials; capecitabine and lapatinib combination was used in EMILIA trial; treatments of physician’s choice were used in TH3RESA trial; and trastuzumab alone was used in KATHERINE trial. The pooled RR of grade 3 and higher thrombocytopenia was significantly higher in the T-DM1 group compared to the control group (pooled RR: 8.59, 95% CI: 1.54-48.00, P= 0.01, I2= 82%). The pooled RR of grade 3 and higher anemia was not significantly different in the T-DM1 group compared to the control group (pooled RR: 1.23, 95% CI: 0.63-2.41, P= 0.54, I2= 72%). The pooled RR of grade 3 and higher neutropenia was significantly lower in the T-DM1 group compared to the control group (pooled RR: 0.16, 95% CI: 0.09 -0.32, P&lt; 0.00001, I2= 76%).

Conclusion: T-DM1 was associated with increased risk of grade 3 and higher thrombocytopenia, but reduced risk of grade 3 and higher neutropenia compared to control regimens. The exact mechanism of these findings is not clear, yet they may have some implications in adopting appropriate therapeutic strategies for the patients. The patients who are on T-DM1, a careful monitoring of the platelet will be helpful for the early identification of thrombocytopenia and initiation of appropriate interventions. On the other hand, T-DM1 may be a relatively safer option for the patients who are at risk of developing neutropenia and infectious complications.

Citation Format: Nusrat Jahan, Rafiullah Khan, Shabnam Rehman, Fred Hardwicke, Francis Mogollon-Duffo, Lukman Tijani. Relative risk of grade 3 and higher hematological toxicities 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 P5-14-10.