Abstract P3-08-52: Systemic toxicities of trastuzumab-emtansine predict tumor response in HER2+ metastatic breast cancer
Authors: Tang Shou-Ching , Capra Carter Louis , Ajebo Germame H , Mairs Simon , Meza-Junco Judith , Hillegass William B. , Craft Barbara S. , Zhu Xiaofu 
Published: March 2020

Introduction: The plant alkaloid Maytansine and its derivatives with anti-microtubule activity failed in early trials due to significant toxicity.When linked to trastuzumab as an antibody-drug conjugate (ADC), emtansine can be delivered directly into the target cell with little systemic toxicity since the emtansine is inactive before the linker of the ADC is cleaved inside the tumor cells. Systemic toxicities with trastuzumab-emtansine (T-DM1) include thrombocytopenia and transaminase elevations, unlike trastuzumab alone. We hypothesized that systemic toxicities of this ADC are in part the result of emtansine released from the lysed tumor cells, and if so, that they may predict its tumor response. To evaluate this hypothesis, the correlation between early toxicity and initial tumor response, as well as progression free survival, are examined in a retrospective multi-center study. Methods: Records of women with metastatic or locally advanced/inoperable HER2+ breast cancer who received at least one dose of T-DM1 were retrospectively abstracted from 3 centers with IRB approval. Eighty-two patients were identified. Nine were excluded—one due to a diagnosis of idiopathic thrombocytopenic purpura and eight due to lack of follow-up imaging after starting T-DM1. Platelet count, AST, and ALT results from baseline up to the 8th cycle were graded with the NCI CTCAEv5.0 toxicity scale and grades were summed as a toxicity score for the 73 evaluable patients. Sequential CT or PET/CT response to therapy were defined by RECIST criteria with the addition of a mixed response category. Results: A significant association between improved ordinal imaging response (complete, partial, stable, mixed, progression) and higher toxicity sum score was observed by the Jonckheere-Terpstra two-sided test (Z=-2.194, p=0.028). 66% of the progression free patients (29/44) had toxicity sum scores ≥2 compared to 45% with disease progression (13/29), Z=-1.89, p=0.059 by two-sided Cochran-Armitage Trend Test. Progression free survival (PFS) was significantly longer with toxicity score ≥ 2 compared to score ≤ 1, p = 0.012 by log-rank test. Further, longer PFS was significantly associated with higher toxicity sum score with HR= 0.67 (β= -0.418, SE(β) = 0.169, χ2 = 6.08, d.f.=1, p = 0.014) indicating a 33% decrease in hazard of progression for each one-point increase in toxicity score. Discussion: This small, retrospective study demonstrates a significant association between higher toxicity sum score and more favorable tumor response as well as progression free survival in women with metastatic or locally advanced/inoperable HER2+ breast cancer treated with T-DM1. Further study in large-scale trials is warranted to confirm this association and determine the clinical utility of toxicity score as a predictor of therapeutic response. Our finding does not exclude systemic toxicity from the possible ADC linker cleavage prior to endocytosis. However, when T-DM1 was studied in the metastatic setting, 48% of patients experienced a Grade 3 or higher adverse event leading to dose reductions or discontinuation of the drug in 19% and 10% of patients, respectively. In the adjuvant setting, with only residual tumor that can account for ADC-related tumor lysis, only 25% had a Grade 3 or higher adverse event leading to 18% of patients discontinuing the drug. Should our observation prove predictive in further studies, it may have ramifications for many more antibody-drug conjugates.

Citation Format: Shou-Ching Tang, Carter Louis Capra, Germame H Ajebo, Simon Mairs, Judith Meza-Junco, William B. Hillegass, Barbara S. Craft, Xiaofu Zhu. Systemic toxicities of trastuzumab-emtansine predict tumor response in HER2+ metastatic breast cancer [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 P3-08-52.