Date of Award

January 2016

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Lajos Pusztai

Abstract

T-DM1/ ado-trastuzumab emtansine, the most recent addition to the HER2-targeted therapies approved to treat HER2-positive metastatic breast cancer (MBC), is an antibody-drug conjugate with a favorable side effect profile. T-DM1 is currently approved for patients with HER2-positive MBC who previously received trastuzumab and a taxane. Since the trial resulting in T-DM1 approval was conducted, the standard first-line therapy for metastatic HER2-positive breast cancer has changed from trastuzumab and a taxane to a three-drug combination of trastuzumab and a taxane plus pertuzumab. Due to the timing of these approvals, there is no clinical trial or observational data on the activity of T-DM1 in patients who have received prior therapy that included pertuzumab. The goal of this study was to assess the efficacy of T-DM1 in routine clinical practice in a contemporary patient population that received both prior trastuzumab and pertuzumab. To address this goal, a retrospective chart review was performed for all patients with HER2-positive MBC who received T-DM1 after pertuzumab between March 1, 2013 and July 15, 2015 at three institutions (Smilow Cancer Hospital at Yale-New Haven, MD Anderson Cancer Center, and The James Cancer Hospital at the Ohio State University). We manually reviewed the medical records of each case to confirm treatment sequencing and outcome. Eighty-two patients were identified who had received single agent T-DM1 and had received pertuzumab at any time previously. Demographic characteristics and prior therapy were reported for these patients. Seventy-eight patients were available for analysis of response. The rate of prolonged duration on therapy (PDT), defined as duration on therapy > 6 months, was 30.8% (95% CI, 20.6-41.1%) and the tumor response rate was 17.9% (95% CI, 9.4-26.4%). The rate of any benefit (AB), defined as PDT and/or TR, was 37.2% (95% CI, 26.5-47.9%). The median duration on therapy was 4.0 months (95% CI, 2.7-5.1, range 0-22.5). The reason for discontinuation of T-DM1 was progression of disease in 84% of patients. Only 7 patients (10%) discontinued T-DM1 due to toxicity or poor tolerance. Overall, this retrospective analysis provides the first data demonstrating the efficacy of T-DM1 in patients who have received pertuzumab previously. Response rates were lower than prior reports in trastuzumab-resistant HER2-positive MBC, but one third of patients received therapy with T-DM1 for at least 6 months, which suggests tumor control and clinically relevant benefit to T-DM1 in patients who received prior trastuzumab and pertuzumab.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 08/23/2017

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