The development of targeted antibody-drug conjugates (ADC) for the treatment of cancer represents a significant – and promising – progress. ADCs are precise and selective by combine targeted antibodies to potent anticancer therapeutics, resulting in an increased antitumor effect and, at the same time, reduced toxicity to surrounding healthy cells.
The preclinical and clinical trials show extreme potential for the future of currently approved ADCs as well as many similar drugs that are likely to come.
One of these ADCs, ado-trastuzumab emtansine (T-DM1, Kadcyla®; Genentech/Roche), which combines the targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1, is well tolerated and has single-agent activity in patients with HER2+ Metastatic Breast Cancer (MBC) who have previously received both approved HER2-directed therapies and multiple chemotherapy agents. The drug earned U.S. FDA approval in February 2013.
Central Nervous System
Trastuzumab emtansine is a large molecule and does not cross the blood–brain barrier. In a recent study published in the October 29, 2014 issue of Annals of Oncology, Ian Krop, MD, PhD, and colleagues from the Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard University School of Medicine, Breast Oncology Center, in Boston, MA, USA, characterized the incidence of Central Nervous System or CNS metastases after treatment with trastuzumab emtansine versus capecitabine (Xeloda®; Genetech/Roche) + lapatinib (Tykerb®; GSK), and treatment efficacy among patients with pre-existing CNS metastases in the phase III EMILIA study.
Brain metastases, a devastating complication of cancer, are frequent in HER2+ breast cancer patients and generally associated with poor prognosis and impaired quality of life as a result of severe neurological symptoms such as neurocognitive decline, aphasia, paresis and seizures. They occur in up to 50% of patients with advanced HER2+ breast cancer.
EMILIA, a Phase III, randomized, multicenter, international, 2-arm, open-label clinical trial was designed to compare the safety and efficacy of trastuzumab emtansine with that of capecitabine + lapatinib for HER2+ MBC. In this study, patients were treated until disease progression, unmanageable toxicity, or study termination. As soon as disease progression was reported, all patients were followed for survival every 3 months until death, loss to follow-up, withdrawal of consent, or study termination.
In their retrospective, exploratory analysis, including 991 randomized patients (trastuzumab emtansine = 495; capecitabine-lapatinib = 496) – of which 95 patients (trastuzumab emtansine = 45; capecitabine-lapatinib = 50) had CNS metastases at baseline – the rate of CNS progression in patients with HER2+ advanced breast cancer was similar for trastuzumab emtansine and for capecitabine-lapatinib, and higher overall in patients with CNS metastases at baseline compared with those without CNS metastases at baseline.
In a separate analyze the rates of adverse events of grade III or above were higher with lapatinib + capecitabine than with trastuzumab emtansine (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with trastuzumab emtansine. The data also showed that the incidences of diarrhea, nausea, vomiting, and palmar–plantar erythrodysesthesia were higher with lapatinib plus capecitabine.
Krop et al. observed that in patients with treated, asymptomatic CNS metastases at baseline, trastuzumab emtansine was associated with significantly improved overall survival compared with capecitabine-lapatinib.
In an unrelated article published in the September 1, 2014 issue of Current Breast Cancer Report, Ciara C O’Sullivan at the Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA and Kyla Smith, at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA, discuss advances in the treatment of HER2+ MBC with a novel HER2-targeted therapies approved by the United States Food and Drug Administration. In the same article, the authors also address the management of brain metastases in HER2+ MBC.