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Whether HER2-positive non-breast cancers are candidates for treatment with Ado-trastuzumab emtansine?

ABSTRACT: The National Comprehensive Cancer Network (NCCN) has recommended Ado-trastuzumab emtansine (T-DM1) as a preferred agent for patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer and prior trastuzumab therapy. Overexpression of HER2 was reported in other cancer types such as bladder, gastric and urogenital carcinosarcomas similar to what is discovered in breast cancer. Some preclinical studies demonstrated the potential anti-tumor effects of T-DM1 in HER2-positive non-breast cancers. There is a paucity of data over the clinical evaluation of T-DM1 in human studies of non-breast cancer patients. We review some preclinical and ongoing clinical studies that assessed the efficacy of T-DM1 administration in the treatment of non-breast HER2 positive malignancies. Performing large and well-designed trials in this area is matter of interest and highly recommended.

SUBMITTER: Moghaddas A

PROVIDER: S-EPMC5084478 | biostudies-other | 2016 Oct-Dec

REPOSITORIES: biostudies-other

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Whether HER2-positive non-breast cancers are candidates for treatment with Ado-trastuzumab emtansine?

Moghaddas Azadeh A Borhani Ali A

Journal of research in pharmacy practice 20161001 4

The National Comprehensive Cancer Network (NCCN) has recommended Ado-trastuzumab emtansine (T-DM1) as a preferred agent for patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer and prior trastuzumab therapy. Overexpression of HER2 was reported in other cancer types such as bladder, gastric and urogenital carcinosarcomas similar to what is discovered in breast cancer. Some preclinical studies demonstrated the potential anti-tumor effects of T-DM1 in HER2 ...[more]

PMID: 27843957

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Project description:Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker.We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted.Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine.T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.).

Project description:PURPOSE:This article reviews the mechanism of action of trastuzumab emtansine (T-DM1), existing clinical data relating to its use for human growth factor receptor 2 (HER2)-positive breast cancer, potential pathways of resistance, and ongoing studies evaluating this novel agent. BACKGROUND:The development of HER2-targeted therapies has dramatically improved clinical outcomes for patients with any stage of HER2-positive breast cancer. Although the positive effect of these treatments cannot be overstated, treatment resistance develops in the vast majority of those diagnosed with stage IV HER2-positive breast cancer. Moreover, HER2-directed therapies are most effective when combined with cytotoxic chemotherapy. The need for chemotherapy leads to significant adverse effects and a clear decrease in quality of life for those dealing with a chronic incurable disease. T-DM1 is a recently developed, novel antibody-drug conjugate in which highly potent maytanisinoid chemotherapy is stably linked to the HER2-targeted monoclonal antibody, trastuzumab. RESULTS:Preclinical and phase 1-3 clinical data support the significant antitumor activity of T-DM1. Importantly, several randomized studies also now demonstrate its clear superiority in terms of tolerability compared with standard chemotherapy-containing regimens. Its role in the treatment of trastuzumab-resistant metastatic breast cancer has now been established on the basis of the results of two phase 3 randomized studies, EMILIA (An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) and TH3RESA (A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy). The most common toxicities seen with T-DM1 are thrombocytopenia and an elevation in liver transaminases. Significant cardiac toxicity has not been demonstrated. Both in vitro cell line-based studies as well as exploratory analyses of archived tumor samples from the clinical trials are seeking to understand potential mechanisms of resistance to T-DM1. Ongoing studies are also evaluating the use of T-DM1 in the first-line metastatic, neoadjuvant, and adjuvant settings, as well as in combination with other targeted therapies. CONCLUSION:T-DM1 represents the first successfully developed antibody drug conjugate for the treatment of HER2-positive advanced breast cancer.

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Whether HER2-positive non-breast cancers are candidates for treatment with Ado-trastuzumab emtansine?

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Whether HER2-positive non-breast cancers are candidates for treatment with Ado-trastuzumab emtansine?

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