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Survival outcomes in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer administered a therapy following trastuzumab emtansine treatment.

ABSTRACT: Since 2013, trastuzumab emtansine (T-DM1) has been widely used in Japan to treat patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who were previously administered trastuzumab and a taxane. However, there is no information about the treatment outcomes after exposure to T-DM1 in Japanese patients with HER2-positive MBC. In this study, we aimed to describe the survival outcomes of patients with HER2-positive MBC who received a treatment following T-DM1 and clarify the predictive factors of their prognosis.We retrospectively identified patients with HER2-positive MBC who received T-DM1 between April 1, 2014, and December 31, 2018, at the National Cancer Center Hospital, and focused on the population that received another line of therapy following T-DM1 discontinuation.Thirty patients were available for the outcome analysis. Median progression-free survival (PFS) of the first subsequent therapy was 6.0 months [95% confidence interval (95% CI) 4.1-6.4], whereas the median overall survival (OS) from the first subsequent therapy was 20.6 months (95% CI 13.5 months to not reached). We divided the patients into 2 groups according to their PFS with T-DM1 treatment and compared their PFS with the subsequent therapy. The results revealed a significant difference in the median PFS with the first subsequent treatment between patients with the PFS of less than and more than 3 months [5.1 (95% CI 1.7-6.2) vs 6.2 (95% CI 4.0-11.3) months, P?=?.03].This is the first study to evaluate the survival outcomes of post-T-DM1 therapy in Japanese patients with HER2-positive MBC. A short PFS with T-DM1 might affect the PFS with a treatment after T-DM1.

SUBMITTER: Watanuki R

PROVIDER: S-EPMC7505390 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Survival outcomes in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer administered a therapy following trastuzumab emtansine treatment.

Watanuki Rurina R Shimomura Akihiko A Yazaki Shu S Noda-Narita Shoko S Sumiyoshi-Okuma Hitomi H Nishikawa Tadaaki T Tanioka Maki M Sudo Kazuki K Shimoi Tatsunori T Noguchi Emi E Yonemori Kan K Tamura Kenji K

Medicine 20200901 38

Since 2013, trastuzumab emtansine (T-DM1) has been widely used in Japan to treat patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who were previously administered trastuzumab and a taxane. However, there is no information about the treatment outcomes after exposure to T-DM1 in Japanese patients with HER2-positive MBC. In this study, we aimed to describe the survival outcomes of patients with HER2-positive MBC who received a treatment following ...[more]

PMID: 32957402

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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.

Project description:PurposeThe KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2-positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE.MethodsPatients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery).ResultsOf patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment.ConclusionCompared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment.

Dataset Information

Survival outcomes in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer administered a therapy following trastuzumab emtansine treatment.

Publications

Survival outcomes in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer administered a therapy following trastuzumab emtansine treatment.

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