scholarly journals Mechanisms contributing to ado-trastuzumab emtansine (T-DM1)-induced toxicities: a gateway to better understanding ADC-associated toxicities

2021 ◽  
Author(s):  
Yukinori Endo ◽  
Nishant Mohan ◽  
Milos Dokmanovic ◽  
Wen Jin Wu
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Metastatic Breast ◽  
Invasive Disease ◽  
Dependent Manner ◽  
Trastuzumab Emtansine ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Humanized Monoclonal Antibody ◽  
Significant Efficacy

Abstract In order to improve the safety of novel therapeutic drugs, better understanding of the mechanisms of action is important. Ado-trastuzumab emtansine (also known as T-DM1) is an antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody directed against HER2 (trastuzumab) and a maytansinoid-derived toxin (DM1), which are linked by a non-cleavable thioether linker. T-DM1 has been approved for the treatment of trastuzumab-resistant HER2-positive metastatic breast cancer and recently for use as an adjuvant treatment option for patients with HER2-positive early breast cancer who have residual invasive disease. While the treatment with T-DM1 results in significant efficacy in the selected patient population, nonetheless, there are also concerns with the side effects such as thrombocytopenia and hepatotoxicity. While current understanding of the mechanism of T-DM1-mediated side effects is still incomplete, there have been several reports of HER2-dependent and/or -independent mechanisms that could be associated with the T-DM1-induced adverse events. The results from our laboratory show that T-DM1 binds to cytoskeleton-associated protein 5 (CKAP5) on the cell surface of hepatocytes via its payload component (DM1). This interaction is independent of HER2 and leads to cell growth inhibition and apoptosis of hepatocytes in a T-DM1 dose dependent manner. This review highlights the importance of HER2-independent mechanism of T-DM1 to induce hepatotoxicity, which offers a new insight into a role for CKAP5 in the overall maytansinoid-based ADC (DM1 and DM4)-mediated cytotoxicity. This discovery provides a molecular basis for T-DM1-induced off-target toxicity and opens a new avenue for developing the next generation of ADCs.

Trastuzumab Emtansine (T-DM1): Hitching a Ride on a Therapeutic Antibody

2012 ◽  
pp. 159-161 ◽  
Author(s):  
Howard A. Burris
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Side Effects ◽  
Phase Ii ◽  
Objective Response ◽  
Metastatic Breast ◽  
Response Rates ◽  
Phase Iii ◽  
Trastuzumab Emtansine ◽  
Her2 Positive

Overview: The treatment of cancers with chemotherapy is frequently limited by side effects. The effectiveness may be improved by the use of monoclonal antibodies to deliver cytotoxic agents to cancer cells while limiting exposure to normal tissues. The use of antibody-drug conjugates (ADCs) is one such strategy: a drug connected by a linker to an antibody specific for a tumor antigen is the basic makeup of an ADC. Overexpression and amplification of HER2 is associated with clinically aggressive breast cancers, and the use of trastuzumab to target HER2 has been highly effective. That said, most patients with HER2-positive metastatic breast cancer will eventually have disease progression during targeted therapy. Trastuzumab emtansine (T–DM1) is a novel ADC that combines the humanized antibody trastuzumab and the potent antimicrotubule agent T-DM1 (derivative of maytansine) using a unique and highly stable linker. The potential of maytansine was found in the 1970s with clinical responses noted against breast cancer; however, substantial toxicity prohibited further development. DM1 possesses in vitro cytotoxicity 10 to 200 times greater than that of taxanes and vinca alkaloids. A phase I trial of T-DM1 for patients with heavily pretreated HER2-positive breast cancer determined a recommended dose of 3.6 mg per kilogram delivered every 3 weeks. Responses were seen in multiple patients. T-DM1 was then studied in phase II trials of patients with HER2-positive metastatic breast cancer. In a studies of 112 and 110 patients in whom disease had progressed during HER2-directed therapy, T-DM1 was associated with objective response rates of 26% and 34%, respectively. The agent was well tolerated in both trials, with most toxicities being grade 1 and 2, and no bleeding episodes or cardiac events occurring. Additional phase II and III trials are now evaluating T-DM1 in the first-line setting. In one such trial, T-DM1 was compared with standard dosing of trastuzumab every 3 weeks plus docetaxel every 3 weeks. Objective response rates were comparable and grade 3 or4 adverse events were substantially reduced in the T-DM1 arm. The anticipated selective activity and reduction in side effects were thus noted. Randomized multicenter phase III trials are ongoing, including the EMILIA trial, an open-label trial of T-DM1 compared with the U.S. Food & Drug Administration-approved regimen of capecitabine plus lapatinib. The results of studies completed to date suggest T-DM1 is active in patients who have cancer resistant to trastuzumab-based combinations.

Projected long-term impact of adjuvant trastuzumab emtansine (T-DM1) on metastatic breast cancer occurrence in Turkey.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12523-e12523
Author(s):  
David J. Press ◽  
Gözde Özcan ◽  
Ezgi Teksoy ◽  
Akanksha Tomar ◽  
Cedric Revil ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Population Level ◽  
Invasive Disease ◽  
Trastuzumab Emtansine ◽  
Her2 Positive ◽  
Adjuvant Trastuzumab ◽  
Disease Free

e12523 Background: Progression from early stage breast cancer (eBC) to metastatic breast cancer (mBC) constitutes a substantial disease burden in Turkey. At a population-level, investment in treatment with curative intent may contribute to long-term reductions or delays in mBC. Women diagnosed with human epidermal growth factor receptor 2 (HER2)-positive eBC who do not achieve pathologic complete response (pCR) after neoadjuvant taxane and trastuzumab-based treatment may be indicated for adjuvant trastuzumab emtansine (T-DM1) monotherapy. For this clinical population, the KATHERINE trial (NCT01772472) demonstrated significantly higher invasive disease-free survival among women who received adjuvant T-DM1 relative to trastuzumab (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; p<0.001). Methods: We developed epidemiology models based on data from cancer registries, observational studies, clinical trials, estimated population-level T-DM1 uptake, and extrapolations, by calendar year to predict the population-level number of women who will avoid mBC in Turkey over the next 10 years (i.e., 2022 to 2031). Weighted transitional probability averages were based on invasive disease-free and overall survival curves from the KATHERINE trial. Results: Over the next 10 years in Turkey, we projected that 22,597 women will be diagnosed with HER2-positive eBC and will not achieve pCR after neoadjuvant therapy. We projected that the total number of women who will experience mBC occurrence following adjuvant T-DM1 use from 2022-2031 will decrease annually from 0 to 249 relative to projections without introduction of T-DM1, with a cumulative total of 1,219 women not experiencing mBC occurrence, corresponding to 17% of total projected mBC occurrence over the next decade. At year 10 (2031), we projected that 29% fewer women would experience mBC occurrence in Turkey (604 with TDM-1 vs. 853 with trastuzumab). Conclusions: Population-level improvements in HER2-positive eBC to mBC disease progression are expected over the next 10 years in Turkey following adjuvant T-DM1 monotherapy. Further research will elucidate treatment-related improvements in costs to society as a result of population-level improvements in disease outcomes for women diagnosed with eBC.[Table: see text]

scholarly journals Clinical benefit of treatment after trastuzumab emtansine for HER2-positive metastatic breast cancer: a real-world multi-centre cohort study in Japan (WJOG12519B)

Breast Cancer ◽  
2021 ◽  
Author(s):  
Takamichi Yokoe ◽  
Sasagu Kurozumi ◽  
Kazuki Nozawa ◽  
Yukinori Ozaki ◽  
Tetsuyo Maeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cohort Study ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Real World ◽  
Treatment Strategies ◽  
Metastatic Breast ◽  
Trastuzumab Emtansine ◽  
Breast Cancer Patients ◽  
Her2 Positive

Abstract Background Trastuzumab emtansine (T-DM1) treatment for human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer after taxane with trastuzumab and pertuzumab is standard therapy. However, treatment strategies beyond T-DM1 are still in development with insufficient evidence of their effectiveness. Here, we aimed to evaluate real-world treatment choice and efficacy of treatments after T-DM1 for HER2-positive metastatic breast cancer. Methods In this multi-centre retrospective cohort study involving 17 hospitals, 325 female HER2-positive metastatic breast cancer patients whose post-T-DM1 treatment began between April 15, 2014 and December 31, 2018 were enrolled. The primary end point was the objective response rate (ORR) of post-T-DM1 treatments. Secondary end points included disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS). Results The median number of prior treatments of post-T-DM1 treatment was four. The types of post-T-DM1 treatments included (1) chemotherapy in combination with trastuzumab and pertuzumab (n = 102; 31.4%), (2) chemotherapy concomitant with trastuzumab (n = 78; 24.0%), (3), lapatinib with capecitabine (n = 63; 19.4%), and (4) others (n = 82; 25.2%). ORR was 22.8% [95% confidence interval (CI): 18.1–28.0], DCR = 66.6% (95% CI 60.8–72.0), median PFS = 6.1 months (95% CI 5.3–6.7), median TTF = 5.1 months (95% CI 4.4–5.6), and median OS = 23.7 months (95% CI 20.7–27.4). Conclusion The benefits of treatments after T-DM1 are limited. Further investigation of new treatment strategies beyond T-DM1 is awaited for HER2-positive metastatic breast cancer patients.

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