Central neurotoxicity induced by trastuzumab emtansine (T-DM1)

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Georgios I. Papageorgiou ◽  
David G. Symeonidis ◽  
Sergios A. Tsakatikas ◽  
Alexandros D. Liatsos ◽  
Konstantinos A. A. Douglas ◽  
...  
Keyword(s):  
Trastuzumab Emtansine ◽  
Central Neurotoxicity

Non-Clinical Disposition and Metabolism of DM1, a Component of Trastuzumab Emtansine (T-DM1), in Sprague Dawley Rats

2015 ◽  
Vol 9 (2) ◽  
pp. 119-131 ◽  
Author(s):  
Ben-Quan Shen ◽  
Daniela Bumbaca ◽  
Qin Yue ◽  
Ola Saad ◽  
Jay Tibbitts ◽  
...  
Keyword(s):  
Trastuzumab Emtansine ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

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.

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.

Heregulin-induced cell migration is prevented by trastuzumab and trastuzumab-emtansine in HER2+ breast cancer

2021 ◽  
Author(s):  
Joselina Magali Mondaca ◽  
Ana Carla Castro Guijarro ◽  
Marina Inés Flamini ◽  
Angel Matias Sanchez
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Trastuzumab Emtansine ◽  
Her2 Breast Cancer

scholarly journals Real-world effectiveness of post-trastuzumab emtansine treatment in patients with HER2-positive, unresectable and/or metastatic breast cancer: a retrospective observational study (KBCSG-TR 1917)

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Takahiro Nakayama ◽  
Tetsuhiro Yoshinami ◽  
Hiroyuki Yasojima ◽  
Nobuyoshi Kittaka ◽  
Masato Takahashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Observational Study ◽  
Real World ◽  
Metastatic Breast ◽  
Trastuzumab Emtansine ◽  
Her2 Positive ◽  
The Real ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Abstract Background Trastuzumab emtansine (T-DM1) is a second-line standard therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Evidence regarding post–T-DM1 treatments is currently lacking. We evaluated the effectiveness of post–T-DM1 drug therapy in patients with HER2-positive, unresectable and/or metastatic breast cancer. Methods In this multicenter, retrospective, observational study, real-world clinical data of female patients with HER2-positive breast cancer who had a history of T-DM1 treatment were consecutively collected from five sites in Japan. We investigated the effectiveness of post–T-DM1 therapy by evaluating the real-world progression-free survival (rwPFS), time to treatment failure (TTF), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Tumor response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) guidelines. Subgroup and exploratory analyses according to background factors were also undertaken. Results Of the 205 patients who received T-DM1 treatment between 1 January 2014 and 31 December 2018, 128 were included in this study. Among the 128 patients analyzed, 105 (82%) patients received anti-HER2 therapy and 23 (18%) patients received regimens without anti-HER2 therapy. Median (95% confidence interval [CI]) rwPFS, TTF, and OS were 5.7 (4.8–6.9) months, 5.6 (4.6–6.4) months, and 22.8 (18.2–32.4) months, respectively. CBR and ORR (95% CI) were 48% (38.8–56.7) and 23% (15.1–31.4), respectively. Cox-regression analysis showed that an ECOG PS score of 0, a HER2 immunohistochemistry score of 3+, recurrent type, ≥12 month duration of T-DM1 therapy, and anti-HER2 therapy were independent variables for rwPFS. An exploratory subgroup analysis of regimens after T-DM1 showed that those with anti-HER2 therapy had a median rwPFS of 6.3 and those without anti-HER2 therapy had a median rwPFS of 4.8 months. Conclusions In the real-world setting in Japan, several post–T-DM1 regimens for patients with unresectable and/or metastatic HER2-positive breast cancer, including continuation of anti-HER2 therapy, showed some effectiveness; however, this effectiveness was insufficient. Novel therapeutic options are still needed for further improvement of PFS and OS in later treatment settings. Trial registration UMIN000038296; registered on 15 October 2019.

Sign in / Sign up

Export Citation Format

Share Document