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https://www.readbyqxmd.com/read/28733983/population-pharmacokinetics-and-exposure-response-of-trastuzumab-emtansine-in-advanced-breast-cancer-previously-treated-with-%C3%A2-2-her2-targeted-regimens
#1
Shang-Chiung Chen, Angelica Quartino, Daniel Polhamus, Matthew Riggs, Jonathan French, Xin Wang, Shweta Vadhavkar, Melanie Smitt, Silke Hoersch, Alexander Strasak, Jin Yan Jin, Sandhya Girish, Chunze Li
AIMS: We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1) to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs. treatment of physician's choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer. METHODS: We compared a historical T-DM1 PopPK model with T-DM1 pharmacokinetics in TH3RESA and performed exposure-response analyses using model-predicted cycle 1 Cmax , cycle 1 Cmin , and AUCss ...
July 21, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28705408/superior-in-vitro-and-in-vivo-activity-of-trastuzumab-emtansine-t-dm1-in-comparison-to-trastuzumab-pertuzumab-and-their-combination-in-epithelial-ovarian-carcinoma-with-high-her2-neu-expression
#2
Gulden Menderes, Elena Bonazzoli, Stefania Bellone, Gary Altwerger, Jonathan D Black, Katherine Dugan, Francesca Pettinella, Alice Masserdotti, Francesco Riccio, Anna Bianchi, Luca Zammataro, Christopher de Haydu, Natalia Buza, Pei Hui, Serena Wong, Gloria S Huang, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Peter E Schwartz, Alessandro D Santin
BACKGROUND: Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. The objective of this study was to compare the anti-tumor activity of HER2/neu-targeting monoclonal antibodies, trastuzumab (T), pertuzumab (P), combination of trastuzumab and pertuzumab (T+P) and trastuzumab-emtansine (T-DM1) in EOC with high HER2/neu expression. METHODS: Primary EOC cell lines were established and cell blocks were analyzed for HER2/neu expression. Cytostatic, apoptotic and antibody-dependent cell-mediated cytotoxicity (ADCC) activities of T, P, T+P and T-DM1 were evaluated in vitro...
July 10, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28687619/resistance-to-the-antibody-drug-conjugate-t-dm1-is-based-in-a-reduction-in-lysosomal-proteolytic-activity
#3
Carla Ríos-Luci, Sara García-Alonso, Elena Díaz-Rodríguez, Mercedes Nadal-Serrano, Joaquin Arribas, Alberto Ocaña, Atanasio Pandiella
Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved recently to treat HER2+ breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2+ clones exhibiting stable drug refractoriness in vitro and in vivo. Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1...
July 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/28682681/de-escalation-strategies-in-human-epidermal-growth-factor-receptor-2-her2-positive-early-breast-cancer-bc-final-analysis-of-the-west-german-study-group-adjuvant-dynamic-marker-adjusted-personalized-therapy-trial-optimizing-risk-assessment-and-therapy-response
#4
Nadia Harbeck, Oleg Gluz, Matthias Christgen, Ronald Ernest Kates, Michael Braun, Sherko Küemmel, Claudia Schumacher, Jochem Potenberg, Stefan Kraemer, Anke Kleine-Tebbe, Doris Augustin, Bahriye Aktas, Helmut Forstbauer, Joke Tio, Raquel von Schumann, Cornelia Liedtke, Eva-Maria Grischke, Johannes Schumacher, Rachel Wuerstlein, Hans Heinrich Kreipe, Ulrike Anneliese Nitz
Purpose Human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor (HR)-positive breast cancer is a distinct subgroup associated with lower chemotherapy sensitivity and slightly better outcome than HER2-positive/HR-negative disease. Little is known about the efficacy of the combination of endocrine therapy (ET) with trastuzumab or with the potent antibody-cytotoxic, anti-HER2 compound trastuzumab emtansine (T-DM1) with or without ET for this subgroup. The West German Study Group trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) compares pathologic complete response (pCR) rates of T-DM1 versus trastuzumab with ET in early HER2-positive/HR-positive breast cancer...
July 6, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28679774/syd985-a-novel-duocarmycin-based-her2-targeting-antibody-drug-conjugate-shows-antitumor-activity-in-uterine-and-ovarian-carcinosarcoma-with-her2-neu-expression
#5
Gulden Menderes, Elena Bonazzoli, Stefania Bellone, Jonathan D Black, Federica Predolini, Francesca Pettinella, Alice Masserdotti, Luca Zammataro, Gary Altwerger, Natalia Buza, Pei Hui, Serena Wong, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Peter E Schwartz, Alessandro D Santin
Purpose: Carcinosarcomas (CS) are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression. We compared the efficacy of SYD985, (Synthon Biopharmaceuticals BV), a novel HER2-targeting antibody-drug conjugate (ADC), to Trastuzumab emtansine (T-DM1, Genentech-Roche) against primary uterine and ovarian CS. <p>Experimental Design: Eight primary CS cell lines were evaluated for HER2/neu surface expression by IHC and gene amplification by FISH assays...
July 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28678590/skin-necrosis-after-ado-trastuzumab-emtansine-extravasation
#6
Maryam Nemati Shafaee, Ahmed A Salahudeen, Vicente Valero
No abstract text is available yet for this article.
July 5, 2017: Journal of Oncology Practice
https://www.readbyqxmd.com/read/28655784/inhibition-of-megakaryocyte-differentiation-by-antibody-drug-conjugates-adcs-is-mediated-by-macropinocytosis-implications-for-adc-induced-thrombocytopenia
#7
Hui Zhao, Sara Gulesserian, Sathish Kumar Ganesan, Jimmy Ou, Karen Morrison, Zhilan Zeng, Veronica Robles, Josh Snyder, Lisa Do, Hector Aviña, Sher Karki, David R Stover, Fernando Doñate
Thrombocytopenia is a common adverse event in cancer patients treated with antibody-drug conjugates (ADCs), including AGS-16C3F, an ADC targeting ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase-3) and Trastuzumab emtansine (T-DM1). This study aims to elucidate the mechanism of action of ADC-induced thrombocytopenia. ENPP3 expression in platelets and megakaryocytes (MKs) was investigated and shown to be negative. The direct effect of AGS-16C3F on platelets was evaluated using platelet rich plasma following the expression of platelet activation markers...
June 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28648785/lc-ms-bioanalysis-of-trastuzumab-and-released-emtansine-using-nano-surface-and-molecular-orientation-limited-nsmol-proteolysis-and-liquid-liquid-partition-in-plasma-of-trastuzumab-emtansine-treated-breast-cancer-patients
#8
Noriko Iwamoto, Akihiko Shimomura, Kenji Tamura, Akinobu Hamada, Takashi Shimada
Antibody-drug conjugates (ADCs) consist of monoclonal antibody and cytotoxic drugs covalently attached via stable crosslinkers, and are prospective antibody drugs for cancer therapy. To cover the overall pharmacokinetic understanding of ADCs, both the antibody and the released drugs are necessary for practical clinical observation. The nano-surface and molecular-orientation limited (nSMOL) proteolysis is a universal approach for antibody bioanalysis that enable Fab-selective proteolysis, which maintains antibody sequence specificity while decreasing excess analyte peptides...
June 19, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28646408/a-mechanism-based-pk-pd-model-for-hematological-toxicities-induced-by-antibody-drug-conjugates
#9
Sihem Ait-Oudhia, Weiyan Zhang, Donald E Mager
Antibody-drug conjugates (ADCs) are complex drug platforms composed of monoclonal antibodies (mAbs) conjugated to potent cytotoxic drugs (payloads) via chemical linkers, enabling selective payload delivery to neoplastic cells, resulting in improved efficacy and reduced toxicity. Brentuximab vedotin (Adcetris®, SGN-35) and adotrastuzumab emtansine (Kadcyla®, T-DM1) are the two FDA-approved and commercially available ADCs, and both drugs exhibit ADC-related thrombocytopenia and neutropenia. A pharmacokinetic/pharmacodynamic (PK/PD) model for ADCs was developed to identify the analyte from each ADC that is most associated with the observed hematopoietic toxicities and to determine the role of the apparent in vivo payload release rate on the severity of thrombocytopenia and neutropenia...
June 23, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28623237/nice-approves-trastuzumab-emtansine-after-deal-with-drug-company
#10
Zosia Kmietowicz
No abstract text is available yet for this article.
June 15, 2017: BMJ: British Medical Journal
https://www.readbyqxmd.com/read/28615520/a-retrospective-multicentric-observational-study-of-trastuzumab-emtansine-in-her2-positive-metastatic-breast-cancer-a-real-world-experience
#11
Patrizia Vici, Laura Pizzuti, Andrea Michelotti, Isabella Sperduti, Clara Natoli, Lucia Mentuccia, Luigi Di Lauro, Domenico Sergi, Paolo Marchetti, Daniele Santini, Emanuela Magnolfi, Laura Iezzi, Luca Moscetti, Agnese Fabbri, Alessandra Cassano, Antonino Grassadonia, Claudia Omarini, Federico Piacentini, Andrea Botticelli, Ilaria Bertolini, Angelo Fedele Scinto, Germano Zampa, Maria Mauri, Loretta D'Onofrio, Valentina Sini, Maddalena Barba, Marcello Maugeri-Saccà, Ernesto Rossi, Elisabetta Landucci, Silverio Tomao, Antonio Maria Alberti, Francesco Giotta, Corrado Ficorella, Vincenzo Adamo, Antonio Russo, Vito Lorusso, Katia Cannita, Sandro Barni, Lucio Laudadio, Filippo Greco, Ornella Garrone, Marina Della Giulia, Paolo Marolla, Giuseppe Sanguineti, Barbara Di Cocco, Gennaro Ciliberto, Ruggero De Maria, Teresa Gamucci
We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28554322/recent-advances-in-antibody-drug-conjugates-for-breast-cancer-treatment
#12
Shanshan Deng, Zongtao Lin, Wei Li
Breast cancer is the most common cancer in women, with roughly half a million deaths per year worldwide. Among various approaches for breast cancer treatment, chemotherapy is predominantly used for patients at stages II-IV, and monoclonal antibody (mAb) therapy is used for patients with human epidermal growth factor receptor 2 (HER2) overexpression. Integrating the tumor specificity provided by unique mAbs and cytotoxicity of small molecule drugs, antibody-drug conjugates (ADCs) are a series of smart chemotherapeutics that have recently shown great promise in treating a number of cancer types...
May 29, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28526538/trastuzumab-emtansine-versus-treatment-of-physician-s-choice-in-patients-with-previously-treated-her2-positive-metastatic-breast-cancer-th3resa-final-overall-survival-results-from-a-randomised-open-label-phase-3-trial
#13
Ian E Krop, Sung-Bae Kim, Antonio Gonzalez Martin, Patricia M LoRusso, Jean-Marc Ferrero, Tanja Badovinac-Crnjevic, Silke Hoersch, Melanie Smitt, Hans Wildiers
BACKGROUND: In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial. METHODS: Eligible patients for the TH3RESA trial were men and women (aged ≥18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting...
June 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28526537/trastuzumab-emtansine-in-her2-positive-metastatic-breast-cancer
#14
Filippo Montemurro
No abstract text is available yet for this article.
May 16, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28526536/trastuzumab-emtansine-versus-capecitabine-plus-lapatinib-in-patients-with-previously-treated-her2-positive-advanced-breast-cancer-emilia-a-descriptive-analysis-of-final-overall-survival-results-from-a-randomised-open-label-phase-3-trial
#15
Véronique Diéras, David Miles, Sunil Verma, Mark Pegram, Manfred Welslau, José Baselga, Ian E Krop, Kim Blackwell, Silke Hoersch, Jin Xu, Marjorie Green, Luca Gianni
BACKGROUND: The antibody-drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. METHODS: EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane...
June 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28526406/trastuzumab-emtansine-suppresses-the-growth-of-her2-positive-small-cell-lung-cancer-in-preclinical-models
#16
Osamu Morimura, Toshiyuki Minami, Takashi Kijima, Shohei Koyama, Tomoyuki Otsuka, Yuhei Kinehara, Akio Osa, Masayoshi Higashiguchi, Kotaro Miyake, Izumi Nagatomo, Haruhiko Hirata, Kota Iwahori, Takayuki Takimoto, Yoshito Takeda, Hiroshi Kida, Atsushi Kumanogoh
Overcoming chemoresistance is essential for achieving better prognoses in SCLC. Previously, we reported that HER2 is upregulated when HER2-positive SCLC cells acquire chemoresistance. HER2-upregulated cisplatin- or etoposide-resistant SCLC cells were sensitive to trastuzumab-mediated ADCC. However, irinotecan-resistant SCLC cells, such as SBC-3/SN-38, were refractory to trastuzumab despite high HER2 expression. To address this issue, we examined the antitumor efficacy of trastuzumab emtansine (T-DM1) on trastuzumab-resistant HER2-positive SCLC...
May 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28493046/trastuzumab-uptake-and-its-relation-to-efficacy-in-an-animal-model-of-her2-positive-breast-cancer-brain-metastasis
#17
Gail D Lewis Phillips, Merry C Nishimura, Jennifer Arca Lacap, Samir Kharbanda, Elaine Mai, Janet Tien, Kimberly Malesky, Simon P Williams, Jan Marik, Heidi S Phillips
PURPOSE: The extent to which efficacy of the HER2 antibody Trastuzumab in brain metastases is limited by access of antibody to brain lesions remains a question of significant clinical importance. We investigated the uptake and distribution of trastuzumab in brain and mammary fat pad grafts of HER2-positive breast cancer to evaluate the relationship of these parameters to the anti-tumor activity of trastuzumab and trastuzumab emtansine (T-DM1). METHODS: Mouse transgenic breast tumor cells expressing human HER2 (Fo2-1282 or Fo5) were used to establish intracranial and orthotopic tumors...
August 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28473206/syd985-a-novel-duocarmycin-based-her2-targeting-antibody-drug-conjugate-shows-promising-antitumor-activity-in-epithelial-ovarian-carcinoma-with-her2-neu-expression
#18
Gulden Menderes, Elena Bonazzoli, Stefania Bellone, Jonathan Black, Gary Altwerger, Alice Masserdotti, Francesca Pettinella, Luca Zammataro, Natalia Buza, Pei Hui, Serena Wong, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Gloria S Huang, Masoud Azodi, Peter E Schwartz, Alessandro D Santin
BACKGROUND: Epithelial ovarian cancer (EOC) is an aggressive and heterogeneous disease. <10% of EOC demonstrate HER2/neu 3+ receptor over-expression. However, moderate to low (i.e., 2+ and 1+) HER2/neu expression is reported in up to 50% of EOC. The objective of this study was to compare the anti-tumor activity of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1) in EOC models with differential HER2/neu expression. METHODS: The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1+, 2+, and 3+ HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments...
July 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28438884/safety-evaluation-of-trastuzumab-emtansine-in-japanese-patients-with-her2-positive-advanced-breast-cancer
#19
Junichiro Watanabe, Yoshinori Ito, Toshiaki Saeki, Norikazu Masuda, Toshimi Takano, Shintaro Takao, Kazuhiko Nakagami, Koichiro Tsugawa, Shintaro Nakagawa, Kazumitsu Kanatani, Takahiro Nakayama
BACKGROUND/AIM: Tolerability and safety of trastuzumab emtansine (T-DM1) was investigated in Japanese patients with HER2-positive advanced breast cancer who were previously treated with chemotherapy and trastuzumab. PATIENTS AND METHODS: Patients with inoperable or recurrent breast cancer who were previously treated with chemotherapy and trastuzumab in adjuvant and/or metastatic disease were included. T-DM1 3.6 mg/kg was administered intravenously every 21 days...
May 2017: In Vivo
https://www.readbyqxmd.com/read/28415567/efficacy-and-safety-of-t-dm1-in-the-common-practice-of-her2-advanced-breast-cancer-setting-a-multicenter-study
#20
Alessandra Fabi, Michelino De Laurentiis, Michele Caruso, Enrichetta Valle, Luca Moscetti, Daniele Santini, Katia Cannita, Luisa Carbognin, Mariangela Ciccarese, Rosalba Rossello, Grazia Arpino, Vita Leonardi, Filippo Montemurro, Nicla La Verde, Daniele Generali, Alberto Zambelli, Giuseppa Scandurra, Michelangelo Russillo, Ida Paris, Anna Maria D'Ottavio, Gianfranco Filippelli, Marianna Giampaglia, Simonetta Stani, Agnese Fabbri, Daniele Alesini, Daniela Cianniello, Diana Giannarelli, Francesco Cognetti
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (mBC). The aim of this 'field-practice' study was to investigate the efficacy and safety of T-DM1, focusing on treatment line, previous lapatinib treatment and patterns of metastasis. Three hundred and three patients with HER2-positive mBC who received T-DM1 were identified by reviewing the medical records of 24 Italian Institutions...
March 18, 2017: Oncotarget
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