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https://www.readbyqxmd.com/read/29156892/trastuzumab-emtansine-in-her2-positive-metastatic-breast-cancer-what-is-the-best-sequence
#1
EDITORIAL
Francesco Ricci, Christophe Le Tourneau
No abstract text is available yet for this article.
November 6, 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/29116596/antibody-drug-conjugates-for-the-treatment-of-solid-tumors-clinical-experience-and-latest-developments
#2
Aiko Nagayama, Leif W Ellisen, Bruce Chabner, Aditya Bardia
Antibody-drug conjugates (ADCs) are complex immunoconjugates designed to selectively deliver toxic small molecules preferentially to cancer cells. These immunoconjugates consist of a monoclonal antibody - directed to a tumor antigen - and a cytotoxic agent that is conjugated to the antibody via a molecular linker. Following the binding to a specific antigen on the surface of cancer cells, the conjugate is internalized and releases its cytotoxic payload to kill the malignant cell. ADCs that have gained regulatory approval from the US Food and Drug Administration (FDA) include brentuximab vedotin for CD30-positive Hodgkin's lymphoma and trastuzumab emtansine for human epidermal growth factor receptor 2 (HER2)-positive breast cancer...
November 8, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/29069935/trastuzumab-modified-dm1-loaded-nanoparticles-for-her2-breast-cancer-treatment-an-in-vitro-and-in-vivo-study
#3
Ling Rong, Shuping Zhou, Xinkuang Liu, Amin Li, Tao Jing, Xueke Liu, Yinci Zhang, Shiyu Cai, Xiaolong Tang
BACKGROUND: Emtansine (DM1) is a highly potent anti-microtubule agent that has shown promising results for breast cancer treatment, but side effects limit its widespread clinical use. In this research, a new nano-drug was developed to integrate DM1 agent with antibody targeting. METHODS: A system of novel nanoparticles (NPs) DM1-NPs-trastuzumab (DM1-NPs-Tmab) of DM1 combined with (anti-HER2 antibody, Herceptin®, Trastuzumab) was developed for HER2(+) breast cancer treatment, and its physical characterization and antitumor biological activity were investigated...
October 25, 2017: Artificial Cells, Nanomedicine, and Biotechnology
https://www.readbyqxmd.com/read/29054985/caveolae-mediated-endocytosis-as-a-novel-mechanism-of-resistance-to-trastuzumab-emtansine-t-dm1
#4
Matthew Sung, Xingzhi Tan, Bingwen Lu, Jonathan Golas, Christine Hosselet, Fang Wang, Laurie Tylaska, Lindsay King, Dahui Zhou, Russell Dushin, Jeremy S Myers, Edward Rosfjord, Judy Lucas, Hans-Peter Gerber, Frank Loganzo
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2+ metastatic breast cancer, however its clinical activity is limited by inherent or acquired drug resistance. The molecular mechanisms that drive clinical resistance to T-DM1, especially in HER2+ tumors, are not well understood. We used HER2+ cell lines to develop models of T-DM1 resistance utilizing a cyclical dosing schema in which cells received T-DM1 in an "on-off" routine until a T-DM1 resistant population was generated...
October 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29043411/population-pharmacokinetics-of-trastuzumab-emtansine-in-previously-treated-patients-with-her2-positive-advanced-gastric-cancer-agc
#5
Shang-Chiung Chen, Matts Kagedal, Yuying Gao, Bei Wang, Marie-Laurence Harle-Yge, Sandhya Girish, Jin Jin, Chunze Li
PURPOSE: Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab conjugated via a stable thioether linker to DM1, a highly potent cytotoxic agent. A population pharmacokinetics (PK) analysis was performed to characterize T-DM1 PK and evaluate the impact of patient characteristics on T-DM1 PK in previously treated patients with HER2-positive advanced gastric cancer (AGC). METHODS: Following T-DM1 weekly or every three weeks dosing, T-DM1 concentration measurements (n = 780) were collected from 136 patients in the GATSBY (NCT01641939) study and analyzed using nonlinear mixed effects modeling...
October 17, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29022084/exposure-response-analyses-of-trastuzumab-emtansine-in-patients-with-her2-positive-advanced-breast-cancer-previously-treated-with-trastuzumab-and-a-taxane
#6
Chunze Li, Bei Wang, Shang-Chiung Chen, Russell Wada, Dan Lu, Xin Wang, Daniel Polhamus, Jonathan French, Shweta Vadhavkar, Alexander Strasak, Melanie Smitt, Amita Joshi, Meghna Samant, Angelica Quartino, Jin Jin, Sandhya Girish
PURPOSE: In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-free survival (PFS) and overall survival (OS) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer. Using EMILIA data, we evaluated the T-DM1 exposure-response relationship. METHODS: Exposure-response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration (C min) and area under the concentration-time curve from time zero to day 21 of T-DM1 at cycle 1] and multiple efficacy (OS, PFS, objective response rate) and safety (grade ≥ 3 adverse events, grade ≥ 3 thrombocytopenia, grade ≥ 3 hepatotoxicity) endpoints...
October 11, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28974266/endophilin-a2-promotes-her2-internalization-and-sensitivity-to-trastuzumab-based-therapy-in-her2-positive-breast-cancers
#7
Tomas Baldassarre, Peter Truesdell, Andrew W Craig
BACKGROUND: Human epidermal growth factor receptor-2 (HER2) is amplified and a clinical target in a subset of human breast cancers with high rates of metastasis. Targeted therapies involving the antibody trastuzumab and trastuzumab-emtansine (T-DM1) have greatly improved outcomes for HER2-positive (HER2+) breast cancer patients. However, resistance to these targeted therapies can develop and limit their efficacy. Here, we test the involvement of the endocytic adaptor protein endophilin A2 (Endo II) in HER2+ breast cancer models, and their responses to treatments with trastuzumab and T-DM1...
October 3, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28969087/efficacy-and-safety-of-t-dm1-in-the-common-practice-of-her2-advanced-breast-cancer-setting-a-multicenter-study
#8
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...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28944112/excellent-response-with-ado-trastuzumab-emtansine-in-a-patient-with-relapsed-metastatic-breast-cancer-presenting-with-pulmonary-lymphangitic-carcinomatosis
#9
Zhou Yu, Shobana Sankar, Marianne Huben
In breast cancer, aggressive tumor biology and the corresponding poor prognosis is associated with amplification or overexpression of the human epidermal growth factor receptor 2 (HER2). Trastuzumab has significantly changed the natural history of HER2-positive breast cancer. However, resistance to trastuzumab remains a substantial clinical problem. Ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate, has demonstrated impressive results in second- or later-line treatment of HER2-positive breast cancer...
July 14, 2017: Curēus
https://www.readbyqxmd.com/read/28923217/current-challenges-in-the-management-of-breast-cancer-brain-metastases
#10
REVIEW
Ciara C O'Sullivan, Nicole N Davarpanah, Jame Abraham, Susan E Bates
Approximately 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer and triple-negative breast cancer (TNBC) ultimately develop breast cancer brain metastases (BCBM), which are associated with significant morbidity and mortality. The advent of HER2-directed therapy resulted in greatly improved survival outcomes, but unfortunately at the price of an increased cumulative incidence of BCBM. We review challenges in the management of BCBM, and potential treatment strategies, including novel agents such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors (olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287)...
April 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/28915642/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...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28877045/advances-in-the-treatment-of-gastric-cancer
#12
David H Ilson
PURPOSE OF REVIEW: To review recent studies in esophagogastric cancer. RECENT FINDINGS: Positive emission tomography (PET) scan in follow-up after curative treatment of esophagogastric cancer did not lead to improved survival. In the preoperative treatment of esophagogastric cancer, the addition of the antivascular endothelial growth factor agent bevacizumab to perioperative chemotherapy with combination epirubicin, cisplatinum, and 5-fluorouracil (5-FU; ECF) failed to improve survival compared with chemotherapy alone...
November 2017: Current Opinion in Gastroenterology
https://www.readbyqxmd.com/read/28833867/development-and-responses-of-brain-metastases-during-treatment-with-trastuzumab-emtansine-t-dm1-for-her2-positive-advanced-breast-cancer-a-single-institution-experience
#13
Alicia Okines, Tazia Irfan, Komel Khabra, Ian Smith, Mary O'Brien, Marina Parton, Jill Noble, Susie Stanway, Navita Somaiah, Alistair Ring, Stephen Johnston, Nicholas Turner
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that does not cross an intact blood-brain barrier. In the EMILIA trial of T-DM1 vs capecitabine/lapatinib for HER2 positive advanced breast cancer, all patients had baseline brain imaging, and 9/450 (2%) of patients with negative baseline imaging developed new brain disease during T-DM1. We assessed the frequency of brain progression in clinical practice, without routine baseline imaging. We undertook a retrospective study of all patients treated with T-DM1 at the Royal Marsden Hospital from 2011 to 2016...
August 22, 2017: Breast Journal
https://www.readbyqxmd.com/read/28821558/defective-cyclin-b1-induction-in-trastuzumab-emtansine-t-dm1-acquired-resistance-in-her2-positive-breast-cancer
#14
MohammadA Sabbaghi, Gabriel Gil-Gómez, Cristina Guardia, Sonia Servitja, Oriol Arpí, Sara García-Alonso, Silvia Menendez, Montserrat Arumi-Uria, Laia Serrano, Marta Salido, Aura Muntasell, Maria Martínez-García, Sandra Zazo, Cristina Chamizo, Paula González-Alonso, Juan Madoz-Gúrpide, Pilar Eroles, Joaquin Arribas, Ignasi Tusquets, Ana Lluch, Atanasio Pandiella, Federico Rojo, Ana Rovira, Joan Albanell
Purpose: Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance.Experimental Design: HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3, and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions...
August 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28818506/development-and-evaluation-of-%C3%AE-galactosidase-sensitive-antibody-drug-conjugates
#15
Sergii Kolodych, Chloé Michel, Sébastien Delacroix, Oleksandr Koniev, Anthony Ehkirch, Jitka Eberova, Sarah Cianférani, Brigitte Renoux, Wojciech Krezel, Pauline Poinot, Christian D Muller, Sébastien Papot, Alain Wagner
The selective destruction of tumour cells while sparing healthy tissues is one of the main challenges in cancer therapy. Antibody-drug conjugates (ADCs) are arguably the most rapidly expanding class of targeted cancer therapies. Efficient drug conjugation and release technologies are essential for the development of these new therapeutic agents. In response to the ever-increasing demand for efficient drug release systems, we have developed a new class of β-galactosidase-cleavable linkers for ADCs. Within this framework, novel payloads comprising a galactoside linker, the monomethyl auristatin E (MMAE) and cysteine-reactive groups were synthesized, conjugated with trastuzumab and evaluated both in vitro and in vivo...
August 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28764748/a-phase-i-trial-of-ganetespib-in-combination-with-paclitaxel-and-trastuzumab-in-patients-with-human-epidermal-growth-factor-receptor-2-her2-positive-metastatic-breast-cancer
#16
Komal Jhaveri, Rui Wang, Eleonora Teplinsky, Sarat Chandarlapaty, David Solit, Karen Cadoo, James Speyer, Gabriella D'Andrea, Sylvia Adams, Sujata Patil, Sofia Haque, Tara O'Neill, Kent Friedman, Francisco J Esteva, Clifford Hudis, Shanu Modi
BACKGROUND: Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer...
August 2, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28757155/antibody-drug-conjugates-for-treatment-of-breast-cancer-novel-targets-and-diverse-approaches-in-adc-design
#17
REVIEW
Pamela A Trail, Gene M Dubowchik, Timothy B Lowinger
Breast cancer is a heterogeneous group of malignancies with a spectrum of molecular subtypes, pathologies and outcomes that together comprise the most common non-cutaneous cancer in women. Currently, over 80% of breast cancer patients are diagnosed at relatively early stages of disease where there are encouraging data on outcomes and long term survival. However, there is currently no curative option for those patients with metastatic disease and there is a substantial medical need to identify effective and safe treatment options for these patients...
July 27, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28753442/the-antitumor-activity-of-imgn529-a-cd37-targeting-antibody-drug-conjugate-is-potentiated-by-rituximab-in-non-hodgkin-lymphoma-models
#18
Stuart W Hicks, Katharine C Lai, L Cristina Gavrilescu, Yong Yi, Surina Sikka, Prerak Shah, Meghan E Kelly, Jenny Lee, Leanne Lanieri, Jose F Ponte, Callum M Sloss, Angela Romanelli
Naratuximab emtansine (IMGN529) is an investigational antibody-drug conjugate consisting of a CD37-targeting antibody conjugated to the maytansine-derived microtuble disruptor, DM1. IMGN529 has shown promising preclinical and clinical activity in non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Due to the aggressive nature of the disease, DLBCL is often treated with combination therapies to maximize clinical outcomes; therefore, we investigated the potential of combining IMGN529 with both standard-of-care and emerging therapies against multiple oncology-relevant targets and pathways...
July 25, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28741467/status-quo-in-antibody-drug-conjugates-can-glyco-enzymes-solve-the-current-challenges
#19
Florentina Kubizek, Britta Eggenreich, Oliver Spadiut
Over the last years, a novel class of anti-cancer drugs named antibody-drug conjugates (ADCs) has been developed. Due to their limited off-target toxicity but highly potent cytotoxicity at tumor sites, ADCs have proven to be a good alternative to ordinary cancer treatment, such as chemotherapy or combination therapy. Numerous enhancements in antibody-drug engineering led to highly potent tumor targeting drugs with a wide therapeutic window. Two ADCs (Brentuximab vedotin and Trastuzumab emtansine) are already on the market and many others in clinical trials...
July 24, 2017: Protein and Peptide Letters
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
#20
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 [A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With human epidermal growth factor receptor 2 (HER2)-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy] study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs...
July 21, 2017: British Journal of Clinical Pharmacology
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