Expanding Frontiers, Transforming Cancer Treatment
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Response to Trastuzumab, Erlotinib, and Bevacizumab, Alone and In
2664 Response to trastuzumab, erlotinib, and bevacizumab, alone and in combination, is correlated with the level of human epidermal growth factor receptor-2 expression in human breast cancer cell lines David R. Emlet, Kathryn A. Brown, not increase apoptosis substantially. These studies sug- Deborah L. Kociban, Agnese A. Pollice, gest that the effects of two and three-drug combinations Charles A. Smith, Ben Brian L. Ong, of trastuzumab, erlotinib, and bevacizumab might offer and Stanley E. Shackney potential therapeutic advantages in HER2-overexpressing breast cancers, although these effects are of low Laboratory of Cancer Cell Biology and Genetics, Department of magnitude, and are likely to be transient. [Mol Cancer Human Oncology, Drexel University College of Medicine and the Ther 2007;6(10):2664–74] Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh, Pennsylvania Introduction Human epidermal growth factor receptor-2 (HER2), a Abstract member of the epidermal growth factor receptor (EGFR) Human epidermal growth factor receptor-2 (HER2) and family of tyrosine kinases, is overexpressed in 25% to 30% epidermal growth factor receptor (EGFR) heterodimerize to of human breast cancers (1). It has been implicated in activate mitogenic signaling pathways. We have shown cancer progression (2, 3), and has been identified as a previously, using MCF7 subcloned cell lines with graded prognostic and predictive marker for breast cancer out- levels of HER2 expression, that responsiveness to trastu- come (4). Clinically, chemotherapeutic -
Press Release
Press Release Daiichi Sankyo and AstraZeneca Announce Global Development and Commercialization Collaboration for Daiichi Sankyo’s HER2 Targeting Antibody Drug Conjugate [Fam-] Trastuzumab Deruxtecan (DS-8201) Collaboration combines Daiichi Sankyo’s scientific and technological excellence with AstraZeneca’s global experience and resources in oncology to accelerate and expand the potential of [fam-] trastuzumab deruxtecan as monotherapy and combination therapy across a spectrum of HER2 expressing cancers AstraZeneca to pay Daiichi Sankyo up to $6.90 billion in total consideration, including $1.35 billion upfront payment and up to an additional $5.55 billion contingent upon achievement of future regulatory and sales milestones as well as other contingencies Companies to share equally development and commercialization costs as well as profits worldwide from [fam-] trastuzumab deruxtecan with Daiichi Sankyo maintaining exclusive rights in Japan Daiichi Sankyo is expected to book sales in U.S., certain countries in Europe, and certain other markets where Daiichi Sankyo has affiliates; AstraZeneca is expected to book sales in all other markets worldwide, including China, Australia, Canada and Russia Tokyo, Munich and Basking Ridge, NJ – (March 28, 2019) – Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced today that it has entered into a global development and commercialization agreement with AstraZeneca for Daiichi Sankyo’s lead antibody drug conjugate (ADC), [fam-] trastuzumab deruxtecan (DS-8201), currently in pivotal development for multiple HER2 expressing cancers including breast and gastric cancer, and additional development in non-small cell lung and colorectal cancer. Daiichi Sankyo and AstraZeneca will jointly develop and commercialize [fam-] trastuzumab deruxtecan as a monotherapy or a combination therapy worldwide, except in Japan where Daiichi Sankyo will maintain exclusive rights. -
TARCEVA for Severe Renal These Highlights Do Not Include All the Information Needed to Use Toxicity
HIGHLIGHTS OF PRESCRIBING INFORMATION patients at risk of dehydration. Withhold TARCEVA for severe renal These highlights do not include all the information needed to use toxicity. (5.2) TARCEVA® safely and effectively. See full prescribing information for • Hepatotoxicity: Occurs with or without hepatic impairment, including TARCEVA. hepatic failure and hepatorenal syndrome: Monitor periodic liver testing. Withhold or discontinue TARCEVA for severe or worsening liver tests. (5.3) TARCEVA (erlotinib) tablets, for oral use • Gastrointestinal perforations: Discontinue TARCEVA. (5.4) Initial U.S. Approval: 2004 • Bullous and exfoliative skin disorders: Discontinue TARCEVA. (5.5) • ---------------------------RECENT MAJOR CHANGES-------------------------- Cerebrovascular accident (CVA): The risk of CVA is increased in patients with pancreatic cancer. (5.6) Indications and Usage, Non-Small Cell Lung Cancer (NSCLC) (1.1) 10/2016 • Microangiopathic hemolytic anemia (MAHA): The risk of MAHA is Dosage and Administration (2.1) 06/2016 increased in patients with pancreatic cancer. (5.7) Dosage and Administration, Dose Modifications (2.4) 05/2016 • Ocular disorders: Discontinue TARCEVA for corneal perforation, Warnings and Precautions, Cerebrovascular Accident (5.6) 10/2016 ulceration or persistent severe keratitis. (5.8) Warnings and Precautions, Embryo-fetal Toxicity (5.10) 10/2016 • Hemorrhage in patients taking warfarin: Regularly monitor INR in patients taking warfarin or other coumarin-derivative anticoagulants. (5.9) ---------------------------INDICATIONS -
07052020 MR ASCO20 Curtain Raiser
Media Release New data at the ASCO20 Virtual Scientific Program reflects Roche’s commitment to accelerating progress in cancer care First clinical data from tiragolumab, Roche’s novel anti-TIGIT cancer immunotherapy, in combination with Tecentriq® (atezolizumab) in patients with PD-L1-positive metastatic non- small cell lung cancer (NSCLC) Updated overall survival data for Alecensa® (alectinib), in people living with anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC Key highlights to be shared on Roche’s ASCO virtual newsroom, 29 May 2020, 08:00 CEST Basel, 7 May 2020 - Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that new data from clinical trials of 19 approved and investigational medicines across 21 cancer types, will be presented at the ASCO20 Virtual Scientific Program organised by the American Society of Clinical Oncology (ASCO), which will be held 29-31 May, 2020. A total of 120 abstracts that include a Roche medicine will be presented at this year's meeting. "At ASCO, we will present new data from many investigational and approved medicines across our broad oncology portfolio," said Levi Garraway, M.D., Ph.D., Roche's Chief Medical Officer and Head of Global Product Development. “These efforts exemplify our long-standing commitment to improving outcomes for people with cancer, even during these unprecedented times. By integrating our medicines and diagnostics together with advanced insights and novel platforms, Roche is uniquely positioned to deliver the healthcare solutions of the future." Together with its partners, Roche is pioneering a comprehensive approach to cancer care, combining new diagnostics and treatments with innovative, integrated data and access solutions for approved medicines that will both personalise and transform the outcomes of people affected by this deadly disease. -
Bevacizumab) Injection, for Intravenous Use Persistent, Recurrent, Or Metastatic Cervical Cancer (2.6) Initial U.S
HIGHLIGHTS OF PRESCRIBING INFORMATION First-Line Nonsquamous nonsmall cell lung cancer (2.3) These highlights do not include all the information needed to use • 15 mg/kg every 3 weeks with carboplatin and paclitaxel AVASTIN safely and effectively. See full prescribing information for Recurrent glioblastoma (2.4) AVASTIN. • 10 mg/kg every 2 weeks Metastatic renal cell cancer (2.5) • 10 mg/kg every 2 weeks with interferon alfa AVASTIN (bevacizumab) injection, for intravenous use Persistent, recurrent, or metastatic cervical cancer (2.6) Initial U.S. Approval: 2004 • 15 mg/kg every 3 weeks with paclitaxel and cisplatin, or paclitaxel and topotecan WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE peritoneal cancer (2.7) See full prescribing information for complete boxed warning. • 10 mg/kg every 2 weeks with paclitaxel, pegylated liposomal doxorubicin, Gastrointestinal Perforations: Discontinue for gastrointestinal or topotecan given every week perforation. (5.1) • 15 mg/kg every 3 weeks with topotecan given every 3 weeks Surgery and Wound Healing Complications: Discontinue in Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary patients who develop wound healing complications that require peritoneal cancer (2.7) medical intervention. Withhold for at least 28 days prior to • 15 mg/kg every 3 weeks with carboplatin and paclitaxel for 6-8 cycles, elective surgery. Do not administer Avastin for at least 28 days followed by 15 mg/kg every 3 weeks as a single agent after surgery and until the wound is fully healed. (5.2) • 15 mg/kg every 3 weeks with carboplatin and gemcitabine for 6-10 cycles, Hemorrhage: Severe or fatal hemorrhages have occurred. -
Partial Response to Erlotinib in a Patient with Imatinib-Refractory
Verma et al. Clin Sarcoma Res (2020) 10:28 https://doi.org/10.1186/s13569-020-00149-1 Clinical Sarcoma Research CASE REPORT Open Access Partial response to erlotinib in a patient with imatinib-refractory sacral chordoma Saurav Verma1, Surya Prakash Vadlamani1, Shamim Ahmed Shamim2, Adarsh Barwad3, Sameer Rastogi4* and S. T. Arun Raj2 Abstract Background: Chordoma is a rare, slow growing and locally aggressive mesenchymal neoplasm with uncommon distant metastases. It is a chemo-resistant disease with surgery and radiotherapy being the mainstay in treatment of localized disease. In advanced disease imatinib has a role. We report a case of metastatic sacral chordoma with symp- tomatic and radiological response to erlotinib post-progression on imatinib. Case presentation: A 48-year-old male with a sacral chordoma underwent partial sacrectomy followed by post- operative radiotherapy. Upon recurrence he received palliative radiotherapy to hemipelvis and was ofered therapy with imatinib. However, the disease was refractory to imatinib and he was started on treatment with erlotinib—show- ing a partial response on imaging at two months. He is currently doing well at 13 months since start of erlotinib. Conclusions: As seen in previously reported cases, erlotinib is a therapeutic option in advanced chordoma, even in imatinib refractory cases and thus warrants exploration of its therapeutic role in prospective clinical trials. Keywords: Chordoma, EGFR, Erlotinib Background adjuvant setting after a full or subtotal resection, and as Chordoma is a rare mesenchymal neoplasm which arises the primary treatment in unresectable disease. from the remnants of primitive notochord [1]. It accounts Chordoma responds poorly to cytotoxic chemotherapy. -
Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities
REVIEW www.jasn.org Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities Chelsea C. Estrada,1 Alejandro Maldonado,1 and Sandeep K. Mallipattu1,2 1Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York; and 2Renal Section, Northport Veterans Affairs Medical Center, Northport, New York ABSTRACT Inhibition of vascular endothelial growth factor A (VEGFA)/vascular endothelial with hypertension and proteinuria. Re- growth factor receptor 2 (VEGFR2) signaling is a common therapeutic strategy in ports describe histologic changes in the oncology, with new drugs continuously in development. In this review, we consider kidney primarily as glomerular endothe- the experimental and clinical evidence behind the diverse nephrotoxicities associ- lial injury with thrombotic microangiop- ated with the inhibition of this pathway. We also review the renal effects of VEGF athy (TMA).8 Nephrotic syndrome has inhibition’s mediation of key downstream signaling pathways, specifically MAPK/ also been observed,9 with the clinical ERK1/2, endothelial nitric oxide synthase, and mammalian target of rapamycin manifestations varying according to (mTOR). Direct VEGFA inhibition via antibody binding or VEGF trap (a soluble decoy mechanism and direct target of VEGF receptor) is associated with renal-specific thrombotic microangiopathy (TMA). Re- inhibition. ports also indicate that tyrosine kinase inhibition of the VEGF receptors is prefer- Current VEGF inhibitors can be clas- entially associated with glomerulopathies such as minimal change disease and FSGS. sifiedbytheirtargetofactioninthe Inhibition of the downstream pathway RAF/MAPK/ERK has largely been associated VEGFA-VEGFR2 pathway: drugs that with tubulointerstitial injury. Inhibition of mTOR is most commonly associated with bind to VEGFA, sequester VEGFA, in- albuminuria and podocyte injury, but has also been linked to renal-specificTMA.In hibit receptor tyrosine kinases (RTKs), all, we review the experimentally validated mechanisms by which VEGFA-VEGFR2 or inhibit downstream pathways. -
Cardiotoxicity Associated with Targeted Cancer Therapies (Review)
MOLECULAR AND CLINICAL ONCOLOGY 4: 675-681, 2016 Cardiotoxicity associated with targeted cancer therapies (Review) ZI CHEN1,2 and DI AI3 1Department of Hematology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China; 2Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; 3Department of Pathology, Baylor Scott and White Memorial Hospital, Texas A&M Health Science Center, Temple, TX 76508, USA Received July 28, 2015; Accepted January 25, 2016 DOI: 10.3892/mco.2016.800 Abstract. Compared with traditional chemotherapy, targeted eliminate rapidly dividing cells, including not only tumor cancer therapy is a novel strategy in which key molecules cells, but also normal tissue cells, such as those in digestive in signaling pathways involved in carcinogenesis and tumor endothelia, hair follicles and bone marrow. This non‑specific spread are inhibited. Targeted cancer therapy has fewer targeting treatment is associated with a broad range of side adverse effects on normal cells and is considered to be the effects, including gastrointestinal (GI) symptoms, alopecia and future of chemotherapy. However, targeted cancer ther- even lethal adverse effects, such as bone marrow suppression. apy-induced cardiovascular toxicities are occasionally critical These negative effects significantly limit the applications issues in patients who receive novel anticancer agents, such of traditional agents and unnecessarily compromise the as trastuzumab, bevacizumab, sunitinib and imatinib. The quality of life of cancer patients. In targeted cancer therapy, aim of this review was to discuss these most commonly used drugs interfere with key signaling molecules and inhibit drugs and associated incidence of cardiotoxicities, including tumorigenesis and metastasis, with fewer associated adverse left ventricular dysfunction, heart failure, hypertension and effects (2). -
Bevacizumab (Avastin) in Combination with Trastuzumab and Docetaxel for Metastatic HER2 Positive Breast Cancer – First Line
Bevacizumab (Avastin) in combination with trastuzumab and docetaxel for metastatic HER2 positive breast cancer – first line August 2010 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research August 2010 Bevacizumab (Avastin) in combination with trastuzumab and docetaxel for metastatic HER2 positive breast cancer – first line Target group • Breast cancer: metastatic; HER2 positive – first line; in combination with trastuzumab and docetaxel. Technology description Bevacizumab (Avastin; anti-VEGF monoclonal antibody; R 435; RG435; rhuMAb- VEGF) is a humanised anti-vascular endothelial growth factor (VEGF) monoclonal antibody that inhibits VEGF induced signalling and VEGF driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. The combination of bevacizumab, trastuzumab (HER2 inhibitor) and docetaxel (mitosis inhibitor), is intended to be used for the treatment of breast cancer with over expression of human epidermal growth factor receptor 2 (HER2). Bevacizumab is administered by IV infusion at 15mg/kg every 3 weeks in combination with trastuzumab (8mg/kg loading dose, thereafter 6mg/kg every 3 weeks) and docetaxel (100mg/m2 every 3 weeks) until disease progression. Bevacizumab is currently licensed for: • Metastatic breast cancer: first line treatment in combination with paclitaxel or docetaxel. • Metastatic colorectal cancer: in combination with fluoropyrimidine based chemotherapy. • Advanced non-small cell lung cancer (NSCLC): first line treatment in combination with platinum based therapy. -
Genomic Aberrations Associated with Erlotinib Resistance in Non-Small Cell Lung Cancer Cells
ANTICANCER RESEARCH 33: 5223-5234 (2013) Genomic Aberrations Associated with Erlotinib Resistance in Non-small Cell Lung Cancer Cells MASAKUNI SERIZAWA1, TOSHIAKI TAKAHASHI2, NOBUYUKI YAMAMOTO2,3 and YASUHIRO KOH1 1Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, Japan; 2Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka, Japan; 3Third Department of Internal Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan Abstract. Background/Aim: Mechanisms of resistance to mutations develop resistance, usually within one year of epidermal growth factor receptor (EGFR)-tyrosine kinase treatment. Therefore, there is an urgent need to elucidate the inhibitors (TKIs) in non-small cell lung cancer (NSCLC) underlying mechanisms of resistance in such tumors to are not fully-understood. In this study we aimed to overcome this obstacle (11-14, 17, 24). Recent studies elucidate remaining unknown mechanisms using erlotinib- suggest that mechanisms of acquired resistance to EGFR- resistant NSCLC cells. Materials and Methods: We TKIs can be categorized into three groups: occurrence of performed array comparative genomic hybridization genetic alterations, activation of downstream pathways via (aCGH) to identify genomic aberrations associated with bypass signaling, and phenotypic transformation (15, 16, 21); EGFR-TKI resistance in erlotinib-resistant PC-9ER cells. therapeutic strategies to overcome these resistance Real-time polymerase chain reaction (PCR) and mechanisms are under development. However, although the immunoblot analyses were performed to confirm the results causes of acquired resistance to EGFR-TKIs have been of aCGH. Results: Among the five regions with copy investigated, in more than 30% of patients with acquired number gain detected in PC-9ER cells, we focused on resistance to EGFR-TKI treatment, the mechanisms remain 22q11.2-q12.1 including v-crk avian sarcoma virus CT10 unknown (15). -
Monovalent Antibody Design and Mechanism of Action of Onartuzumab, a MET Antagonist with Anti-Tumor Activity As a Therapeutic Ag
Monovalent antibody design and mechanism of PNAS PLUS action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent Mark Merchanta,1,2, Xiaolei Mab,2,3, Henry R. Maunc,2, Zhong Zhenga,2,4, Jing Penga, Mally Romeroa,5, Arthur Huangd,6, Nai-ying Yanga, Merry Nishimuraa, Joan Grevee, Lydia Santellc, Yu-Wen Zhangf, Yanli Suf, Dafna W. Kaufmanf, Karen L. Billecig, Elaine Maih, Barbara Moffatg,7, Amy Limi, Eileen T. Duenasi, Heidi S. Phillipsa, Hong Xiangj, Judy C. Youngh, George F. Vande Woudef, Mark S. Dennisd, Dorothea E. Reillyk, Ralph H. Schwalla,8, Melissa A. Starovasnikb, Robert A. Lazarusc, and Daniel G. Yansurad Departments of aTranslational Oncology, bStructural Biology, cEarly d e Discovery Biochemistry, Antibody Engineering, Biomedical Imaging, fi gProtein Chemistry, hBiochemical and Cellular Pharmacology, iPurification Signi cance Development, jPharmacokinetic and Pharmacodynamic Sciences, and kEarly Stage Cell Culture, Genentech, Inc., South San Francisco, CA 94080; and Therapeutic antibodies have revolutionized the treatment of hu- fLaboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503 man disease. Despite these advances, antibody bivalency limits their utility against some targets. Here, we describe the de- Edited by Richard A. Lerner, The Scripps Research Institute, La Jolla, CA, and velopment of a one-armed (monovalent) antibody, onartuzumab, approved June 3, 2013 (received for review February 15, 2013) targeting the receptor tyrosine kinase MET. While initial screening Binding of hepatocyte growth factor (HGF) to the receptor tyrosine of bivalent antibodies produced agonists of MET, engineering kinase MET is implicated in the malignant process of multiple can- them into monovalent antibodies produced antagonists instead. -
Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy
Published OnlineFirst October 4, 2013; DOI: 10.1158/1078-0432.CCR-13-0358 Clinical Cancer Cancer Therapy: Clinical Research See related article by Gwin and Spector, p. 278 Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy Gail D. Lewis Phillips1, Carter T. Fields1, Guangmin Li1, Donald Dowbenko1, Gabriele Schaefer1, Kathy Miller5, Fabrice Andre6, Howard A. Burris III8, Kathy S. Albain9, Nadia Harbeck10, Veronique Dieras7, Diana Crivellari11, Liang Fang2, Ellie Guardino3, Steven R. Olsen3, Lisa M. Crocker4, and Mark X. Sliwkowski1 Abstract Purpose: Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-positive cancers. We investigated combining the HER2-directed antibody–drug con- jugate trastuzumab emtansine (T-DM1) with the HER2 dimerization inhibitor pertuzumab (Perjeta). Experimental Design: Drug combination studies with T-DM1 and pertuzumab were performed on cultured tumor cells and in mouse xenograft models of HER2-amplified cancer. In patients with HER2- positive locally advanced or metastatic breast cancer (mBC), T-DM1 was dose-escalated with a fixed standard pertuzumab dose in a 3þ3 phase Ib/II study design. Results: Treatment of HER2-overexpressing tumor cells in vitro with T-DM1 plus pertuzumab resulted in synergistic inhibition of cell proliferation and induction of apoptotic cell death. The presence of the HER3 ligand, heregulin (NRG-1b), reduced the cytotoxic activity of T-DM1 in a subset of breast cancer lines; this effect was reversed by the addition of pertuzumab. Results from mouse xenograft models showed enhanced antitumor efficacy with T-DM1 and pertuzumab resulting from the unique antitumor activities of each agent.