DOCSLIB.ORG

Attachment 2. Extract from the Clinical Evaluation Report for Dabrafenib

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Attachment 2. Extract from the Clinical Evaluation Report for Dabrafenib AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Dabrafenib mesilate Proprietary Product Name: Tafinlar Sponsor: GlaxoSmithKline Australia Pty Ltd Date of CER: 20 February 2013 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) · The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health, and is responsible for regulating medicines and medical devices. · The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. · The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. · The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. · To report a problem with a medicine or medical device, please see the information on the TGA website <http://www.tga.gov.au>. About the Extract from the Clinical Evaluation Report · This document provides a more detailed evaluation of the clinical findings, extracted from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not include sections from the CER regarding product documentation or post market activities. · The words [Information redacted], where they appear in this document, indicate that confidential information has been deleted. · For the most recent Product Information (PI), please refer to the TGA website <http://www.tga.gov.au/hp/information-medicines-pi.htm>. Copyright © Commonwealth of Australia 2013 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <[email protected]>. Submission PM-012-02231-3-4 Extract from the Clinical Evaluation Report for Tafinlar dabrafenib mesilate Page 2 of 91 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 4 1. Introduction _____________________________________________________________ 8 2. Clinical rationale _______________________________________________________ 8 3. Contents of the clinical dossier_______________________________________ 9 3.1. Scope of the clinical dossier ___________________________________________________ 9 3.2. Formulation __________________________________________________________________ 10 3.3. Guidance ______________________________________________________________________ 10 3.4. Paediatric data _______________________________________________________________ 10 3.5. Good clinical practice ________________________________________________________ 10 4. Pharmacokinetics ____________________________________________________ 11 4.1. Studies providing pharmacokinetic data ___________________________________ 11 4.2. Summary of pharmacokinetics _____________________________________________ 12 4.3. Evaluator’s overall conclusions on pharmacokinetics ____________________ 26 5. Pharmacodynamics __________________________________________________ 28 5.1. Studies providing pharmacodynamic data _________________________________ 28 5.2. Summary of pharmacodynamics ___________________________________________ 28 5.3. Evaluator’s overall conclusions on pharmacodynamics __________________ 33 6. Dosage selection for the pivotal studies __________________________ 34 7. Clinical efficacy _______________________________________________________ 35 7.1. Treatment of patients with BRAF V600 mutation positive unresectable or metastatic (Stage IV) melanoma ___________________________________________________ 35 7.2. Evaluator’s conclusions on clinical efficacy of dabrafenib for treatment of patients with BRAF V600 mutation positive unresectable or metastatic (Stage IV) melanoma ___________________________________________________________________________ 50 8. Clinical safety__________________________________________________________ 53 8.1. Studies providing evaluable safety data ____________________________________ 53 8.2. Pivotal studies that assessed safety as a primary outcome _______________ 55 8.3. Patient exposure _____________________________________________________________ 55 8.4. Adverse events _______________________________________________________________ 58 8.5. Laboratory tests ______________________________________________________________ 67 8.6. Post-marketing experience__________________________________________________ 72 8.7. Safety issues with the potential for major regulatory impact ____________ 72 8.8. Other safety issues ___________________________________________________________ 73 8.9. Evaluator’s overall conclusions on clinical safety _________________________ 75 9. First round benefit-risk assessment ______________________________ 78 Submission PM-012-02231-3-4 Extract from the Clinical Evaluation Report for Tafinlar dabrafenib mesilate Page 3 of 91 Therapeutic Goods Administration 9.1. First round assessment of benefits _________________________________________ 78 9.2. First round assessment of risks _____________________________________________ 78 9.3. First round assessment of benefit-risk balance ___________________________ 79 10. First round recommendation regarding authorisation ________ 79 11. Clinical questions _____________________________________________________ 80 11.1. Pharmacokinetics __________________________________________________________ 80 11.2. Efficacy ______________________________________________________________________ 80 11.3. Safety ________________________________________________________________________ 80 12. Second round evaluation of clinical data submitted in response to questions ______________________________________________________________________ 81 13. References _____________________________________________________________ 81 14. Appendix 1. Population PK of dabrafenib in subjects with solid tumours: ______________________________________________________________________ 82 14.1. Summary ____________________________________________________________________ 82 List of abbreviations Abbreviation Meaning a.k.a. Also known as AE Adverse event AML Acute myeloid leukaemia AMS Accelerator mass spectrometry ARF Acute renal failure ATP Adenosine triphosphate AUC Area under the plasma drug concentration-time curve AUC(0- Area under the concentration-time curve from zero to infinity ∞) AUC(0- Inter-dose interval area under the concentration-time curve BCC τ) Basal cell carcinoma Bcrp Breast cancer resistance protein BCS Biopharmaceutics Classification System Submission PM-012-02231-3-4 Extract from the Clinical Evaluation Report for Tafinlar dabrafenib mesilate Page 4 of 91 Therapeutic Goods Administration Abbreviation Meaning BID Twice a day BRAF A member of the RAF kinases Cavg Average concentration CL/F Apparent oral clearance (L/h) CL0 Initial (non-inducible) clearance (L/h) CLind Inducible clearance (L/h) Cmax Maximum observed concentration CPH Cox proportional hazards CR Complete response CSR Clinical Study Report Pre-dose (trough) concentration at the end of the dosing interval Cτ CT Computed tomography Ctrough Trough concentration CYP Cytochrome P450 DTIC dacarbazine ECG Electrocardiogram ECHO Echocardiogram ECOG Eastern Cooperative Oncology Group ED50 Daily dose resulting in 50% of maximum response EMA European Medicines Agency Emax Maximum response ERK Extracellular signal regulated kinase EU European Union F Absolute bioavailability FDG-PET Fluorodeoxyglucose-positron emission tomography Submission PM-012-02231-3-4 Extract from the Clinical Evaluation Report for Tafinlar dabrafenib mesilate Page 5 of 91 Therapeutic Goods Administration Abbreviation Meaning FTIH First time in humans GGT Gamma glutamyl transferase GI Gastrointestinal HPMC hydroxypropylmethylcellulose HR Hazard ratio HRQoL Health-related quality of life IIV Inter-individual variability IR Independent review ISS Integrated summary of safety ITT Intention-to-treat IUO Investigational use only IV Intravenous Ka Absorption rate constant (L/h) LDH Lactate dehydrogenase LLE Liquid-liquid extraction LLQ Lower limit of quantification LS Least squares LVEF Left ventricular ejection fraction MAPK pathway The RAS/RAF/MEK/ERK pathway (MAP kinase pathway) MEK Mitogen-activated ERK kinase MRI Magnetic resonance imaging OIRR Overall intracranial response rate ORR Overall response rate OS Overall survival pERK Phosphorylated ERK Submission PM-012-02231-3-4 Extract from the Clinical Evaluation Report for Tafinlar dabrafenib mesilate Page 6 of 91 Therapeutic
Load more

Recommended publications
  • Successful Chemotherapy Is Possible for Seemingly Inoperable Anaplastic Thyroid Cancer
    ® Clinical Thyroidology for the Public VOLUME 12 | ISSUE 12 | DECEMBER 2019 THYROID CANCER Successful chemotherapy is possible for seemingly inoperable anaplastic thyroid cancer BACKGROUND form of standard chemotherapy and 2 received another While the vast majority of thyroid cancers are slow tyrosine kinase inhibitor called pembrolizumab. Of the 6 growing and have an excellent prognosis, anaplastic patients that had surgery after this treatment, 4 patients thyroid cancer, which makes up <1% of all thyroid cancer, had the entire primary cancer removed and the other 2 is one of the most aggressive of all cancers, with a survival patients only had microscopic pieces of cancer left after averaging ~6 months after diagnosis. Surgery, radiation the surgery. After the surgery, 5 of 6 patients received and single drug chemotherapy is all ineffective in most standard chemotherapy and radiation to the surgical area. cases. The aim of this study is to study if combination Of the 6 patients, 4 patients had no evidence of cancer at chemotherapy will make previously inoperable anaplastic the last check, some over 2 years after surgery. The 2 other thyroid cancers safe to remove with surgery. patients did pass away from anaplastic cancer; however, there was no re-growth of cancer in the area where surgery THE FULL ARTICLE TITLE occurred. Wang JR et al 2019 Complete surgical resection following neoadjuvant dabrafenib plus trametinib in BRAFV600E- WHAT ARE THE IMPLICATIONS mutated anaplastic thyroid carcinoma. Thyroid 29:1036– OF THIS STUDY? 1043. PMID: 31319771. In selected patients with anaplastic thyroid cancer with the BRAF V600E mutation, treatment with dabrafenib SUMMARY OF THE STUDY and trametinib may increase the chance of having a In this study from the MD Anderson Cancer Center successful surgery of the primary tumor.
    [Show full text]
  • Combined BRAF and MEK Inhibition with Vemurafenib and Cobimetinib for Patients with Advanced Melanoma
    Review Melanoma Combined BRAF and MEK Inhibition with Vemurafenib and Cobimetinib for Patients with Advanced Melanoma Antonio M Grimaldi, Ester Simeone, Lucia Festino, Vito Vanella and Paolo A Ascierto Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, Napoli, Italy cquired resistance is the most common cause of BRAF inhibitor monotherapy treatment failure, with the majority of patients experiencing disease progression with a median progression-free survival of 6-8 months. As such, there has been considerable A focus on combined therapy with dual BRAF and MEK inhibition as a means to improve outcomes compared with monotherapy. In the COMBI-d and COMBI-v trials, combined dabrafenib and trametinib was associated with significant improvements in outcomes compared with dabrafenib or vemurafenib monotherapy, in patients with BRAF-mutant metastatic melanoma. The combination of vemurafenib and cobimetinib has also been investigated. In the phase III CoBRIM study in patients with unresectable stage III-IV BRAF-mutant melanoma, treatment with vemurafenib and cobimetinib resulted in significantly longer progression-free survival and overall survival (OS) compared with vemurafenib alone. One-year OS was 74.5% in the vemurafenib and cobimetinib group and 63.8% in the vemurafenib group, while 2-year OS rates were 48.3% and 38.0%, respectively. The combination was also well tolerated, with a lower incidence of cutaneous squamous-cell carcinoma and keratoacanthoma compared with monotherapy. Dual inhibition of both MEK and BRAF appears to provide a more potent and durable anti-tumour effect than BRAF monotherapy, helping to prevent acquired resistance as well as decreasing adverse events related to BRAF inhibitor-induced activation of the MAPK-pathway.
    [Show full text]
  • Original Research Paper In-Silico FDA-Approved Drug Repurposing to Find
    Original Research Paper In-silico FDA-approved drug repurposing to find the possible treatment of Coronavirus Disease-19 (COVID-19) Kumar Sharp1, Dr. Shubhangi Dange2* 12nd MBBS undergraduate student, Government Medical College and Hospital, Jalgaon 2Associate Professor, Dept. of Microbiology, Government Medical College and Hospital, Jalgaon *Corresponding author: - Dr. Shubhangi Dange, Associate Professor, Department of Microbiology, Government Medical College and Hospital, Jalgaon Email: [email protected] Abstract Identification of potential drug-target interaction for approved drugs serves as the basis of repurposing drugs. Studies have shown polypharmacology as common phenomenon. In-silico approaches help in screening large compound libraries at once which could take years in a laboratory. We screened a library of 1050 FDA-approved drugs against spike glycoprotein of SARS-CoV2 in-silico. Anti-cancer drugs have shown good binding affinity which is much better than hydroxychloroquine and arbidol. We have also introduced a hypothesis named “Bump” hypothesis which and be developed further in field of computational biology. Keywords: spike glycoprotein; FDA; drug repurposing; anti-cancer; hydroxychloroquine Introduction Identification of potential drug-target interaction for approved drugs serves as the basis of repurposing drugs. Studies have shown polypharmacology as common phenomenon [1][2]. Since the three-dimensional structures of proteins of SARS-CoV2 have been mapped it opens opportunity for in-silico approaches of either novel drug discovery or drug repurposing. In the absence of an exact cure or vaccine, coronavirus disease-19 has taken a huge toll of humanity. Our study of target specific drug docking and novel hypothesis contributes in this fight. In-silico approaches help in screening large compound libraries at once which could take years in a laboratory.
    [Show full text]
  • Tafinlar, INN-Dabrafenib
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Tafinlar 50 mg hard capsules Tafinlar 75 mg hard capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Tafinlar 50 mg hard capsules Each hard capsule contains dabrafenib mesilate equivalent to 50 mg of dabrafenib. Tafinlar 75 mg hard capsules Each hard capsule contains dabrafenib mesilate equivalent to 75 mg of dabrafenib. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Hard capsule (capsule). Tafinlar 50 mg hard capsules Opaque dark red capsules, approximately 18 mm long, with capsule shell imprinted with “GS TEW” and “50 mg”. Tafinlar 75 mg hard capsules Opaque dark pink capsules, approximately 19 mm long, with capsule shell imprinted with “GS LHF” and “75 mg”. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Melanoma Dabrafenib as monotherapy or in combination with trametinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (see sections 4.4 and 5.1). Adjuvant treatment of melanoma Dabrafenib in combination with trametinib is indicated for the adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection. Non-small cell lung cancer (NSCLC) Dabrafenib in combination with trametinib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600 mutation. 2 4.2 Posology and method of administration Treatment with dabrafenib should be initiated and supervised by a qualified physician experienced in the use of anticancer medicinal products. Before taking dabrafenib, patients must have confirmation of tumour BRAF V600 mutation using a validated test.
    [Show full text]
  • Oncology Drug Shortage Update
    ] ] [ News ] Analysis ] Commentary ] Controversy ] June 25, 2013 Vol. 35 No. 12 oncology-times.com ONCOLOGY e 5 Y ars 3 of g P in u t b a l r i s b h e i l n e g IMES C 35 TThe Independent Hem/Onc News Source Oncology Drug Shortage Update BY HEATHER LINDSEY new survey documents that cancer drug shortages have occurred A frequently, led to treatment delays, increased the risks of errors and adverse outcomes, complicated research, and increased the costs of medications� The survey, by the Hematology-Oncology Pharmacy Association, is the first to focus specifically on oncology� Page 14 • Advanced NSCLC: 60 Gy Standard • Seminoma: Opting Out of Adjuvant Therapy Safe LUNG CANCER: • Immunotherapy ‘Poised to Change Treatment Paradigm’ Leukemia Researcher Lukas Meeting Spotlights • DLBCL: CT Surveillance Adds Little Value Wartman Describes 10-Year Progress in Molecularly • CLL: Enthusiasm for Idelalisb Personal Battle Against Guided Therapy p.10 • Fitness & Cancer Prognosis pp.18, 25, 28, 33, 36, 37 Adult ALL p.20 [ALSO] SHOP TALK �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �3 EDITH PEREZ: How I Treat Patients with Advanced HER2-Positive Breast Cancer � � � � � � � � � � �5 Exercise, Estrogen, & Breast Cancer Risk: New Data �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �11 JOE SIMONE: Changing Views of Leaders and Leadership � � � � � � � � � � � � � � � � � � � � � � � � � � � � �16 Science Symposium for ACS’s 100th Anniversary �� � � � � � � � � � � � � � � � � � � � � � � �
    [Show full text]
  • MEKINIST (Trametinib) Tablets for Oral Use Are Supplied As 0.5 Mg and 2 Mg Tablets for Oral Administration
    HIGHLIGHTS OF PRESCRIBING INFORMATION Colitis and Gastrointestinal Perforation: Colitis and gastrointestinal These highlights do not include all the information needed to use perforation can occur in patients receiving MEKINIST. (5.3) MEKINIST safely and effectively. See full prescribing information for Venous Thromboembolism: Deep vein thrombosis and pulmonary MEKINIST. embolism can occur in patients receiving MEKINIST. (5.4, 2.7) MEKINIST® (trametinib) tablets, for oral use Cardiomyopathy: Assess LVEF before treatment, after one month of Initial U.S. Approval: 2013 treatment, then every 2 to 3 months thereafter. (5.5, 2.7) ------------------------------RECENT MAJOR CHANGES------------------------ Ocular Toxicities: Perform ophthalmologic evaluation for any visual Indications and Usage (1.1-1.3) 4/2018 disturbances. For Retinal Vein Occlusion (RVO), permanently Indications and Usage (1.4, 1.5) 5/2018 discontinue MEKINIST. (5.6, 2.7) Dosage and Administration Interstitial Lung disease (ILD): Withhold MEKINIST for new or (2.2, 2.3, 2.4) 4/2018 progressive unexplained pulmonary symptoms. Permanently discontinue (2.1, 2.5, 2.6, 2.7) 5/2018 MEKINIST for treatment-related ILD or pneumonitis. (5.7, 2.7) Warnings and Precautions (5) 4/2018 Serious Febrile Reactions: Can occur when MEKINIST is used with dabrafenib. (5.8, 2.7) ------------------------------INDICATIONS AND USAGE------------------------- Serious Skin Toxicity: Monitor for skin toxicities and for secondary MEKINIST is a kinase inhibitor indicated as a single agent for the treatment infections. Discontinue MEKINIST for intolerable Grade 2, or Grade 3 of patients with unresectable or metastatic melanoma with BRAF V600E or or 4 rash not improving within 3 weeks despite interruption of V600K mutations as detected by an FDA-approved test.
    [Show full text]
  • First-Line Treatment Options for Patients with Stage IV Non-Small Cell Lung Cancer with Driver Alterations
    First-Line Treatment Options for Patients with Stage IV Non-Small Cell Lung Cancer with Driver Alterations Patients with stage IV non-small cell lung cancer Nonsquamous cell carcinoma and squamous cell carcinoma Activating EGFR mutation other Sensitizing (L858R/exon 19 MET exon 14 skipping than exon 20 insertion mutations, EGFR exon 20 mutation ALK rearrangement ROS1 rearrangement BRAF V600E mutation RET rearrangement NTRK rearrangement mutations KRAS alterations HER2 alterations NRG1 alterations deletion) EGFR mutation T790M, L858R or Ex19Del PS 0-2 Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options Emerging target; no Emerging target; no Emerging target; no Platinum doublet † † † Osimertinib monotherapy S Afatinib monotherapy M M Alectinib S Entrectinib M Dabrafenib/trametinib M Capmatinib M Selpercatinib M Entrectinib M conclusions available conclusions available conclusions available chemotherapy ± bevacizumab Gefitinib with doublet Standard treatment based on Standard treatment based on Standard treatment based on M M M Brigatinib S Crizotinib M M Tepotinib M Pralsetinib* W Larotrectinib M chemotherapy non-driver mutation guideline non-driver mutation guideline non-driver mutation guideline If alectinib or brigatinib are not available If entrectinib or crizotinib are not available Standard treatment based on Standard treatment based on Standard treatment based on Dacomitinib monotherapy M Osimertinib W M M M Ceritinib S Ceritinib W non-driver mutation guideline non-driver mutation guideline non-driver mutation guideline Monotherapy with afatinib M Crizotinib S Lortlatinib W Standard treatment based on Erlotinib/ramucirumab M M non-driver mutation guideline Erlotinib/bevacizumab M Monotherapy with erlotinib M Strength of Recommendation Monotherapy with gefitinib M S Strong M Moderate W Weak Monotherapy with icotinib M Notes.
    [Show full text]
  • CDER Breakthrough Therapy Designation Approvals Data As of December 31, 2020 Total of 190 Approvals
    CDER Breakthrough Therapy Designation Approvals Data as of December 31, 2020 Total of 190 Approvals Submission Application Type and Proprietary Approval Use Number Number Name Established Name Applicant Date Treatment of patients with previously BLA 125486 ORIGINAL-1 GAZYVA OBINUTUZUMAB GENENTECH INC 01-Nov-2013 untreated chronic lymphocytic leukemia in combination with chlorambucil Treatment of patients with mantle cell NDA 205552 ORIGINAL-1 IMBRUVICA IBRUTINIB PHARMACYCLICS LLC 13-Nov-2013 lymphoma (MCL) Treatment of chronic hepatitis C NDA 204671 ORIGINAL-1 SOVALDI SOFOSBUVIR GILEAD SCIENCES INC 06-Dec-2013 infection Treatment of cystic fibrosis patients age VERTEX PHARMACEUTICALS NDA 203188 SUPPLEMENT-4 KALYDECO IVACAFTOR 21-Feb-2014 6 years and older who have mutations INC in the CFTR gene Treatment of previously untreated NOVARTIS patients with chronic lymphocytic BLA 125326 SUPPLEMENT-60 ARZERRA OFATUMUMAB PHARMACEUTICALS 17-Apr-2014 leukemia (CLL) for whom fludarabine- CORPORATION based therapy is considered inappropriate Treatment of patients with anaplastic NOVARTIS lymphoma kinase (ALK)-positive NDA 205755 ORIGINAL-1 ZYKADIA CERITINIB 29-Apr-2014 PHARMACEUTICALS CORP metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib Treatment of relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients NDA 206545 ORIGINAL-1 ZYDELIG IDELALISIB GILEAD SCIENCES INC 23-Jul-2014 for whom rituximab alone would be considered appropriate therapy due to other co-morbidities
    [Show full text]
  • MAP Kinase Signaling and Inhibition in Melanoma
    Oncogene (2013) 32, 2373–2379 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW MAP kinase signaling and inhibition in melanoma RJ Sullivan and K Flaherty The mitogen-activated protein kinase (MAPK) pathway is critical to oncogenic signaling in the majority of patients with malignant melanoma. Driver mutations in both NRAS and BRAF have important implications for prognosis and treatment. The development of inhibitors to mediators of the MAPK pathway, including those to CRAF, BRAF, and MEK, has led to major advances in the treatment of patients with melanoma. In particular, the selective BRAF inhibitor vemurafenib has been shown to improve overall survival in patients with tumors harboring BRAF mutations. However, the duration of benefit is limited in many patients and highlights the need for understanding the limitations of therapy in order to devise more effective strategies. MEK inhibitors have proven to particularly active in BRAF mutant melanomas also. Emerging knowledge about mechanisms of resistance as well as a more complete understanding of the biology of MAPK pathway signaling provides insight into rational combination regimens and sequences of molecularly targeted therapies. Oncogene (2013) 32, 2373–2379; doi:10.1038/onc.2012.345; published online 3 September 2012 Keywords: melanoma; targeted therapy; BRAF INTRODUCTION activation. The RAS GTPases are a critical link between activated The mitogen-activated protein kinase (MAPK) pathway is activated growth factor receptors and downstream signal transduction in the great majority of melanomas and typically occurs through pathways. In light of this central role, it is not surprising that three activating mutations of either NRAS (15–20% cutaneous melano- RAS isoforms (HRAS, KRAS and NRAS) collectively represent the mas) or BRAF (40–50%).1 These mutations can be identified in most commonly mutated oncogene in human malignancies and 13,14 benign melanocytic proliferation and all stages of invasive and distribute across a variety of cancers.
    [Show full text]
  • Estonian Statistics on Medicines 2016 1/41
    Estonian Statistics on Medicines 2016 ATC code ATC group / Active substance (rout of admin.) Quantity sold Unit DDD Unit DDD/1000/ day A ALIMENTARY TRACT AND METABOLISM 167,8985 A01 STOMATOLOGICAL PREPARATIONS 0,0738 A01A STOMATOLOGICAL PREPARATIONS 0,0738 A01AB Antiinfectives and antiseptics for local oral treatment 0,0738 A01AB09 Miconazole (O) 7088 g 0,2 g 0,0738 A01AB12 Hexetidine (O) 1951200 ml A01AB81 Neomycin+ Benzocaine (dental) 30200 pieces A01AB82 Demeclocycline+ Triamcinolone (dental) 680 g A01AC Corticosteroids for local oral treatment A01AC81 Dexamethasone+ Thymol (dental) 3094 ml A01AD Other agents for local oral treatment A01AD80 Lidocaine+ Cetylpyridinium chloride (gingival) 227150 g A01AD81 Lidocaine+ Cetrimide (O) 30900 g A01AD82 Choline salicylate (O) 864720 pieces A01AD83 Lidocaine+ Chamomille extract (O) 370080 g A01AD90 Lidocaine+ Paraformaldehyde (dental) 405 g A02 DRUGS FOR ACID RELATED DISORDERS 47,1312 A02A ANTACIDS 1,0133 Combinations and complexes of aluminium, calcium and A02AD 1,0133 magnesium compounds A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 811120 pieces 10 pieces 0,1689 A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 3101974 ml 50 ml 0,1292 A02AD83 Calcium carbonate+ Magnesium carbonate (O) 3434232 pieces 10 pieces 0,7152 DRUGS FOR PEPTIC ULCER AND GASTRO- A02B 46,1179 OESOPHAGEAL REFLUX DISEASE (GORD) A02BA H2-receptor antagonists 2,3855 A02BA02 Ranitidine (O) 340327,5 g 0,3 g 2,3624 A02BA02 Ranitidine (P) 3318,25 g 0,3 g 0,0230 A02BC Proton pump inhibitors 43,7324 A02BC01 Omeprazole
    [Show full text]
  • Corporate Medical Policy Template
    Corporate Medical Policy BRAF Genetic Testing In Patients With Melanoma AHS-M2029 “Notification” File Name: braf_genetic_testing_in_patients_with_melanoma Origination: 1/1/2019 Last CAP Review: NA Next CAP Review: 1/1/2020 Last Review: 1/1/2019 Description of Procedure or Service BRAF (V-raf murine sarcoma viral oncogene homolog B1) is a serine-threonine protein kinase involved in cell survival, proliferation, and differentiation (H. Davies et al., 2002; Tatsuno et al., 2016). The most common missense mutation of BRAF (mainly V600E) contributes to the incidence of various cancers, including melanoma (Flaherty et al., 2012). ***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician. Policy BCBSNC will provide coverage for BRAF genetic testing in patients with melanoma when it is determined to be medically necessary because the medical criteria and guidelines shown below are met. Benefits Application This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy. When BRAF Genetic Testing in Patients with Melanoma is covered BRAF genetic testing in patients with melanoma is considered medically necessary for the following: 1. Testing of tumor tissue for BRAF V600 and KIT mutation analysis is considered medically necessary for individuals with unresectable or metastatic melanoma (stage IV), prior to initiation of molecular targeted treatment. Note: Mutation testing on the metastatic lesion is preferred, if possible.
    [Show full text]
  • Phase II Trial of Nilotinib in Patients with Metastatic Malignant Melanoma Harboring KIT Gene Aberration: a Multicenter Trial of Korean Cancer Study Group (UN10-06)
    Melanoma and Cutaneous Malignancies Phase II Trial of Nilotinib in Patients With Metastatic Malignant Melanoma Harboring KIT Gene Aberration: A Multicenter Trial of Korean Cancer Study Group (UN10-06) SU JIN LEE,a,* TAE MIN KIM,c,* YU JUNG KIM,d KEE-TAEK JANG,b HYO JIN LEE,e SOON NAM LEE,f MI SUN AHN,g IN GYU HWANG,h SUEE LEE,i MOON-HEE LEE,j JEEYUN LEEa Departments of aMedicine and bPathology and Translational Genomics, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; cDepartment of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; dDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea; eDivision of Hematology/Oncology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea; fDivision of Hemato-Oncology, Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Republic of Korea; gDepartmentofHematology-Oncology,AjouUniversitySchoolofMedicine,Suwon,RepublicofKorea; hDepartmentofInternalMedicine,Chung-Ang University College of Medicine, Seoul, Republic of Korea; iDepartment of Internal Medicine, Dong-A University Hospital, Dong-A University College of Medicine, Busan, Republic of Korea; jDepartment of Hemato-Oncology, Inha University School of Medicine, Incheon, Republic of Korea *Contributed equally. Disclosures of potential conflicts of interest may be found at the end of this article. Key Words. Nilotinib x Melanoma x KIT mutation x KIT amplification ABSTRACT Background. KIT has been suggested to be a potential were enrolled in the study. Overall, 25 (59.5%), 15 (35.7%), and therapeutic target for malignant melanoma.
    [Show full text]