Recent Results in Cancer Research Series Editors: Alwin Krämer · Jiade J. Lu Editor Uwe M. Martens Small Molecules in Oncology Third Edition Recent Results in Cancer Research Volume 211 Series editors Alwin Krämer, German Cancer Research Center (DKFZ) and University of Heidelberg, Heidelberg, Germany Jiade J. Lu, Shanghai Proton and Heavy Ion Center, Shanghai, China More information about this series at http://www.springer.com/series/392 Uwe M. Martens Editor Small Molecules in Oncology Third Edition 123 Editor UweM.Martens MOLITInstitute Cancer CenterHeilbronn-Franken, SLK-Clinics Heilbronn, Baden-Württemberg Germany ISSN 0080-0015 ISSN 2197-6767 (electronic) Recent Resultsin Cancer Research ISBN978-3-319-91441-1 ISBN978-3-319-91442-8 (eBook) https://doi.org/10.1007/978-3-319-91442-8 LibraryofCongressControlNumber:2018941220 Originallypublishedinonevolumeinpreviousedition 1stand2ndedition:©Springer-VerlagBerlinHeidelberg2010,2014 3rdedition:©SpringerInternationalPublishingAG,partofSpringerNature2018 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpart of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission orinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar methodologynowknownorhereafterdeveloped. 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Printedonacid-freepaper ThisSpringerimprintispublishedbytheregisteredcompanySpringerInternationalPublishingAG partofSpringerNature Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland Preface The past two decades have resulted in major breakthroughs in the treatment of cancer.Eventhoughconventionalchemotherapycurrentlyremainsthebackboneof mosttreatmentregimens,theparadigmofcancertherapyisshiftingunambiguously toward more selective, mechanism-based strategies. Withthetremendousadvancesinourrecentunderstandingofaberrantsignaling pathways in various types of cancer—including leukemia, breast and lung cancer, and melanoma—plenty of crucial regulators of malignant behavior in cancer cells haveemergedaspromisingcandidatesformolecular target-basedcancertherapies. Specific alterations in key signaling molecules driving the progression of indi- vidual cancers can now precisely be targeted by small low-molecular-weight compounds. This new class of rationally designed anticancer agents is able to induce striking regressions in molecularly defined subsets of patients. One of the early pioneers has been imatinib mesylate (Glivec®) that showed remarkable efficacy for the treatment of patients with Philadelphia chromosome-positive CML, changing the course of this formerly deadly disease profoundly. A recent major breakthrough represents the discovery of synthetic lethality of PARP inhibitors in cancers defective in homologous recombination repair (HR), e.g., those associated with BRCA1 and BRCA2 mutations. With the third edition of Small Molecules in Oncology, we aim to give you a comprehensive survey of both, already established drugs as well as promising new substances.Allchaptershavebeencontributedbyrenownedscientistsandclinicians, offering first-hand insight into the exciting and rapidly evolving field of targeted cancer therapies. Due to the tremendous amount of available agents, the book has now been divided into two volumes, while “Small Molecules in Oncology” covers thetreatmentoptionsinsolidtumorsand“SmallMoleculesinHematology”focuses mainly on molecularly targeted drugs in hematologic malignancies. Heilbronn, Germany Uwe M. Martens v Contents Erlotinib.. .... .... .... .... ..... .... .... .... .... .... ..... .... 1 Martin Steins, Michael Thomas and Michael Geißler Lapatinib. .... .... .... .... ..... .... .... .... .... .... ..... .... 19 Minna Voigtlaender, Tanja Schneider-Merck and Martin Trepel Regorafenib... .... .... .... ..... .... .... .... .... .... ..... .... 45 Thomas J. Ettrich and Thomas Seufferlein Crizotinib. .... .... .... .... ..... .... .... .... .... .... ..... .... 57 David F. Heigener and Martin Reck Cabozantinib: Multi-kinase Inhibitor of MET, AXL, RET, and VEGFR2.. .... .... .... ..... .... .... .... .... .... ..... .... 67 Carsten Grüllich Vemurafenib .. .... .... .... ..... .... .... .... .... .... ..... .... 77 Claus Garbe and Thomas K. Eigentler Trametinib (GSK1120212) ... ..... .... .... .... .... .... ..... .... 91 Robert Zeiser, Hana Andrlová and Frank Meiss Everolimus.... .... .... .... ..... .... .... .... .... .... ..... .... 101 Jens Hasskarl Vismodegib ... .... .... .... ..... .... .... .... .... .... ..... .... 125 Frank Meiss, Hana Andrlová and Robert Zeiser Larotrectinib (LOXO-101)... ..... .... .... .... .... .... ..... .... 141 Stephanie Berger, Uwe M. Martens and Sylvia Bochum Palbociclib—The First of a New Class of Cell Cycle Inhibitors ... .... 153 Marcus Schmidt and Martin Sebastian Cobimetinib (GDC-0973, XL518)... .... .... .... .... .... ..... .... 177 Hana Andrlová, Robert Zeiser and Frank Meiss vii viii Contents Lenvantinib: A Tyrosine Kinase Inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRa, KIT and RET.... .... .... .... .... ..... .... 187 Stefanie Zschäbitz and Carsten Grüllich Afatinib .. .... .... .... .... ..... .... .... .... .... .... ..... .... 199 Helga Wecker and Cornelius F. Waller Olaparib . .... .... .... .... ..... .... .... .... .... .... ..... .... 217 Sylvia Bochum, Stephanie Berger and Uwe M. Martens Gefitinib.. .... .... .... .... ..... .... .... .... .... .... ..... .... 235 Justyna Rawluk and Cornelius F. Waller Alectinib.. .... .... .... .... ..... .... .... .... .... .... ..... .... 247 M. Herden and Cornelius F. Waller Osimertinib ... .... .... .... ..... .... .... .... .... .... ..... .... 257 Umberto Malapelle, Biagio Ricciuti, Sara Baglivo, Francesco Pepe, Pasquale Pisapia, Paola Anastasi, Marco Tazza, Angelo Sidoni, Anna M. Liberati, Guido Bellezza, Rita Chiari and Giulio Metro Erlotinib Martin Steins, Michael Thomas and Michael Geißler Contents 1 Introduction........................................................................................................................ 2 2 MechanismofAction......................................................................................................... 3 3 Non-smallCellLungCancer............................................................................................ 5 4 PancreaticAdenocarcinoma............................................................................................. 8 5 HepatocellularCarcinoma................................................................................................ 11 6 OtherTumourEntities...................................................................................................... 13 References................................................................................................................................. 13 M.Steins(&)(cid:1)M.Thomas(&) ClinicforThoracicDiseases,UniversityofHeidelberg,Röntgenstr.1,69126Heidelberg, Germany e-mail:[email protected] M.Thomas e-mail:[email protected] M.Geißler DepartmentofOncology,GastroenterologyandInternalMedicine,StädtischeKliniken Esslingen,Hirschlandstr.97,73730Esslingen,Germany e-mail:[email protected] ©SpringerInternationalPublishingAG,partofSpringerNature2018 1 U.M.Martens(ed.),SmallMoleculesinOncology,RecentResultsinCancer Research212,https://doi.org/10.1007/978-3-319-91442-8_1 2 M.Steinsetal. Abstract The epidermal growth factor receptor (EGFR) has been implicated in a multiplicity of cancer-related signal transduction pathways like cellular prolif- eration, adhesion, migration, neoangiogenesis and apoptosis inhibition, all of which are important features of cancerogenesis and tumour progression. Its tyrosinekinaseactivityplaysacentralroleinmediatingtheseprocessesandhas been intensely studied to exploit it as a therapeutic target. Inhibitors of this pathway have been developed and assessed in trials with significant efficacy in clinicalapplications.Thecurrentreviewfocusesinparticularontheclinicaldata of EGFR tyrosine kinase inhibition in different tumour entities, preferably non-smallcelllungcancerandpancreaticcancerwithemphasistotheapproved small molecule erlotinib. Its clinical applications, evidence-based efficacy and toxicity as well as predictive markers of response are discussed. Keywords (cid:1) (cid:1) Epidermal growth factor receptor Erlotinib Tyrosine kinase inhibitor 1 Introduction The development of small molecule inhibitors against various tyrosine kinases evoked a new era of antineoplastic agents in cancer therapy besides conventional cytotoxicdrugs.Theprincipleofthisanticancertreatmentisbasedontheinhibition of receptor tyrosine kinases which are essential components of the intracellular signalling apparatus. Several cellular receptors on the cell surface regulate their signalling via extracellular binding of ligands with consecutive activation of intracellular tyrosine kinase domains and tyrosine phosphorylation. One of these receptors, the epidermal growth factor receptor (EGFR), has gained considerable interest as a possible useful therapeutic target of tumour cells. EGFR is frequently overexpressed in solid tumours and plays a pivotal role in signal transduction pathwaysinvolvedincellproliferation,migration,adhesion,angiogenesisinduction andapoptosisinhibition.Itsoverexpressioncorrelatesinsometumourentitieswith disease progression and poorer prognosis (Brabender et al. 2001). Inclinicalpractice,theusesoftheEGFRtyrosinekinaseinhibitors(EGFR-TKI) erlotinib (Fig. 1), gefitinib, afatinib and osimertinib have been approved so far for patients with non-small cell lung cancer (NSCLC) for selected indications. In addition, erlotinib combined with gemcitabine has also gained approval for sys- temictreatmentinadvanced,non-operablepancreaticcarcinoma.TheTKIbenefitis mainlybasedontumourcontrolandoverallsurvival(OS)ratherthanrapidtumour responses and complete remission rates. In contrast to cytotoxic agents, these responses have been achieved by a specific molecular mechanism disturbing enzyme-mediated signal pathways in cancerogenesis.