Resistance to tyrosine kinase inhibitors

Resistance to Targeted Anti-Cancer Therapeutics 10 Series Editor: Benjamin Bonavida Daniele Focosi Editor Resistance to Tyrosine Kinase Inhibitors Resistance to Targeted Anti-Cancer Therapeutics Volume 10 Series Editor Benjamin Bonavida More information about this series at http://www.springer.com/series/11727 Daniele Focosi Editor Resistance to Tyrosine Kinase Inhibitors Editor Daniele Focosi Pisa University Hospital Pisa, Italy ISSN 2196-5501 ISSN 2196-551X (electronic) Resistance to Targeted Anti-Cancer Therapeutics ISBN 978-3-319-46090-1 ISBN 978-3-319-46091-8 (eBook) DOI 10.1007/978-3-319-46091-8 Library of Congress Control Number: 2016957745 © Springer International Publishing Switzerland 2016 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part 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 or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland To my wife Emona and my children Enea and Anna Preface To reduce the adverse effects of chemotherapy agents, various targeted cancer therapies have been developed Target-based cancer therapy has revolutionized cancer treatment, and several agents have shown more specific effects on tumor cells than chemotherapies Small molecule inhibitors and monoclonal antibodies are specific agents that mostly target tumor cells but have few side effects on normal cells Although these agents have been very useful for cancer treatment, however, the presence of natural and acquired resistance has often blunted the potential of targeted therapies A better understanding of tumor cell resistance mechanisms to current treatment agents may provide an appropriate platform for developing and improving new treatment modalities Tyrosine kinases represent one of the commonest and most important enzyme classes in the cell physiome Tyrosine kinases on the cell surface often act as receptors for important intercellular mediators, while intracellular tyrosine kinases are fundamental mediators of signal transduction from receptors to effector proteins This volume will provide readers with a primer on tyrosine kinase inhibitors (TKIs) in cancer, resistance to TKIs, and how to overcome resistance to TKI The reader will be first introduced to the pathways stemming from tyrosine kinase signaling and then to the common denominators of resistance Then specific reviews will focus on resistance to the most commonly used classes of tyrosine kinase inhibitors, namely, BCR-ABL, FLT3, angiokinase, and ALK family members Pisa, Italy Daniele Focosi vii Editor’s Biography Dr Daniele Focosi, M.D., Ph.D., M.S was born in Lucca (Italy) in 1980 He graduated in medicine with full grades in 2005 at the University of Pisa and completed specialization in hematology in 2009 He achieved a Ph.D degree in clinical and fundamental virology in 2014 and a master’s degree in clinical trials in oncologyhematology in 2014 He has authored peer-reviewed manuscripts indexed on PubMed and has also been a fellow of the International Centre for Genetic Engineering and Biotechnology (ICGEB) in Trieste and of the Collegio Ghislieri in Pavia, Italy He is currently employed full-time at the Pisa University Hospital, where he is also a member of the Faculty of the Ph.D School in Clinical and Translational Sciences at the University of Pisa ix x Editor’s Biography Focosi has received awards from the European Federation for Immunogenetics, the European Society for Organ Transplantation, the Italian Society of Hematology, the Italian Interregional Transplant Association, the Italian Bone Marrow Donor Association, the Italian Society of Experimental Hematology, and the Italian Society against Leukemia/Lymphoma/Myeloma Acknowledgments The series editor, Benjamin Bonavida, wishes to acknowledge the dedication of the various assistants who had worked diligently in editing and formatting the various contributions in this volume Many thanks to Leah Moyal, Kevin Li, and Ailina Heng for their valuable efforts xi Contents Tyrosine Kinase Signaling Pathways in Normal and Cancer Cells Ewa Marcinkowska and Elżbieta Gocek Resistance to Tyrosine Kinase Inhibitors in Different Types of Solid Cancer Giovanna Mirone, Stefania Perna, and Gabriella Marfe 27 The Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: An Overview 109 Sara Galimberti, Claudia Baratè, Mario Petrini, Daniele Focosi, Elena Arrigoni, Romano Danesi, and Antonello Di Paolo Resistance to FLT3 Inhibitors 131 Timothy Ferng and Catherine Choy Smith Resistance to ALK Inhibitors 147 Francesca Simionato, Carmine Carbone, Giampaolo Tortora, and Davide Melisi Resistance to Angiokinase Inhibitors 165 Yuhui Huang Indications for Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors 179 Maria Vergoulidou xiii 174 Y Huang 4599 trial, patients treated with bevacizumab who developed hypertension had longer survival than those who did not experience hypertension [89] In contrast, a meta-analysis of phase III trials of bevacizumab-containing regimens in metastatic NSCLC, colorectal, breast, and renal cancer, found that hypertension was not predictive of outcome in five of the six studies [90] 6.5 Conclusions Antiangiogenic agents represent a significant advance in the treatment of solid cancers, but the rapid developing of drug resistance limits their clinic benefits Mechanisms of intrinsic and evasive resistance to these agents include upregulation of compensatory angiogenic factors and acquired tumor cell mutations The use of antiangiogenic drug combinations and the development of multitargeted TKIs may combat this resistance, but this has not been convincingly demonstrated to date Predictive biomarkers will be crucial to help to determine which patients are likely to respond to a particular type of therapy and further individualize treatment decisions, however, reliable biomarkers haven’t been validated to date Acknowledgments This work is supported in part by grants from the National Natural Science Foundation of China (81372245), the Collaborative Innovation Center of Hematology and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China Conflict of Interest Statement The author declares no conflict of interest related to this manuscript References Hanahan D, Weinberg RA Hallmarks of cancer: the next generation Cell 2011;144(5):646–74 Carmeliet P, Jain RK Molecular mechanisms and clinical applications of angiogenesis Nature 2011;473(7347):298–307 Dvorak HF et al Fibrin gel investment associated with line and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line tumor regression J Natl Cancer Inst 1979;62(6):1459–72 Senger DR et al Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites 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carcinoma Cancer Res 2010;70(3):1063–71 88 Nikolinakos PG et al Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib Cancer Res 2010;70(6):2171–9 89 Dahlberg SE et al Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599 J Clin Oncol 2010;28(6):949–54 90 Hurwitz HI et al Analysis of early hypertension and clinical outcome with bevacizumab: results from seven phase III studies Oncologist 2013;18(3):273–80 Chapter Indications for Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors Maria Vergoulidou Abstract Tyrosine kinase inhibitors (TKIs) constitute an important element in the treatment of solid tumors Their use is expanding in the last years since clinical trials showed survival benefit, setting new treatment indications Moreover, new molecules are being developed targeting resistance mechanisms such as acquired mutations or feedback mechanisms of the upregulated signaling pathway The available TKIs and their indications of use through clinical trials are listed and discussed Keywords Signaling pathways • Targeted therapies • Tyrosine kinase inhibitors Abbreviations ALK EGFR FGFR GIST HER2 NSCLC OS PDGFRA PFS TKI VEGFR Anaplastic lymphoma kinase Epidermal growth factor receptor Fibroblast growth factor receptor Gastrointestinal stromal tumor Human epidermal growth factor receptor Non-small-cell lung cancer Overall survival Platelet-derived growth factor receptor alpha progression free survival Tyrosine kinase inhibitor Vascular endothelial growth factor vs versus M Vergoulidou (*) Department of Haematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charitè Medical University, Berlin, Germany e-mail: marivergi@yahoo.com © Springer International Publishing Switzerland 2016 D Focosi (ed.), Resistance to Tyrosine Kinase Inhibitors, Resistance to Targeted Anti-Cancer Therapeutics, DOI 10.1007/978-3-319-46091-8_7 179 180 7.1 M Vergoulidou Introduction Tyrosine kinase inhibitors (TKIs) are small inhibitory molecules that bind the adenosine triphosphate (ATP) site of tyrosine kinases In the setting of malignancy, the signal transduction pathway is often abnormally upregulated TKIs can successfully down regulate the pathway through autophosphorylation [1] The first revolutionary use of a TKI was imatinib for chronic myelogenous leukemia targeting the Philadelphia translocation The understanding of the signaling pathways led to the development of more inhibitory molecules [2, 3], which were put in clinical trials, changing the course of disease for several solid tumors Despite encouraging results, patients often develop resistance to the TKIs treatment and fail to achieve prolonged response [4] The development of new targeted molecules as well as combination regimes to overcome resistance are in ongoing trials We alphabetically list the commercially available TKIs with references to the major clinical trials 7.2 7.2.1 Tyrosine Kinase Inhibitors Afatinib Afatinib irreversibly blocks EGFR as well as HER2 and HER4 and is used for patients with EGFR mutated metastatic lung adenocarcinoma In a phase IIb/III trial vs best supportive care for patients pre-treated with platinum doublet and at least months of another EGFR TKI (gefitinib or erlotinib) PFS was increased although a benefit in OS was not reached [5] As first line treatment in the LUX-Lung trial afatinib showed vs chemotherapy a statistically significant PFS of 11 months vs 5.6 month (p < 0.001), without difference in OS Subpopulation analysis of patients with a Del-19 mutation showed a benefit in OS (31.4 months vs 18.4 months with chemotherapy; p = 0.02) [6] 7.2.2 Axitinib Axitinib is an antiangiogenic TKI used in the second line treatment in advanced renal cancer In a phase III trial against sorafenib PFS was statistically significant (8.3 months for axitinib vs 5.7 months for sorafenib; p < 0.001) without significantly different OS (20.1 months for axitinib vs 19.2 months for sorafenib; p = 0.3744) [7] Indications for Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors 7.2.3 181 Cabozantinib Cabozantinib is used for progressive metastatic medullary thyroid cancer Patient population in the phase III trial comparing cabozantinib vs placebo 48.2 % harbored M918T RET mutations, 12 % were negative and for the rest RET mutation status was unknown, whereas the majority suffered from sporadic medullary thyroid cancer Cabozantinib showed a significantly longer PFS (11.2 months) vs placebo (4 months; p < 0.001) One-year survival and progression free was estimated 47.3 % for cabozantinib vs 7.2 % for placebo [8] 7.2.4 Ceritinib The potent ALK inhibitor ceritinib is approved for the second line treatment of advanced non-squamous non-small cell lung cancer harboring ALK-EML4 fusion protein Overall response rate was 58 % and PFS was months, whereas the majority of patients were pretreated with crizotinib In this subgroup response rate was 56 % with a PFS of 6.9 months Crizotinib naive patients responded up to 62 %, whereas the median PFS had not been reached at the time of analysis [9] 7.2.5 Crizotinib Crizotinib is a dual TKI of MET and ALK used in the first line treatment of advanced non-squamous non-small cell lung cancer harboring ALK-EML4 fusion protein Crizotinib showed a significant benefit in median PFS (7.7 vs 3.0 months in the chemotherapy group; p < 0.001) in pretreated patients with advanced disease [10] The phase III clinical trial in the first line treatment showed advantage in PFS (median, 10.9 months with crizotinib vs 7.0 months with chemotherapy; p < 0.001) The endpoint of OS was not reached at evaluation while the probability of 1-year survival was 84 % with crizotinib and 79 % with chemotherapy The relief of symptoms and the quality of life were greater in the crizotinib arm [11] 7.2.6 Dabrafenib Dabrafenib is a BRAF inhibitor for the treatment of patients with advanced BRAF V600 mutated melanoma In the phase III trial vs dacarbazine there was a significant benefit in PFS (5.1 months for dabrafenib vs 2.7 months for dacarbazine; p < 0.001) [12] The short lasting duration, attributed to MEK feedback mechanisms, led to current studies in combination with the MEK inhibitor trametinib [13] 182 7.2.7 M Vergoulidou Erlotinib Erlotinib is approved for use in non-small non-squamous lung cancer in the first line treatment for patients harboring EGFR mutations and further line treatments for unmutated EGFR status PFS benefit was statistically significant in randomized phase III trials vs chemotherapy (9.7 months vs 5.2 months for the chemotherapy arm; p < 0.001) [14] In EGFR umnutated metastatic lung cancer, erlotinib is an option for maintenance therapy after first line treatment without tumor progression or after failure of first-line or second-line chemotherapy [15] Erlotinib had similar PFS and OS compared to chemotherapy with docetaxel [16] Erlotinib is used in advanced pancreatic cancer in combination with gemcitabine OS was prolonged (median 6.24 months vs 5.91 months) and one-year survival was increased to 23 % for the combination therapy vs 17 % for gemcitabine monotherapy (p = 0.023) [17] 7.2.8 Gefitinib Gefitinib is used in EGFR mutated non-small non-squamous lung cancer In two Japanese trials in the first line treatment vs chemotherapy PFS was 9.2 and 10.8 months for gefitinib vs 6.3 and 5.4 months for the chemotherapy arm After showing the above results at the interim analysis the latest study was stopped and most patients crossed over to gefitinib [18, 19] 7.2.9 Imatinib Imatinib is due to inhibition of KIT or PDGFRA (platelet-derived growth factor receptor alpha) mutated receptor tyrosine kinases, standard first-line treatment for unresectable or metastatic GIST The majority of patients responded to imatinib (53.7 % with partial response and 27.9 % with stable disease) with improved survival (durable responses more than 42 weeks) and delayed disease progression [20] 7.2.10 Lapatinib Lapatinib has been approved in metastatic breast cancer patients with HER2 overexpression and hormone receptor-positive without prior therapy for metastatic disease The randomized trial with lapatinib plus letrozole vs placebo plus letrozole Indications for Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors 183 showed an improved PFS of 35.4 weeks vs 13.0 weeks for the placebo plus letrozole arm (hazard ratio = 0.71; p = 0.019) [21] Lapatinib is also approved for HER2 overexpressing metastatic breast cancer in combination with capecitabine Compared with capecitabine alone in pretreated patients time to progression was 27.1 vs 18.6 weeks (hazard ratio 0.57; p < 0.001) [22] 7.2.11 Lenvatinib Lenvatinib is licensed for differentiated thyroid cancer In the phase III trial vs placebo PFS was significantly prolonged (18.3 months vs 3.6 months; p < 0.001) [23] 7.2.12 Nintetanib Nintetanib is a TKI targeting VEGFR, FGFR and PDGFR, approved for the second line treatment of NSCLC in combination with docetaxel In the LUME-lung randomised phase III trial with nintetanib plus docetaxel vs placebo plus docetaxel PFS was significanlty prolonged in the 7.1-month median follow up (3.4 vs 2.7 months; p = 0.0019) OS in the 31.7-month follow up for adenocarcinoma patients progressing within months after first-line therapy was 10.9 months for nintetanib plus docetaxel vs 7.9 months for placebo plus docetaxel (p = 0.0073) whereas OS in the total patient population was 10.1 vs 9.1 months (p = 0.2720)[24] 7.2.13 Osimertinib Osimertinib has been approved for the treatment of EGFR mutated NSCLC harbouring T790M mutation after failure or progression under a previous EGFR targeting TKI treatment In the dose escalation study, centrally confirmed EGFR T790M mutated patients responded up to 61 % and PFS was 9.6 months, while patients without EGFR T790M mutation responded up to 21 % with 2.8 months PFS[25] 7.2.14 Pazopanib Pazopanib is approved for the second-line treatment of metastatic renal cell cancer In the randomised trial compared to placebo, PFS was significantly prolonged (9.2 vs 4.2 months) with response rate 30 % vs % (p < 0.001)[26] Compared to sunitinib, the efficacy was similar but the tolerability was better[27] 184 M Vergoulidou Pazopanib is approved for the treatment of non-adipocytic soft tissue sarcomas after chemotherapy In two EORTC trials PFS was significantly improved (4.6 months for pazopanib vs 1.6 months for placebo; p < 0.001) OS was12.5 months for pazopanib vs 10.7 months for placebo (p = 0.25) [28, 29] Pazopanib being a VEGFR targeting TKI showed efficacy in ovarian cancer and is approved for maintenance treatment in advanced ovarian cancer who has not progressed after first-line chemotherapy In a randomised trial vs placebo the median PFS improvement was 5.6 months (hazard ratio 0.77) without OS benefit [30, 31] 7.2.15 Regorafenib Regorafenib inhibits multiple membrane-bound and intracellular kinases such as VEGFR, KIT, TIE2, PDGFR, FGFR and BRAF It is approved for pre-treated patients with metastatic colon cancer The phase III trial showed an OS benefit vs placebo (6.4 vs 5.0 months; P = 0.0052) [32] Regorafenib is approved for patients with GIST after failure of imatinib and sunitinib The GRID study with regorafenib showed a PFS of 4.8 months vs 0.9 months for placebo (p < 0.001) [33] 7.2.16 Sorafenib Sorafenib is approved for the treatment of advanced unresectable hepatocellular carcinoma In the trial vs placebo it has shown an OS benefit (10.7 vs 7.9 months, p < 0.001) although the median time to symptomatic progression was not significant different in the two groups (4.1 months for sorafenib vs 4.9 months for placebo; p = 0.77) The study endpoint of radiological progression was significantly different (5.5 months for sorafenib vs 2.8 months for placebo; p < 0.001) [34] Sorafenib is approved for advanced renal cell carcinoma patients after failure of prior treatment The phase III trial vs placebo showed significant progression in PFS (5.5 months vs 2.8 months, p < 0.001) and reduction in risk of progression of 51 % OS was not statistically significant (9.3 months for sorafenib vs 15.9 months for the placebo group) [35] Sorafenib is approved for locally advanced or metastatic differentiated thyroid cancer refractory to radioactive iodine In the randomised phase III trial vs placebo, OS was not different but PFS was significantly longer (10.8 vs 5.8 months) Risk of progression or death was reduced by 41 % during the double-blind phase [36] Indications for Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors 7.2.17 185 Sunitinib Sunitinib is approved for non-resectable GIST after imatinib resistance In a randomised trial the median time to progression was 27.3 weeks vs 6.4 weeks for placebo (hazard ratio 0.33; p < 0.0001) [37] Sunitinib is approved for patients with advanced well-differentiated pancreatic neurendocrine tumours In the phase III trial vs placebo PFS was significantly prolonged (11.4 months for sunitinib and 5.5 months for placebo; p < 0.001) [38] Sunitinib is approved for the first line treatment of patients with advanced renal cancer In a trial compared against interferon alfa PFS was prolonged (11 months vs months) and the objective response rate was overall higher (31 % vs %, P < 0.001) [39] 7.2.18 Vandetanib Vandetanib is used for patients with advanced sporadic and hereditary medullary thyroid cancer In the phase III trial vs placebo PFS was significantly longer (30.5 months vs 19.3 months; p < 0.001) At the time of analysis median PFS had not been reached, the reported PFS refers to the predicted one Patients with M918T mutations showed higher response rate in the subgroup analysis [40] 7.2.19 Vemurafenib Vemufarefib is used in patients with BRAF mutated metastatic melanoma In the phase III randomised trial vs dacarbazine, OS was significantly increased (84 % OS after months for vemurafenib vs 64 % for dacarbazine) and the response rate to vemurafenib was up to 48 % compared to % for dacarbazine [41] Later on, the observation of a rather short lasting effect of vemurafenib was attributed to feedback mechanism through MEK-mediated reactivation of the ERK signaling pathway Consequently a dual inhibition of RAF and MEK [42] or reexposure to BRAF inhibitor after drug holiday could overcome resistance 7.3 Conclusions TKIs are widely used in the treatment of solid tumors For entities like melanoma, GIST or renal cell cancer, where conventional chemotherapy has limited efficacy, TKIs have shown encouraging results being the backbone of systemic treatment On the contrary, their use in hepatocellular carcinoma or colon cancer has yet failed to 186 M Vergoulidou provide a major impact in OS Routine testing for harbouring mutations mainly 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Resistance to Tyrosine Kinase Inhibitors in Different Types of Solid Cancer Giovanna Mirone, Stefania Perna, and Gabriella Marfe 27 The Resistance to Tyrosine Kinase Inhibitors in Chronic... Antonello Di Paolo Resistance to FLT3 Inhibitors 131 Timothy Ferng and Catherine Choy Smith Resistance to ALK Inhibitors 147 Francesca Simionato, Carmine Carbone, Giampaolo Tortora,