Chapter 24 tyrosine kinase inhibitors

1. •Tyrosine kinase inhibitors- cml,breast ,lung ,head and neck

2. Introduction  Tyrosine kinases are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli.  A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an “on” or "off" switch in many cellular functions.  Tyrosine kinases are implicated in several steps of neoplastic development and progression.  Tyrosine kinases represent a major portion of all oncoprotein that play a transforming role in a plethora of cancers. Structural Classification of Proteins (SCOP) • Class: Alpha and beta proteins (a+b) • Fold: SH2-like • Superfamily: SH2 domain • Family: SH2 domain • Protein Domain: Tyrosine-protein kinase 2

3. Introduction cont.  The identification and development of therapeutic agents for disease states that are linked to abnormal activation of tyrosine kinases due to enhanced expression, mutation or autocrine stimulation leading to abnormal downstream oncogenic signaling have taken a center stage as a potent target for cancer therapy.  The discovery that SRC oncogene having a transforming non receptor tyrosine kinase activity , and the finding of EGFR, the first receptor tyrosine kinase paved the way to the understanding of the role and significance of tyrosine kinase in cancer 3

4. General Characteristic  The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes.Up to 30% of all human proteins may be modified by kinase activity.  Protein Tyrosine Kinase generally made up of Transmembrane Glycoprotein.  Substrate Specificity. 4

5. Structure 5

6. Biochemical mechanismof action of tyrosine kinase Schematic representation of the mode of action of tyrosine kinase. PK represents protein kinase and PP stands for protein phosphatase 6  …

7. Mechanismof Tyrosine Kinase Receptors  When the receptors aggregate, the tyrosine kinase domains phosphorylate the C terminal tyrosine residues.  This phosphorylation produces binding sites for proteins with SH2 domains. GRB2 is one of these proteins. GRB2, with SOS bound to it, then binds to the receptor complex. This causes the activation of SOS. 7

8. Mechanismof Tyrosine Kinase Receptors  SOS is a guanyl nucleotide-release protein (GNRP). When this is activated, it causes certain G proteins to release GDP and exchange it for GTP. Ras is one of these proteins. When ras has GTP bound to it, it becomes active.  Activated ras then causes the activation of a cellular kinase called raf-1. 8

9. Mechanismof Tyrosine Kinase Receptors  Raf-1 kinase then phosphorylates another cellular kinase called MEK. This cause the activation of MEK.  Activated MEK then phosphorylates another protein kinase called MAPK causing its activation. This series of phosphylating activations is called a kinase cascade. It results in amplification of the signal. 9

10. Mechanismof Tyrosine Kinase Receptors  Among the final targets of the kinase cascade are transcriptions factors (fos and jun showed here). Phosphorylation of these proteins causes them to become active and bind to the DNA, causing changes in gene transcription. 10

11. Classificationof RTK 11  Receptor tyrosine kinases (RTKs)-The RTK family includes the receptors for insulin and for many growth factors such as  Epidermal growth factor (EGF)  Fibroblast growth factor(FGF)  Platelet-derived growth factor (PDGF)  Vascular endothelial growth factor(VEGF)  Nerve growth factor (NGF)  Nonreceptor tyrosine kinases (NRTKs)  Src  Janus kinases (Jaks)  Abl

12. Application  Tyrosine kinases as targets for anticancer agents 12

13. Application 13

14. • Targeted therapy is a type of medication which blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, survival, angiogenesis,invasion and metastasis rather than by simply interfering with rapidly dividing cells.

15. Targeted Therapy in Oncology  Goals  Identify potential targets – Identify agents that target tumor-specific molecules, thus sparing normal cells • Increased specificity leads to decreased toxicity – Identify ideal drug target • Drives tumor growth • Turns on key mechanisms of cancer progression • Reversible by inhibition with agent • Dispensable in normal cells • Target measurable in tumor tissue

16. Six Essential Alterations in Cell Physiology in Malignancy Limitless replicative potential Tissue invasion & metastasis Sustained angiogenesis Insensitivity to anti-growth signals Self-sufficiency in growth signals Evading apoptosis Targets for classical drugs? Targets for novel drugs? Hanahan & Weinberg, Cell 100:57 (2000)

17. Evolution of targeted therapy-Recommendation • Rituximab- Chimeric monoclonal antibody against CD20- 1. Refractory /low grade follicular lymphoma 2. Mainstay with CHOP/CVP in DLBCL ,Follicular lypmhoma • Imatinib (Gleevac)- bcr/abl TKI 1. Interferon refractory CML 2. Approved For CML (Blast ,Accelerated), Unresectable/metastatic GIST, Ph + ALL • Dasatinib 1. phases of CML with resistance or intolerance to prior therapy, including imatinib. 2. Ph-positive ALL with resistance or intolerance to prior therapy • Nilotinib 1. Chronic phase or accelerated phase Ph- positive CML for adult patients resistent to or intolerant of prior imatinib therapy • Gefitinib 1. locally advanced or metastatic NSCLC who have failed platinum-based and docetaxel chemotherapies FDA-May 2001 FDA Oct 2007 July 2002 FDA-1997

18. • Erlotinib 1. locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen 2. combination with gemcitabine for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer. • Lapatinib 1. combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab • Sunitinib 1. GIST after disease progression on or intolerance to imatinib mesylate 2. Advanced renal cell carcinoma • Sorafenib 1. Advanced renal cell carcinoma FDA Nov 2004 FDA March 2007 FDA Dec 2005 FDA Feb 2007

20. Target ?? • Major biological pathways – Cell proliferation – Cell cycle check – Angiogenesis – Apoptosis – Senesence – DNA repair

21. Theoretical advantage over chemotherapy • Chemotherapy  the main drawback lies in its exacerbation of acute and late RT-induced toxicity to normal tissues. • Targeted agents •  Theoretical advantage over chemotherapy •  Relative tumor-specificity •  Wide therapeutic margin •  Overlapping toxicity with RT on normal tissue is potentially minimized. •  Improve therapeutic index • 400 – 500 drugs under development • Challenge  target specificity and acceptable toxicity

22. Introduction of molecular-targeted agents: an important paradigm-shift in our approach to the treatment of cancer 4. Proteasome 1 2 3 4 5 6 1. Growth factors and growth-factor receptors HER family, VEGF/R, c-kit/SCFR 2. Signal-transduction pathways Ras, raf, MAPK, MEK, ERK, protein kinase C, PI3K 3. Tumor-associated antigens/markers Gangliosides, CEA, MAGE, CD20, CD226. Extracellular matrix/ angiogenic pathways MMPs, VEGF, integrins 5. Cell-survival pathways Cyclin-dependent kinases, mTOR, cGMP, COX-2, p53, Bcl-2 Ullrich A. Oncology 2002;63(Suppl. 1):1–5 Tumour cell

23. HER (erbB) & VEGF Family) • HER & erbB Family – EGFR Inhibitors • Monoclonal Antibodies- Cetuximab, Panitumumab • Tyrosine Kinase Inhibitors- Gefitinib, Erlotinib – HER 2 Inhibitors • Monoclonal Antibodies- Trastuzumab, Pertuzumab • Tyrosine Kinase Inhibitors • VEGF Family – VEGF Inhibitors • Monoclonal Antibodies- Bevacizumab • Tyrosine Kinase Inhibitors

24. Multi Targeted Therapies • Dual kinase Inhibitor – EGFR/VEGF Inhibitors • Tyrosine Kinase Inhibitors- Vandatanib (ZD6474) – EGFR/HER 2 Inhibitors • Tyrosine Kinase Inhibitors- Lapatinib • Multi kinase Inhibitor – VEGFR, PDGFR, KIT and FLT3R • Tyrosine Kinase inhibitor- Sunitinib – VEGFR2 and VEGFR3, FLT-3, PDGFR, c-KIT • Tyrosine Kinase Inhibitor- Sorafenib – Sorafenib is an oral inhibitor of RAF

25. Targeted Therapies • Kinase Inhibitors –PDGFR Inhibitors- • Tyrosine Kinase Inhibitors- Imatinib –Proteosome Inhibitors – Apoptosis • Tyrosine Kinase Inhibitors- Bortezomib

26. Molecular targeted therapy • Large molecules (antibodies) – long t1/2 less frequent adm – High specificity – Too large to cross epi. less GI toxicity – Limited bioavailability /Distibution to certain anatomic sites – Risk of allergic/ anaphylactic response • Small molecules – Short t1/2 daily dosing – Oral bioavailability – No antibody response – High tissue penetration – High GI toxicity

27. TK Intracellular Domain Transmembrane Domain Extracellular Domain EGFR Structure

28. Overexpression of ErbB-1 and ErbB-2 in Solid Tumors Tumor Type Overexpressing ErbB-1 (%) Overexpressing ErbB-2 (%) Bladder 31%-48% 7%-36% Breast 14%-91% 10%-37% Colorectal 25%-77% 7% Esophageal 71% 13%-73% Glioma 40%-50% – NSCLC 40%-80% 3%-56% Ovary 30%-75% 20%-32% Pancreatic 30%-50% – Renal 50%-90% 24%-40% Head and Neck 30%-75% 32%-62% Stomach – 5%-55% Rowinsky. Horiz Cancer Ther 2001; 2:3-35; Itakura et al. Cancer 1994; 74:795-804

29. TK TKTK erbB1 HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4 No specific ligands - often acts as dimer partner Heregulins NRG2 NRG3 Heregulins β-cellulin EGF, TGFa , b Cellulin Amphiregulin, HB-EGF Human Epidermal Growth Factor Receptor Family

30. TK EGFR Function in Normal Cell TKATP ATP Cell Proliferation Antiapoptosis Angiogenesis Gene Transcription Cell Cycle Progression +

31. TKTK EGFR signal transduction in tumour cells Survival (anti-apoptosis) PI3-K STAT3 AKTPTEN MEK Gene transcription MAPK Proliferation/ maturation Chemotherapy / radiotherapy resistance Angiogenesis Metastasis pY pY RAS RAF SOS GRB2pY G1 SM G2

32. TK TK TK TK Strategies to inhibit EGFR signaling - - - - EGFR tyrosine kinase inhibitors Anti-EGFR mAbs Anti-ligand mAbs Bispecific Abs Immuneeffectorcell ATP

33. EGFR signal transduction in tumor cells Survival (anti-apoptosis) PI3-K EGFR Ligand PTEN AKT STAT3 MEK Gene transcription Cell cycle progression DNA Myc Myc Cyclin D1 JunFos P P MAPK Proliferation / maturation Chemotherapy / radiotherapy resistance Angiogenesis Metastasis Cyclin D1 EGFR-TKKK pY pY RAS RAFSOS GRB2pY

34. FDA-Approved TKIs Generic Name Cancer Imatinib CML,GIST, others Dasatinib CML,ALL Nilotinib CML Gefitinib Lung Erlotinib Lung, Pancreas Lapatinib Breast Sorafenib Kidney, Liver Sunitinib Kidney

36.  In recent years,TKs have increasingly become an important focus in targeted drug development.2,3,4,5,6There are two main groups ofTKs: receptorTKs and nonreceptor (cellular)TKs. ReceptorTKs, which consist of an extracellular domain, a transmembrane domain, and an intracellular domain, are stimulated by growth factors, and recruit a series of downstream effector molecules to conduct complex activation pathways. NonreceptorTKs are present within the cytoplasm, nucleus, or the intracellular portion of the plasma membrane. SeveralTKs have been implicated in oncogenesis, and research in cell signaling has allowed insight into how aberrant activation of signaling cascades originating fromTKs contributes to the formation of tumors.Thus, antitumor properties resulting fromTK inhibition is an important focus for drug development.Two methods of inhibitingTK activation have been used  First, monoclonal antibodies have been used to compete for the extracellular ligand domain of receptorTKs through ligand sequestration (e.g., bevacizumab) or receptor binding (e.g. cetuximab).These antibodies limit binding of the actual ligand and prohibit activation of the ensuing signal cascade. Several monoclonal antibodies directed against the extracellular domain of receptorTKs have shown promise against a variety of tumor types; however, most kinase activities are located in the intracellular domain.

37. The second method of blockingTK activation is through the use of agents that prohibit the phosphorylation of intracellular tyrosine residues located on receptorTKs (e.g., erlotinib) or cytosolic TKs (e.g., imatinib) through the blocking of their adenosine 5â€²-triphosphate (ATP)-binding sites These agents are referred to as small-molecule tyrosine kinase inhibitors (TKIs).

38. Role of EGF INHIBITORS IN BREAST CANCER TRASTUZUMAB

39. Transtuzumab /Herceptin ( Genetech) • Recombinant humanised antibody directed against extracellular domain of Her2/neu EGFR. • MOA:-Downregulates Her2/neu receptor/Inhibits signalling/Apoptosis/ADCC /CMCL • Half life 5-6 D • Approved Indications: 1. MBC- First line with taxane in Her-2/neu postive tumours 2. MBC –second/third line single agent 3. Adjuvant therapy Node positive/Her-2/neu positive breast cancer with standard AC+Taxane • Doses: 8 mg/kg over 90 mins loading followed by 6 mg/Kg 3weekly over 30 min • Doses: 4 mg/kg loading over 90 min followed by 2 mg/kg weekly over 30 min • Caution/ toxicity 1. Baseline LVEF>55% (cautious with antracyclines)- CHF 2. Infusion reactions-fever, chills, bronchospasm,flushing,palpitaion,hypotension,angioedema 3. Pulmonary infiltrates 4. Myelosuppression.

40. Normal HER2 expression Normal Epithelial cell has 2 copies of HER 2 gene & 20000 to 50000 HER 2 receptors on cell surface

41. HER2 amplification  HER2 overexpression Mutations affecting HER 2 gene results in gene amplification thereby Causing 100 fold increase in no. of HER 2 receptors on cell surface

42. HER2 overexpression  tumour proliferation Excess amounts of HER 2 leads to Tumor Proliferation Prof. Tim Cooke at Special EONS symposia, ECCO 10, Austria

43. Binding of Trastuzumab to HER2

44. HER2 in Breast Cancer Slamon et al. 1987 HER2 oncoprotein overexpression HER2 oncogene amplification Shortened median survival HER2 overexpressing 3 years HER2 normal 6–7 years

45. Trastuzumab (Herceptin) • Humanised monoclonal antibody against EC domain of HER2 • 20-30% of CaBR  overexpress/amplification HER2  poor response • Poorly diff / high grade • Lack ER positivity  poor res. to HT • Low Tpot, high S-phase, MIB-1, Ki-67 • Poor res. to CT (5FU,MTx,Cyclophos) • Single agent in MBC response  14% • Phase I  Herceptin + CTRT in Ca Esophagus(pacli+cisplat)  feasible

46. 0 No membrane staining is observed, or staining is observed in <10% of tumor cells. Receptors/Cell ~20,000 1+ A faint/barely perceptible membrane staining is detected in >10% of the tumor cells. The cells are stained only in part of their membrane. Receptors/Cell ~100,000 2+ A weak-to-moderate complete membrane staining is observed in >10% of the tumor cells. Receptors/Cell ~500,000 3+ A moderate-to-strong complete membrane staining is observed in >10% of the tumor cells. Receptors/Cell ~1-2 million HER-2:GRADING

47. FISH for HER2 status detection Normal Amplification

48. 1694 pts Menopausal: both LN: both Hormone: both HER2+ Adjuvant C/T New England Journal of Medicine 2005; 353: 1659-1672HERA 2001-2005 Adjuvant C/T Adjuvant C/T Herceptin 1 yr Herceptin 2 yr Observation Herceptin: 8mg/kg loading, 6mg/kg q3w

53. NSABP B-31 2000-2005 AC x 4 T: 225mg/m2, q3w H: 4mg/kg ->2mk/kg/wk A: 60mg/m2, D1 C: 600mg/m2, D1 q3w AC x 4 2043 pts Menopausal: both LN: positive Hormone: both HER2+ T x 4 T x 4 H x 52 1 2 NCCTG N9831 2000-2005 2766 pts Menopausal: both LN: both Hormone: both HER2+ AC x 4 H x 52 AC x 4 AC x 4 T x 12 T: 80mg/m2/wk A B C New England Journal of Medicine 2005; 353: 1673-1684 T x 12 T x 12 H x 52

54. Joint Analysis AC x 41 AC x 4A AC x 4 T x 4 2 AC x 4C 1679 pts 1672 pts H x 52 H x 52 New England Journal of Medicine 2005; 353: 1673-1684 DFS OS T x 12 T x 12 T x 4 q3w qw

55. FinHer, Finland 2000-2003 1010 pts Menopausal: both Hormone: both LN: positive or LN- & <2cm & PR- Vinorelbine x 3 Taxotere x 3 FEC x 3 FEC x 3 Herceptin (qw) x9 Vinorelbine x 3 Taxotere x 3 FEC x 3 FEC x 3 Herceptin (qw) x9 HER2+ 232 pts HER2- 778 pts F:600mg/m2,D1 E:60mg/m2, D1 C:600mg/m2,D1 N: 25mg/m2, D1,8,15; q3w T: 100mg/m2, D1; q3w H: 4mg/kg  2mg/kg,qw q3w Vinorelbine x 3 Taxotere x 3 FEC x 3 FEC x 3

57. The median left ventricular ejection fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up; only one woman treated with trastuzumab was diagnosed with a heart failure.

61. Meta -analysis

62. OS and DFS better for Herceptin

63. LAPATINIB-dual kinase inhibitor

64. Lapatinib: Targeting EGFR and HER2 • Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2 – Blocks signaling through EGFR and HER2 homodimers and heterodimers – May also prevent signaling between ErbB1/ErbB2 and other ErbB family members Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94. Xia W, et al. Oncogene. 2002;21:6255-6263. PTEN Lapatinib P13K pAkt Ras Raf pErk Shc Grb2 So8 Phospholipid cell membrane

65. Lapatinib- Tykerb (GSK) • Small molecule dual TKI- intracellular domain of EGFR/HER-2neu • Metabolised By CYP3A4 liver microsomal enzymes. • Approved indication:- 1. With cepcitabine in advanced/metastatic Her-2/neu breast cancer progressed on antracyclines, taxanes and herceptin • Dose: 1250 mg PO D1-21 with Cepcitabine 1000mg/m2 D1-D14 in 21 day cycle. • Drug interaction: Cautious with Enzyme inducers/suppressors and with warfarin. Caution/ toxicity 1. Diarrhoea 2. Cardiotoxicity:LVEF 3. Prolonged QT interval- hypokalemia,hypomagnesemia,hypercalcemia 4. Hepatic- raised transaminases. 5. Rash

66. LAPATINIB • Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. 1. objective tumor response and clinical benefit rates were 7.7% and 14.1%, respectively. Blackwell,Annals of Oncology 20: 1026–1031, 2009 • Efficacy and Safety of Lapatinib As First-Line Therapy for ErbB2-Amplified Locally Advanced or Metastatic Breast Cancer • The overall response rate (complete response [CR] plus partial response [PR]) was 24% • 31% of patients derived clinical benefit (CR, PR, or stable disease for 24 weeks Gomez et al. Clin Oncol 26:2999-3005 • Lapatinib plus Letrozole as First-Line Therapy for HER-2 Hormone Receptor– Positive Metastatic Breast Cancer • objective response rate (ORR) (28% versus 15%) and clinical benefit rate (CBR) (48% versus 29%) » SCHWARTZBERG et al, The Oncologist 2010;15:122–129

67. Lapatinib plus capecitabine versus capecitabine alone for HER2+ (ErbB2+) metastatic breast cancer: quality-of-life assessment • The longer time to disease progression with lapatinib+capecitabine versus capecitabine alone was achieved without more time with serious AEs. • L+C combination therapy provided on average 6.1 weeks more quality- adjusted survival than monotherapy for patients in this study (p =0.006). Zhou X, Breast Cancer Res Treat. 2009 Oct;117(3):577-89.

68. BCR-ABL Tyrosine Kinase Inhibitors • Mechanism of action : • IMATINIB & NILOTINIB: bind to a segment of the kinase domain that fixes the enzyme in a closed or nonfunctional state, in which the protein is unable to bind its substrate/phosphate donor, ATP. • DASATINIB: binds both the open and closed configuration of BCR-ABL kinase.

69. Imatinib (Gleevec) 69

70. BCR-ABL Tyrosine Kinase Inhibitors • PHARMACOKINETICS 0f Imatinib / Dasatinib • Absorption – Oral bioavailability ~ 98% • Distribution – highly protein bound • Metabolism - Primarily by CYP3A4 • Elimination – Fecal ~ 65-80% renal ~ 10-13% – Half life = Imatinib-18 hrs, N-desmethyl derivative- 40 hrs Dasatinib- 3-5 hrs Nilotinib- 17 hrs

71. IMATINIB MESYLATE • First molecularly targeted protein kinase inhibitor to receive FDA approval. • It targets the BCR-ABL tyrosine kinase, which underlies chronic myelogenous leukemia (CML). • BCR-ABL tyrosine kinase is present in virtually all patients with chronic myelogenous leukemia (CML) and some patients with acute lymphoblastic leukemia (ALL)

72. IMATINIB MESYLATE Dosing and Administration • Treatment of Philadelphia chromosome(+) chronic myelogenous leukemia – Chronic phase, initial therapy • 400 mg PO once daily - continue as long as the patient continues to benefit • May increase to 600 mg PO once daily – Accelerated phase or blast crisis • 600 mg PO once daily - continue as long as the patient continues to benefit • May increase to 800 mg/day PO

73. IMATINIB MESYLATE • Toxicity • Gastrointestinal – Nausea, vomiting, abdominal pain • Edema – Periorbital edema or peripheral edema in the lower extremities • Diarrhea • Muscle cramps • Fatigue • Skin rash • Cytopenias

74. Imatinib (Gleevec®) FDA Approved Indications • Chronic Myeloid Leukemia • Pediatric CML • Acute Lymphoblastic Leukemia • Gastrointestinal Stromal Tumors • Myelodysplastic/Myeloproliferative Diseases • Aggressive Systemic Mastocytosis • Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia • Dermatofibrosarcoma Protuberans

75. DASATINIB • Multi-kinase inhibitor • BCR-ABL, SRC family, c-KIT, EPHA2, PDGFRβ • FDA Approved Indications – Treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase CML – Treatment of adults with Philadelphia- chromosome (+) ALL with resistance or intolerance to prior therapy

76. NILOTINIB • Indication: treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant to or intolerant to prior therapy that included imatinib.

77. NILOTINIB • Pharmacokinetics • Absorption – Peak plasma levels – 3 hours – Approximately 30% of an oral dose of Nilotinib is absorbed after administration – Food (fatty meal) increases absorption • Distribution – Highly protein bound – Plasma concentrations reach a steady state only after 8 days of daily dosing

78. NILOTINIB Toxicities • Thrombocytopenia and Neutropenia • QT-prolongation – with sudden death reported • Liver function abnormality – elevated bilirubin,AST/ALT and alkaline phosphatase • Electrolyte abnormality ( hyper and hypo K, hypo Mg, Phos, Ca, Na)

79. Mechanism of resistance to Bcr-Abl kinase inhibitors • POINT MUTATIONS CONTACT POINTS BETWEEN Imatinib and the enzyme become the sites of mutation. • Amplification of Wild type of Kinase gene • Philadelphia –ve clones.

80. Angiogenesis VEGF

81. Angiogenesis is involved throughout tumour formation, growth & metastasis Adapted from Poon RT-P, et al. J Clin Oncol 2001;19:1207–25 Stages at which angiogenesis plays a role in tumour progression Premalignant stage Malignant tumour Tumour growth Vascular invasion Dormant micrometastasis Overt metastasis (Avascular tumour) (Angiogenic switch) (Vascularised tumour) (Tumour cell intravasation) (Seeding in distant organs) (Secondary angiogenesis)

82. Bevacizumab/Avastin-Genetech • Recombinant humanised monoclonal antibody directed against VEGF-A. • MOA: inhibits neoangiogenesis/improves tumor blood flow/ADCC/CMCL. • Approved indications: 1. Metastatic/advanced colorectal cancer first line with 5FU 2. Metastatic/advanced colorectal cancer second/ third line with FOLFIRI 3. Single agent in High grade gliomas progressed on previous chemotherapy 4. Her2/neu negative metastatic breast cancer as first line with taxane. 5. Metastatic RCC with Interferons. 6. Locally advance/Metastatic Adeno ca lung nonsmokers/ pheripheral/non brain mets as first line with platin doublet. Doses 15mg/kg (lung) 3 wkly 10mg/kg (RCC,colorectal,Brain, breast)-2 wkly Caution/ toxicity 1. Thromboembolism/ MI 2. Hypertension 3. Hemoptysis 4. Wound dehisence/ delayed healing 5. Bowel perforation 6. GI hemorrhage, epistaxis 7. RPLS 8. Interstitial pneumonia 9. Infusional reactions 10.Nephrotic syndromme

83. The VEGF Family and Its Receptors Neufeld G, et al. FASEB J. 1999;13:9-22. VEGFR-3 (Flt-4) VEGFR-2 (Flk-1/KDR) VEGFR-1 (Flt-1) Angiogenesis Lymphangiogenesis Angiogenesis Lymphangiogenesis PIGF VEGF-A VEGF-B VEGF-C VEGF-D

84. Targeting VEGF: The Bevacizumab Story P P P P VEGF Bevacizumab

85. VEGF Bevacizumab P P P P VEGF Activation BLOCKED Targeting VEGF: The Bevacizumab Story

86. Combination therapy significantly increased the response rates (19.8% v 9.1%; P .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio 0.98).

87. BEVACIZUMAB •The addition of bevacizumab to paclitaxel resulted in a statistically significant improvement in PFS (0.48, 95% CI, 0.385 to 0.607; P.0001 •Improvement in median PFS (11.3 v 5.8 months

88. LUNG GEFITINIB (Iressa)

89. Gefitinib/Irressa (AstraZenca) • Small molecule TKI- intracellular domain EGFR • Proposed resistance: Mutation intracellular domain/ KRAS mutuation/ cross talk • Metabolism: Liver CYP3A4 microsomal enzymes. • Approved indication: 1. Locally advance/metastatic NSCLC progression to platin /taxanes based chemotherapy • Drug interaction; Enxymes inducer/suppressors/ warfarin • Special mention 1. Response within first few weeks of therapy 2. Bronchoalvelor ,adenoca, females ,nonsmokers,asian increased sensitivity • CAUTION/ TOXICITY 1. Hypertension 2. Pruritis,rash 3. Hemoptysis 4. Nausea/ vomiting

90. Phase II Studies IDEAL 1 and 2 trial design IRESSA 250 mg/day IRESSA 500 mg/day Continue IRESSA until disease progression or unacceptable toxicity IDEAL, IRESSA Dose Evaluation in Advanced Lung cancer Randomisation  IDEAL 1 (n=209) 1 or 2 prior regimens  IDEAL 2 (n=216) >2 prior regimens Fukuoka et al 2003; Kris et al 2003 Primary end points  Objective tumour response  Symptom improvement (IDEAL 2)  Safety (IDEAL 1)

91. Tumour response and disease control rates with 250 mg gefitinib IDEAL 1 IDEAL 2 18.4 0 10 20 30 40 50 60 54.4 42.2 11.8 Objective response Disease control Patients (%) Objective response, complete plus partial response Disease control, objective response plus stable disease Fukuoka et al 2003; Kris et al 2003

92. IDEAL 1 and 2: rapid and durable symptom improvement • Symptom improvement occurred rapidly; median time to symptom improvement was 8 days in IDEAL 1 and 10 days in IDEAL 2 • Moreover, symptom improvement was durable, with the median duration being >6 months in both studies

93. Phase III placebo-controlled study (ISEL) of gefitinib (IRESSA) plus best supportive care in patients with advanced non-small-cell lung cancer (NSCLC) who had received 1 or 2 prior chemotherapy regimens ISEL study Thatcher, N; Chang, A, Parikh, P et al. Lancet 2005; 366: 1527-37. ISEL – IRESSA Survival Evaluation in Lung Cancer

94. End points Primary:  Survival Secondary:  TTF  ORR  QoL, symptoms  Safety Exploratory:  Tumour biomarker analysis (eg EGFR) ISEL trial design • 1692 patients in 210 centres across 28 countries • Stratified for histology, gender, intolerant / refractory, PS and smoking history Gefitinib (250 mg/day) + BSC Placebo + BSC Randomisation (2:1 ratio) CT, chemotherapy; BSC, best supportive care; TTF, time to treatment failure; ORR, objective response rate; QoL, quality of life Patients with:  Histologically / cytologically confirmed NSCLC  Locally advanced or metastatic disease  1 or 2 prior CT regimens  Intolerant to most recent CT regimen or progression <90 days of last CT cycle

95. 1692 Patients in 210 Centres Across 28 Countries Northern Europe 16% Australia 2% Canada 1% Central and Eastern Europe 36% Southern Europe 7% Asia 24% Central and South America 14%

96. 0 2 4 6 8 10 12 14 Survival in the overall population 16 Time (months) At risk: 1692 1347 877 485 252 104 31 2 Median, months 1-year survival, % Log-rank HR (95% CI), 0.89 (0.77, 1.02); p=0.087 Cox analysis, p=0.030 Gefitinib 5.6 27 Placebo 5.1 21 0.0 0.2 0.4 0.6 0.8 1.0Proportion surviving Gefitinib Placebo HR, hazard ratio; CI, confidence interval Median follow-up 7 months (range 3-15), 58% deaths

97. Median, months 1-year survival, % Log-rank HR (95% CI), 0.84 (0.68, 1.03); p=0.089 Cox analysis, p=0.033 Gefitinib 6.3 30 Placebo 5.4 18 Survival in adenocarcinoma population Time (months) At risk: 812 669 446 262 145 66 18 1 Gefitinib Placebo 0 2 4 6 8 10 12 14 16 0.0 0.2 0.4 0.6 0.8 1.0Proportion surviving

98. Survival HR and 95% CI 0.4 0.6 0.8 1.0 1.5 Adenocarcinoma All patients Female PS 0, 1 1 prior line Refractory Never smoked Non-adenocarcinoma Ever smoked Intolerant 2 prior lines PS 2, 3 Male 11.9% 8.0% 14.7% 8.8% 7.6% 7.9% 18.1% 4.8% 5.3% 9.4% 8.4% 6.6% 5.1% Gefitinib ORR Survival: effects in subsets (1) Favours gefitinib Favours placebo

99. Survival Survival: effects in subsets (2) 11.1% 8.0% 12.4% 7.4% 6.9% 9.0% 6.8% 7.5% 10.1% 7.7% 6.4% 7.2% 10.2% Prior docetaxel All patients Asian ethnicity <65 years No prior docetaxel >65 years Non-Asian ethnicity Prior CT response: PD/NE Prior CT response: CR/PR Prior CT response: SD Time since Dx: <6 months Time since Dx: 6-12 months Time since Dx: >12 months Gefitinib ORR Favours gefitinib Favours placebo 0.4 0.6 0.8 1.0 1.5 HR and 95% CI

100. Survival by smoking history Gefitinib Placebo Proportionsurviving 0 2 4 6 8 10 12 14 16 0.0 1.0 0.8 0.6 0.4 0.2 Time (months) 0 2 4 6 8 10 12 14 16 Cox regression HR (95% CI), 0.92 (0.79, 1.06); p=0.242 Median: 5.0 vs 4.9 months Never smoked (n=375) Ever smoked (n=1317) Cox regression HR (95% CI), 0.67 (0.49, 0.92); p=0.012 Median: 8.9 vs 6.1 months

101. Survival by ethnic originProportionsurviving Time (months) Cox regression HR (95% CI), 0.92 (0.80, 1.07); p=0.294 Median 5.2 vs 5.1 months Asian ethnicity (n=342) Non-Asian ethnicity (n=1350) Cox regression HR (95% CI), 0.66 (0.48, 0.91); p=0.010 Median: 9.5 vs 5.5 months 0.0 1.0 0.8 0.6 0.4 0.2 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16 Gefitinib Placebo

102. Tolerability data • Adverse-event (AE) profile consistent with established safety profile for gefitinib • Rash (37% vs 10%) and diarrhoea (27% vs 9%) were the most common AEs for gefitinib- vs placebo-treated patients • No difference in incidence of serious AEs (19% for gefitinib vs 17% for placebo) • Few withdrawals due to AEs (5% for gefitinib vs 2% for placebo) • No difference in the incidence of interstitial lung disease- like events (1% in each arm)

103. • Gefitinib in combination with platinum doublets – gemcitabine / cisplatin (INTACT 11) – carboplatin / paclitaxel (INTACT 22) • No survival advantage over placebo reported in Phase III trials for Iressa (INTACT 1 and 2) INTACT, IRESSA NSCLC Trial Assessing Combination Treatment 1st-line Iressa (Gefitinib) + CT combination therapy in NSCLC 1Giaccone et al 2004; 2Herbst et al 2004

105. Why was there no additive effect of Gefitinib in combination with chemotherapy in INTACT 1 & 2? • No indication from supportive studies of a pharmacokinetic interaction between Gefitinib and any of the chemotherapy agents • Possible that – chemotherapy (at maximum tolerated dose) and Gefitinib are targeting the same cell population and chemotherapy response thus masks that of Gefitinib – chemotherapy directly/indirectly affects EGFR function/expression thereby reducing/abrogating the effects of Gefitinib

106. •phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmoke or former light smokers. •gefitinib (250 mg per day) (609 patients) or carboplatin plus paclitaxel (608 patients). •The primary end point was progression-free survival. Ipass- Iressa Pan Asia Study

107. •rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group. neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin–paclitaxel group.

108. First-line gefitinib for patients with advanced NSCLC who were selected on the basis of EGFR mutations improved PFS, with acceptable toxicity, as compared with standard chemotherapy

109. Erlotinib/Tarceva ( Genetech) • Small molecule TKI- intracellular domain EGFR • Proposed resistance: Mutation intracellular domain/ KRAS mutuation/ cross talk • Metabolism: Liver CYP3A4 microsomal enzymes. • Approved indication: 1. Single agent(monotherapy) - NSCLC resistant/ progression to at least one line of chemotherapy. 2. In combination with gemcitabine as first line in advanced/ metastatic pancreatic carcinoma • Drug interaction; Enxymes inducer/suppressors/ warfarin • Special mention 1. Close monitor in patients with pulmonary symptoms- cough,dyspnea 2. Dose increase to 300mg/d in active smokers • CAUTION/ TOXICITY 1. Diarrhoea 2. Interstitial pneumonia 3. Pruritis,rash 4. Hemoptysis

110. Erlotinib BR21 • randomized, placebo-controlled, double-blind trial • stage IIIB or IV non–small-cell lung cancer, with performance status from 0 to 2 • had received one or two prior chemotherapy regimens • 2:1 ratio to receive oral erlotinib, at a dose of 150 mg daily,or placebo. • 731 patients, 49 percent had received two prior chemotherapy regimens

111. •response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group (P<0.001) •median duration of the response was 7.9 months and 3.7 months •Overall survival was 6.7 months and 4.7 months, respectively (P<0.001) •Progression-free survival was 2.2 months and 1.8 months (P<0.001) Five percent of patients discontinued erlotinib because of toxic effects.

114. • TRIBUTE: A Phase III Trial of Erlotinib Hydrochloride (OSI-774) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non–Small-Cell Lung Cancer Herbst , J Cli Onc 25;12:2007 • Erlotinib with concurrent carboplatin and paclitaxel did not confer a survival advantage over • carboplatin and paclitaxel alone in patients with previously untreated advanced NSCLC Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non–Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial No improvement in survival Non smokers

115. Phase II Trial of Cetuximab in Patients With Previously Treated Non–Small-Cell Lung Cancer • response rate with single-agent cetuximab in this heavily pretreated patient population with advanced NSCLC was only 4.5%, • the disease control rates and overall survival seem comparable to that of pemetrexed, docetaxel, and erlotinib in similar groups of patients. J Clin Oncol 24:5253-5258 • Randomized Phase II Trial of Docetaxel Plus Cetuximab or Docetaxel Plus Bortezomib in Patients With Advanced Non– Small-Cell Lung Cancer and a Performance Status of 2: CALGB 30402 • While the results in the D + C arm are numerically superior, These results confirm the poor prognosis associated with a PS of 2 and the difficulty in translating recent advances in targeted therapy J Clin Oncol 27:4487-4491.

116. Targeted therapy + chemo –First line •ECOG -878 patients with recurrent or advanced non–small-cell lung cancer (stage IIIB or IV) •Group A - chemotherapy with paclitaxel and carboplatin alone (444) 3 weeks for six cycles •Group B - paclitaxel and carboplatin plus bevacizumab (434). • bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable •squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status, >1) were excluded

117. Median Survival-12.3m Vs 10.3mP = 0.003 PFS – 6.2 Vs 4.5 mthsP<0.001 response rates of 35% and 15% (P<0.001). bleeding were 4.4% and 0.7%, respectively (P<0.001) 15 treatment-related deaths in the chemotherapy-plus- bevacizumab group, including 5 from pulmonary hemorrhage..

118. Targeted therapy - Head neck

119. Cetuximab/ Erbitux (BMS/Eli Lilly) • Recombinant chimeric IgG1 monoclonal AB- EGFR extracellular domain. • MOA: 10 X more affinity than ligands/ inhibits EGFR signalling/ ADCC/CMCL. • Resistance: Decreased affinity OF receptor/decreased expression/KRAS/BRAF/cross talk • Half life :5-6 days • Approved indications 1. Metastatic colorectal carcinoma: first line with irinotecan/irenotecan intolerant/resistant non KRAS mutation (approved wild type KRAS) 2. Head neck cancer: Along with radiation in locally advanced HNSCC. Dose : 400mg/m2 IV over 120 mins (loading) : 250 mg /m2 every week (maintenance) Special mention: Hypersensitivity to murine porteins Level of EGFR expression does not predict cetuximab response: no need for EGFR testing. KRAS mutation test should be performed. Acneform rash correlated/predictor of better response/survival Toxcity 1. Rash 2. Interestitial pneumonia 3. Infusional reactions

120. Author No. Cancer Chemother apy RR (%) Median PFS Median OS Herbst 79 SCC - POD on CDDP- based CDDP- based + cetuximab 6 – 20 2.0 - 3.0 4.3 - 6.1 Baselga 96 SCC - POD on platin- based CDDP- based + cetuximab 10 – 11 2.4 - 2.8 4.9 - 6.0 Trigo 103 SCC - POD on platin- based cetuximab 13 2.3 5.9 Burtness 117 SCC - no chemo for R/M CDDP- based +CDDP cetuximab 10 26 2.7 4.2 8.0 9.2 Cetuximab for Recurrent or Metastatic Head and Neck Cancer

121. EXTREME TRIAL The response rate for patients in arm A with skin toxicity was 33%, compared with 7% for patients who did not develop skin toxicity (P.08).

122. N Engl J Med 2008;359:1116-27 Cetuximab plus platinum–fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck.

126. overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0·49, 0·34–0·72; p=0·002).

128. Kalyani N, Agarwal JP et al

129. CONCLUSION • Kinase inhibitors are most effective against tumors that are heavily, perhaps solely, dependent on the targeted kinase. • Monotherapy with TKIs is limited by the development of resistance. Translational research studies are critical to understanding the results from clinical trials of targeted therapeutics.

Chapter 24 tyrosine kinase inhibitors

Chapter 24 tyrosine kinase inhibitors

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