1. Presented by : PharmD Group 5 Supervised by : Dr. Nashaat Lotfy

2. What is Tyrosine Kinase Non-receptor Tyrosine Kinase inhibitors Receptor Tyrosine Kinase inhibitors Monoclonal Antibodies

3. Targeting antitumor therapy has been directed against cancer specific molecules & signling pathway, thus has more limited non specific toxicities. Tyrosine kinase = phosphorlation of tyrosine residue, this convert tyrosine kinase into active form (i.e switch on ). Tyrosine kinase play an important role in modulation of growth factor signling.

4. TK signaling pathway maintain normal cellular communication & maintain homeostasis (by prevent deregulated pathway or contributed to sensitivity towered apoptotic stimuli ). Excessive activation of receptor tyrosine kinases can lead to uncontrolled growth and malignant transformation. Many defective of tyrosine kinases and associated proteins are oncogenic : V-src ABL EGFR-related family

5. Roles of Tyrosine Kinases Differentiation control Cell cycle control Apoptosis Immune Response scontrol Development control Growth control Cell-cell recognition In cancer cells Angiogensis

6. TYROSINE KINASE TARGETING 1-Receptor TK: a-Platelet derived growth factor ( PDGFR) b-Epidermal growth factor receptor (EGFR) which include ( ErBB2,ErBB3,ErBB4,HER FAMILY). C-Vascular endothelial growth factor receptor (VEGF). D-stem cell factor receptor or (KIT receptor) 2- Non receptor TK : BCR ABL

9. Ligand Binding induces dimerization

10. activation of the intracellular TK ( Protien kinase cascade)

11. TK inhibitor

12. DYSREGULATION OF TK IN CANCER CELLS Strategies for Targeting TK in Cancer Therapy Fusion of Receptor or Non receptor With Partener Protein Dominant Negative protein Imatinib Nilotinib Over expression of receptor TK or ligend Neutralizing Antibody as MAb Or Gefinitib Decrease in factor that limit the activity as Impaired tyrosine phosphatase Mutation of receptor TK causing Constitutive Activation Gefitinib Erlotinib Imatinib Sorafenib

14. Tyrosine kinase targets for anticancer agent Small molecule inhibitor Monoclonal antibodies Receptor TK Non - Receptor TK Antibody to ligand: Antibody to recepto TK (EGFRs ) bevacizumab cetuximab EGFRs TK PDGF Tk VEGF TK trastuzumab imatinib ErlotinibGefitinib Dual Action Imatinib Anti angiogensis sunitinibZD6474 Pazopanib Dual Action lapatinib L eflun -omide Dual Action Sorafenib Dual Action Vatalanib Dual Action Dasatinib Dual Action Nilotinib Temsirolimus Multiple action

15. EGFR Inhibitor Erlotinib (traceva®) Gefitinib (IRESSA®)

16. GEFITINIB IRESSA ® ERLOTINIB (TRACEVA ® ) 250 mg Oral tablet Oral tablet (25mg,100mg,150mg ) Drug description NSCLC 250 mg / daily orally Now it restricted to patient who already received &benefited from therapy. 1- Non small cell lung cancer (NSCLC) 100mg \day after failure of one previous therapy 2- in pancreatic cancer : in combination with gemcitabine as first line therapy. Gemcitabine: 1 mg /m2 weekly for 7 week then 1 week rest, subsequence cycle 1 mg /m2 for 3 week then 1 week rest. Erlotinib 100 mg /day Indication Same as Erlotinib but the Interstitial lung disease (1% ). No MI Rash, diarrhoea, interstitial lung disease which can be fatal (0.8 % alone & 2.3 % in combination with gemcitabine ), treatment should be inerrupted if cough, dyspnoea, fever. Myocardial infaraction( MI ) only in combination with gemcitabine (2.3%) Adverse effect

17. As Erlotinib but no effect of smoking 1-CYP3A4 inhibitors as ketoconazole can increase concentration ( i..e toxicity). 2-CYP3A4 inducer : as Rifampicin can reduced it concentration (i.e efficacy). 3-P-glucoprotien inhibitor : as Ciclosporine : altered distribution or elimination of Erlotinib 4- Antiacid, proton pump inhibitor, H2 antagonist → impaired absorption 5- Smoking :reduce Erlotinib exposure. Drug interactions 60% Bioavilability Hepatic mainlyHepatic 83%Execration Cmax3-7hrs after dosing Cmax2-4 hrs after dosingPlasma pk As ErlotinibDose adjustment only in very advanced liver disease hepatic dysfunction SameCategory DPrengancy SameNo study due to risk of dehydrationPediatric SameNo differences in safety or pk than adultGeriatric use

18. Imatinib mesylate (Gleevec®) Approved by FDA in 2001 Tablets for oral use

19. DOSAGE INDICATIONS 400 mg/day 600 mg/day for adult patients in accelerated phase or blast crisis. For newly diagnosed 340 mg/m /day not exceeding 600 mg /day After resistance to interferone therapy 260mg/m/day Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy Pediatric patients with Ph +CMLin chronic phase 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. Ph+ Acute Lymphoblastic Leukemia (ALL) 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, Kit+ Gastrointestinal Stromal Tumors (GIST).

20. Mutations in c-KIT result in a constitutively active receptor without the normally required ligand binding. In normal cells activation of the receptor only occurs after binding of the corresponding ligand ( the stem cell factor in the case of c- KIT ) This constitutive activation results in stimulation of numerous downstream signal transduction pathways results in malignancy.

21. (CML). Mechanism of Action Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the bcr-abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It inhibits proliferation and induces apoptosis in bcr-abl positive cell lines from Philadelphia chromosome positive chronic myeloid leukemia.

22. Mechanism of Action.)GISTs) Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and c-kit Not all GISTs express c-KIT mutations. Activating mutations in the PDGFRA gene are frequently demonstrated to occur( 3-5% of all GISTs) A mutated PDGFRA, which induces activation of the same signal transduction pathways as gain-of-function mutations in c- KIT.

23. .Mechanism of Action. Panel A shows the BCR-ABL oncoprotein with a molecule of adenosine triphosphate (ATP) in the kinase pocket. The substrate is activated by the phosphorylation of one of its tyrosine residues. It can then activate other downstream effector molecules. When imatinib occupies the kinase pocket (Panel B), the action of BCR-ABL is inhibited, preventing phosphorylation of its substrate.

24. ADVERSE REACTIONS Hepatotoxicity occasionally severe Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. If elevations in bilirubin >3 x institutional upper limit of normal (IULN) or in liver transaminases >5 x IULN occur Gleevec should be withheld until bilirubin levels have returned to a <1.5 x IULN and transaminase levels to <2.5 x IULN.

25. ADVERSE REACTIONS Hematologic Toxicity Anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated

26. Dose Adjustments for Neutropenia and Thrombocytopenia 1. Stop Gleevec until ANC ≥1.5 x 109/L and platelets ≥75 x 10^9/L or GIST (starting dose either 400 mg or 600 mg) 2. Resume treatment with Gleevec at the original starting dose of 400 mg or 600 mg 3. If recurrence of ANC <1.0 x 10^9/L and/or platelets <50 x 10^9/L, repeat step 1 and resume Gleevec at a reduced dose (300 mg if starting dose was 400 mg, 400 mg if starting dose was 600( ANC <1.0x10^9/L and/or Platelets <50 x 10^9/L Chronic Phase CML (starting dose 400mg) or GIST (starting dose either 400 mg or 600 mg) ANC:absolute neutrophile count

27. 1. Reduce dose of Gleevec to 400 mg 3. If cytopenia persists 2 weeks, reduce further to 300 mg 4. If cytopenia persists 4 weeks stop Gleevec until ANC ≥1 x 10^9/L and platelets ≥20 x 10^9/L and then resume treatment at 300 mg ANC <0.5 x 10^9/L and/or Platelets <10 x 10^9/L Accelerated Phase CML and Blast Crisis (starting dose 600mg)

28. ADVERSE REACTIONS Gastrointestinal Disorders Gleevec is associated with GIT irritation ( nausea particularly if taken on empty stomach). Gleevec should be taken with food and a large glass of water to minimize this problem. Fluid Retention and Edema The probability of edema was increased with higher Gleevec dose and age >65 yearsand in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention: (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites

29. ADVERSE REACTIONS Dermatologic Toxicities Hemorrhage Arthralgia, myalgia,and bone pain. Teratogenic

30. Metabolism and Elimination CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 play a minor role in its metabolism. Elimination is predominately in the feces, mostly as metabolites (68% of dose) and urine (13% of dose).

31. Drug Interactions Drugs that May Alter Imatinib Plasma Concentrations Drugs that may increase imatinib plasma concentrations: Drugs that may decrease imatinib plasma concentrations: inhibitors of the CYP3A4 activity (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin). inducers of CYP3A4 activity (e.g., dexamethasone, phenytoin, carbamazepine, rifampin phenobarbital

32. Drug Interactions Drugs that May Have their Plasma Concentration Altered by Gleevec CYP3A4 substrates cyclosporine benzodiazepines, Dihydropyridine calcium channel blockers statins

33. Drug Interactions Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin. Gleevec inhibits acetaminophen O- glucuronidation at therapeutic levels. Systemic exposure to acetaminophen is expected to be increased when coadministered with Gleevec.

34.  Resistance to imatinib is still a problem,mainly in patients in the accelerated Or blast crisis phases of the disease.  Resulting in : relapse or no progression (persistence). Imatinib resistance divided into the broad categories of primary and secondary resistance: 1- Primary resistance to imatinib, defined as an inability to achieve landmark response, is comprised of the 2% of patients who fail to achieve hematologic response and 8-13% who fail to achieve major or complete cytogenetic response using early chronic phase CML treated with imatinib at diagnosis as a benchmark. 2- Patients with secondary resistance—those who achieve but subsequently lose relevant response—is most straightforward for overt relapse such as loss of cytogenetic or hematologic response and progression from chronic to advanced-stage disease.

35. Mechanisms of Imatinib resistance: 1. Over-expression of BCR/ABL & BCR/ABL point mutations in imtinib resistant leukemia: the relapse is characterized by reactivation of BCR/ABL kinase activity. 2. c-Kit & PDGFRa point mutations in GIST: an “enzymatic site” activating mutation which affects that catalytic portion of the KIT receptor kinase is associated with resistant to imatinib.

36. Mechanism of Imatinib resistance: 3. P-glycoprotein up regulation: i.e. over expression of multidrug resistance P-gp (efflux pump). 4. Alpha acid glycoprotein binding of imatinib: the plasma protein alpha 1 acid glycoprotein (AGP) has been proposed to bind to imatinib & prevent imatinib from reaching its target. Strategies to overcome imatinib resistance: 1- Combination therapy with imatinib: to improve response includes; the standard chemotherapeutic agents : cytosine arabinoside, daunorubicin, interferon alpha. 2- Modulation of imatinib dosing: by administration of higher (than conventional) doses of imatinib. 3- Second line therapy: Nilotinib, Dasatinib.

37. It is a selective BCR/ABL tyrosine kinase inhibitor, also it inhibits the receptor tyrosine kinases platelet-derived growth factor receptor (PDGF-R) and c-kit, a receptor tyrosine kinase mutated and constitutively activated in most gastrointestinal stromal tumors (GISTs). Nilotinib

38. Dasatinib It binds to multiple conformations of the ABL kinase, dasatinib inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-B. By targeting these kinases, dasatinib inhibits the overproduction of leukemia cells in the bone marrow of patients with CML and Ph+ALL and allows normal red cell, white cell, and blood platelet production to resume.

39. DasatinibNilotinib SPRYCEL®Tasigna ® Brand name Oral,tabOral, cap.Route of administration treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib. treatment of adults with Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. Philadelphia chromosome- positive chronic myelogenous leukemia in adult patients resistant or intolerant to prior therapy. Ph+ acute lymphoblastic leukemia. Systemic mastocytosis Hypereosinophilic syndrome. Indications

40. DasatinibNilotinib 94% protein bound. eliminated primarily by hepatic metabolism and excreted in feces. excreted <1% in the urine. primarily metabolized by CYP3A4; mean half life ≈ 4 to 6 h. not altered in absorption with co-administration of food. A – AUC ↑ 82% when given after high fat meals. D – 98% protein bound. M – hepatic: oxidation and hydroxylation. E – 90% eliminated in feces; t 1/2 = 17 hrs. PKs

41. DasatinibNilotinib 70 mg orally twice a day, Chronic phase CML: 100 mg once daily. Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL: 70 mg twice daily. Administered orally, with or without a meal. Tablets should not be crushed or cut. 400 mg orally twice daily,approximately 12 hours apart and should not be taken with food. Dose Rifampicin, phenytoin, clozapine, digoxin, simvastatin, famotidine. Clarithromycin, moxifloxacin, telithromycin, Phenytoin, ketoconazole, itraconazole, voriconazole, cloazapine, ritonavir, midazolam, digoxin Drug- drug interactions

42. DasatinibNilotinib Myelosuppression. Bleeding related events. Fluid retention. QT prolongation. QT prolongation and Sudden Deaths. Myelosuppression. Elevated serum lipase. Hepatotoxicity. Electrolyte abnormalities. ADVERSE REACTIONS Diarrhea, anorexia, colitis….Rash, Prorates, Nausea Neutropenia, Thrombocytopenia Side effects Breast feeding.Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome, & breast feeding. Contraindications Category D Pregnancy

43. DasatinibNilotinib Myelosuppression: Severe thrombocytopenia, neutropenia, and anemia may occur and require dose interruption or reduction. Monitor complete blood counts regularly Bleeding Related Events (mostly associated with severe thrombocytopenia): CNS hemorrhages, including fatalities, have occurred. Severe gastrointestinal hemorrhage may require treatment interruptions and transfusions. Black Box Warning Tasigna prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome, Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Warning

44. DasatinibNilotinib Use SPRYCEL with caution in patients requiring medications that inhibit platelet function or anticoagulants. Fluid Retention. QT Prolongation. Use SPRYCEL with caution in patients with hepatic impairment. Patients should avoid food 2 hours before and 1 hour after taking dose. Use with caution in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. Warning

45. SORAFENIB Nexavar®

46. Indications Approved by the FDA on December 20, 2005 for the treatment of patients with advanced renal cell carcinoma. tumor progress The FDA has granted marketing authorization to Nexavar (sorafenib) tablets for the treatment of patients with hepatocellular carcinoma (HCC), the most common form of liver cancer, on November 19, 2007.

48. Mode Of Action Sorafenib is a small molecular inhibitor of several protein kinases (dual specificity kinases).inhibitorprotein kinases Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous. These pathways include Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor.Rafplatelet-derived growth factorVEGFc KitStem cell factor Sorafenib is unique in targeting the Raf/Mek/Erk pathway.

50. Dosage And Administration The recommended daily dose of Sorafenib is 400 mg (2 x 200 mg tablets) taken twice daily without food. Tablets should be taken on empty stomach, (at least 1 hour before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

51. Side effects 1.Risk of myocardial ischemia and/or infarction. 2.Risk of hemorrhage. 3.Risk of hypertension. 4.Risk of dermatologic toxicity (hand-foot skin reaction) 5.Risk of gastrointestinal perforation. 6.Wound healing complications. 7.Fatigue, weight loss, anorexia 8.Teratogenicity and embryofetal toxicity Due to disruption of normal vasculature

52. Drug Interactions 1- Docetaxel & Doxorubicin: Increase in the AUC and Cmax when co- administered with Sorafenib. 2- Fluorouracil: Increase and decrease in the AUC. 3- CYP3A4 Inducers concomitant administration of Sorafenib and CYP3A4 Inducers resulted in reduction of sorafenib AUC. 4- CYP3A4 Inhibitors and CYP Isoform Substrates Sorafenib metabolism is unlikely to be altered by CYP3A4 inhibitors.

53. Hepatic Impairment Sorafenib is cleared primarily by the liver. Comparison of data across studies suggests that in HCC patients with mild (Child-Pugh A) or moderate (Child- Pugh B) hepatic impairment, 400 mg doses of sorafenib appear to be associated with AUC values that were 23 to 65% lower than those of other subjects without hepatic impairment. The AUC of sorafenib is similar between HCC patients with mild (Child-Pugh A) and moderate (Child- Pugh B) hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment

54. Temsirolimus (Torisel®)

55. Indication Renal cell carcinoma (RCC ) as single agent therapy.

56. Dosage and Administration 25 mg IV infused over 30–60 minutes once per week until disease progression.

58. Side effects 1-fatigue, 2- skin rash, stomatitisstomatitis 3-Hematologic abnormalities

59. Drug Interaction & Dose Modification 1- Concomitant Strong CYP3A4 Inhibitors should be avoided (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice. If patients must be co-administered a strong CYP3A4 inhibitor, TORISEL dose reduction to 12.5 mg/week should be considered.

60. 2- Concomitant Strong CYP3A4 Inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a TORISEL dose increase from 25 mg/week up to 50 mg/week should be considered.

61. Trade Name : Tykerb Classification : Signal translation inhibitors Mechanism of Action: Small Cell Molecular Inhibitor of tyrosine Kinase EGFRHER 2 inhibition of critical mitogenic and antiapoptotic signals involved in proliferation, growth, invasion/metastasis, angiogenesis, and response to chemotherapy and/or radiation therapy.

62. Pharmacokinetics Absorption Incomplete and variable Systemic exposure increase with food Distribution 99% bind to plasma protein Peak plasma levels are achieved 4 hrs after ingestion. Steady-state concentration are reached in 6 – 7 days Metabolism Metabolized by the liver by the CYP3A4 and CYP3A5 Elimination Mainly hepatically – 2 % renally

63. Indications Advanced metastatic breast cancer in combination with capecitabine ( prodrug converted to 5-fluorouracil at tumor site) in patients have received prior therapy including an anthracycline, taxane and trastuzumab Dosage Regimen 1250 mg PO Days 1-21 continuously one hour before or one hour after a meal capecitabine 2,000 mg/m2/day on Days 1-14 should be taken with food or within 30 minutes after food 21 days Cycle

64. Drug Interactions Drugs that stimulate CYP3A4. Carbamazebine – rifamibicin, Phenobarbital and St.John's wort Inactivation of Lapatinib Drugs that inihibit CYP3A4 Ketoconazole, erythromycin and clarithromycin Toxicity Lapatinib inhibits human P-glycoprotein Increased conc. Of substrate drugs Lapatinib may inhibit the metabolism of Warfarin

65. Special Consideration 1.Use caution in patient with hepatic impairment, and dose reduction should be considered. 2.Lapatinib may cause reduction of LVEF. Monitor cardiac function at baseline and periodically during therapy. 3.QTprolongation is observed. Monitor QT parameter at baseline 4.Lapatinib should be taken one hour before or after a meal, and the daily dose should not be divided. When capecitabine is co-administered, capecitabine should be taken with a galss of water 30 min. after meals. 5.Avoid grapefruit 6.Closely monitor patient for diarrhea. Aggressive management should be followed 7.Pregnancy category D.

66. Side Effects 1.Diarrhea 2.Reduction of LVEF and QT prolongation. 3.Myelosuppression with anemia more common than thrombocytopenia or neutopenia. 4.Fatigue and anorexia 5.Mild to moderate elevation of serum transaminases and serum bilirubin. 6.Hand-food syndrome and skin rash.

67. Mechanism of Action: Sunitinib is oral small molecule that inhibits multiple receptor tyrosine kinases (RTKs ), some of which are implicated in: 1- Tumor growth, 2- Pathologic angiogenesis 3- Metastatic progression of cancer. Sunitinib was identified as an inhibitor of 1- Platelet-derived growth factor receptors, 2- Vascular endothelial growth factor receptors, 3- Stem cell factor receptor, 4- Colony stimulating factor receptor Type 1 (CSF-1R)

69. Indications FDA approved Sunitinib in 2006 for the treatment of adults with: 1- Advanced renal cellular carcinoma 2- Gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.(Gleevec®) Recommended dose : 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2). SUTENT may be taken with or without food.

70. Pharmacokinetics Absorption oral bioavailability 100% Not affected with food. Distribution 90 – 95 % binds to plasma protein. Peak plasma level are achei ed 6 – 12 hrs. Steady state concentration reached 10 – 14 days. Metabolism Metabolized mainly by the liver by CYP3A4 produce primary active Elimination Mainly hepatically – 16 % renally

71. Special Considerations: 1.Baseline and periodic evaluation of LVEF should be performed. 2.Use with caution in patient with underlying cardiac disease, especially those who presented with cardiac events within 12 months prior to initiation of Sunitinib such as MI & CHF. 3.In presence of clinical manifestations of CHF, discontinuation if Sunitinib is recommended or reduction of the dose 4.Closely monitoring of blood pressure ( Hypertension) 5.Monitoring of adrenal insufficiency in patient who experience increased stress such as surgery, trauma or sever infection. 6.Closely monitoring of thyroid function, as Sunitinib results is hypothyroidism. 7.Avoid grapefruit or grapefruit juice. 8.Pregnancy category D. Breast feeding should be avoided

72. 1.Hypertension. 2.Yellowish discoloration of the skin, skin rash, depigmentation of hair and/or skin 3.Bleeding complication with epistaxis. 4.Fatigue and asthma. 5.Diarrhea 6.Myelosuppression with neutropenia. 7.Adrenal insufficiency and hypothyroidism. Side Effects:Drug Interactions CYP3A4 Inducers ( ↓Sreum level of Sunitinb) Dexamethasone, phenytoin, carbamazepine, rifampin,Phenobarbital, St. John’s Wort CYP3A4 Inhibitors ( ↑Sreum level of Sunitinb) Ketoconazole, itraconazole, clarithromycin, saquinavir, grapefruit

74. Trastuzumab (Herceptin®) Bevacizumab (Avastin®) Cetuximab (Erbitux®)

75. Mechanism of Action Mechanism of Resistance Indications and Dosage Ranges Drug Interactions Special considerations Trastuzumab (Herceptin®)

76. Mechanism of Action

77. Breast cancer cells divide and grow when human epidermal growth factor protein attaches itself to another protein known as HER2 (human epidermal growth factor receptor-2), which is found on the surface of some breast cancer cells. Herceptin blocks this process by attaching itself to the HER2 protein i.e Inhibits HER-2 intercellular signalling pathways. Herceptin also works by attracting the body’s own immune cells to help destroy the cancer cells. HER2 Testing (to inhibit the proliferation of human tumor cells that overexpress HER2) Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown.

78. Mechanism of Resistance Mutation in the HER-2/neu growth factor receptor leading to decreased binding affinity to trastuzumab. Decreased expression of HER-2/neu receptors. Activation/induction of alternative cellular signalling pathways, such as IGF-IR (Insulin- like growth factor-I receptor) which plays an important role in tumor cell growth and survival

79. Indications and Dosage Ranges IndicationDosage Range Metastatic breast cancer – First-line therapy in combination with paclitaxel Recommended loading dose of 4 mg/kg IV administered over 90 minutes, followed by maintenance dose of 2 mg/kg IV on a weekly basis. Alternative schedule is to give a loading dose of 9 mg/kg IV administered over 90 minutes, followed by maintenance dose of 6 mg/kg IV every 3 weeks. Matastatic breast cancer – Second and third-line therapy as a single agent FDA-approved for the adjuvant therapy of node-positive, HER2-overexpressing breat cancer as part of the treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel.

80. Drug Interactions Anthracyclines, taxanes – Increased risk of cardiotoxicity when trastuzumab is used in combination with anthracyclines and/or taxanes. Administration of paclitaxel in combination with Herceptin resulted in a 1.5-fold increase in trastuzumab serum levels

81. Special Considerations 1.Caution should be exercised in treating patients with pre-existing cardiac dysfunction. Careful baseline assessment of cardiac function before treatment and frequent monitoring of cardiac while on therapy. Trastuzumab should be stopped immediately in patients who develop clinically significant congestive heart failure. 2.Administer initial loading dose of 90 minutes and then observe patient for 1 hour following completion of the loading dose. Carefully monitor for infusion-related symptoms. Diphenhydramine and acetaminophen are used for treatment. 3.Maintenance doses are administered over 30 minutes if loading dose was well tolerated without fever and chills. However, if fever and chills were experienced with loading dose, need to administer over 90 minutes. 4.Increased risk of myelosuppression when it is administered with Chemotherapy 5. Pulmonary toxicity have been reported.

82. Cetuximab (Erbitux®) Mechanism of Action EGFR (epidermal growth factor receptor) is overexpressed in a broad range of human solid tumors, including colorectal cancer, head and neck cancer, non-small cell lung cancer, pancreatic cancer, and breast cancer. Cetuximab is directed against the epidermal growth factor receptor (EGFR), which leads to inhibition of autophosphorylation and inhibition of EGFR signalling. Indications Colorectal cancer in combination with irinotecan or as monotherapy in patients who are deemed to be irinotecan-intolerant- FDA approved Head and neck cancer - FDA approved Pancreatic cancer – remains investigational. Non-small cell lung cancer – remains investigational. Breast cancer – remains investigational.

83. Mechanism of Action Indications and Dosage Ranges Special considerations Bevacizumab (Avastin®)

84. Mechanism of Action A tumor creates a network of blood vessels a process called angiogenesis. An anti-angiogenic agent may inhibit blood vessel formation, which starves the tumor.

85. Avastin is thought to work by blocking one of the key signals that causes angiogenesis. Avastin blocks a protein called vascular endothelial growth factor (VEGF). This may allow Avastin to affect the tumor in different ways: 1.Avastin may cause the blood vessels to shrink away from the tumor, blocking the supply of oxygen and nutrients that the tumor needs 2.Avastin may interfere with the growth of new blood vessels, potentially helping to block further growth and spread of the cancer 3.Avastin may also cause the existing blood vessels to change in ways that help the chemotherapy reach the tumor more effectively

86. Indications and Dosage Ranges IndicationDosage Range Metastatic colorectal cancer FDA approved use in combination with any IV 5-FU based-chemotherapy in first line therapy 5mg/kg IV in combination with IV 5-FU based-chemotherapy on an every 2-week schedule Metastatic colorectal cancer FDA approved use in combination with FOLFOX4 (Oxaliplatin, Leucovorin, and Fluorouracil) in second line therapy 10 mg/kg IV in combination with FOLFOX4 on an every 2 week schedule Non-small cell lung cancer FDA approved in combination with carboplatin/paclitaxel 15 mg/kg IV every three weeks Renal cell cancer Remains investigational Breast cancer Remains investigational N.B: for advanced cell carcinoma, 7.5 mg/kg IV ever 3 weeks when used in combination with capecitabine-based regimens for advanced colorectal cancer.

87. Special Considerations 1.Patients should be warned of the increased risk of arterial thromboembolic events (MI or stroke). Risk factors are age > 65 years old, history of angina, stroke. 2.Patients should be warned of serious hemorrhage resulting from hemoptysis in patients with Non-small cell lung cancer. Patients with recent hemoptysis should not receive Bevacizumab. 3.GI perforations and wound dehisecence (bursting open of a surgically closed wound) Bevacizumab should be taken at least 28 days after any surgical and/or invasive procedures 4.Carefully monitor for infusion related symptoms Diphenhydramine and acetaminophen are used for treatment.

88. Special Considerations “Cont’d” 5.Bevacizumab can result in grade 3 hypertension Use with caution in patients with uncontrolled hypertension increase the dose of antihypertensive and/ or addition of another antihypertensive medication 6.It can result in protein uria with nephrotic syndrome It should be terminated in patients that develop the nephrotic syndrome 7.It can result in Reversible Posterior Leucoencephalopathy Syndrome (RPLS) manifested by neurologic disturbances, it can occur from 16 hours to 1 year after initiation of therapy MRI is necessary to confirm diagnosis