ORAL TYROSINE KINASE INHIBITORS

1. BCR-ABL Tyrosine Kinase Inhibitors(TKI) Imatinib Mesylate, Dasatinib, Nilotinib, Bosutinib Ponatinib

2. Epidermal Growth Factor Receptor - TKI Gefitinib, Lapatinib, Erlotinib

3. Vascular Endothelial Growth Factor – TKI Vatalanib, Sunitinib, Sorafenib, Pazopanib

IMATINIB(Gleevac)• First molecularly targeted protein kinase inhibitor to

receive FDA approval• MOA: Binds to a segment of the BCR- ABL tyrosine

kinase domain that fixes it in a closed or non-functional state

• Indications: - Chronic myelogenous leukemia( CML) - Acute lymphoblastic leukemia (ALL) - Gastrointestinal Stromal Tumors - Myelodysplastic/Myeloproliferative Diseases - Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia - Dermatofibrosarcoma Protuberans

IMATINIB

• Dosage :- CML 1) Chronic phase , initial therapy 400 mg OD P.O – increase upto 600 mg OD 2) Accelerated phase or blast crisis 600 mg OD P.O – increase upto 800 mg OD• Half life –18 hours

IMATINIB

• Toxicity- GI – Nausea, vomiting, abdominal pain- Edema - Diarrhoea - Muscle cramps- Fatigue- Skin rash- Cytopenias

DASATINIB(Sprycel)• MOA: Binds to both the open and closed

configuration of BCR- ABL kinase• 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

• Dosage : 100 mg OD (chronic phase) 70 mg OD (accelerated phase)• Half life: 3-5 hrs

NILOTINIB(Tasigna)• Indications: In adult patients with CML who are

resistant or intolerant to Imatinib• Dosage : 400 mg BD ( both chronic and acc phase)• Half life – 15 -17 hrs• Toxicities : - Thrombocytopenia and Neutropenia - QT-prolongation - Elevated liver enzymes - Electrolyte abnormality (hyper & hypo K, hypo Mg, Phos, Ca, Na)

GEFITINIB(Iressa, Geftib, Geftinat)• MOA: Inhibit the EGFR tyrosine kinase by virtue of

competitive blockade of ATP binding

• IndicationsNon-small Cell Lung Cancer (NSCLC) Monotherapy for continued treatment of locally

advanced or metastatic NSCLC after failure of both platinum-based and Docetaxel regimens

• Half life : 48 hrs• Dosage : 250 mg OD

GEFITINIB• Toxicities Dermatologic– Rash, acne, xerosis, pruritus

Gastrointestinal– Diarrhea, Nausea, vomiting, anorexia

Ocular– Pain and corneal erosion/ulcer, aberrant eyelash

growth Pulmonary -- Interstitial lung disease, consisting of interstitial pneumonia, pneumonitis, and alveolitis

ERLOTINIB(Tarceva)

• MOA: Inhibitor of HER1/EGFR tyrosine kinase.• Indications :– First-line treatment of patients with locally

advanced, unresectable, or metastatic pancreatic cancer in combination with Gemcitabine.

– Second-line treatment of patients with locally advanced or metastatic non–small cell lung cancer

Dosage: 150 mg ODHalf life: 41 hrs

ERLOTINIB• Toxicities Pulmonary - Dyspnea , cough Rash Gastrointestinal

– Diarrhea , anorexia , nausea/vomiting Fatigue

Ocular– Irritation, conjunctivitis and keratoconjunctivitis sicca , corneal ulcerations

Hepatotoxicity– Asymptomatic in liver enzymes, including hyperbilirubinemia

Bleeding events– Gastrointestinal bleeds, elevations in INR values in patients receiving

concomitant warfarin administration

LAPATINIB(Tykerb)

• MOA: 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both EGFR and HER2 receptors

• INDICATION: Metastatic Breast Cancer in combination with Capecitabine in patients whose tumors overexpress HER2 and who have received prior therapy including an Anthracycline, a Taxane, and Trastuzumab

LAPATINIBDOSAGE: 250 mg tablets– In combination with Capecitabine, for the treatment of

advanced or metastatic breast cancer which overexpresses HER2 and have received prior therapy including an Anthracycline, a Taxane, and Trastuzumab.

– 1250mg (5 tabs) PO once daily, Days 1-21 on an empty stomach

HALF LIFE : 24 hrs

• ToxicitiesWhen combined with Capecitabine• Diarrhea• Palmar-plantar erythrodysesthesia• Nausea/vomiting• Rash• Fatigue• Decrease in LVEF• ECG changes

SUNITINIB(Sutent)MOA: VEGF –TKIIndications : - RCC - GIST - PNET Dosage: 12.5 mg, 25 mg, 50 mg capsules

- For advanced RCC and GIST• 50 mg PO once daily, on a schedule of 4 weeks on

treatment followed by 2 weeks off

• Half life – 40 -60 hrs

SUNITINIBToxicities

• QT-prolongation • Left Ventricular Dysfunction• Hemorrhagic Events• Hypertension (30%)• Hypothyroidism – baseline thyroid function and monitor for signs• Adrenal Insufficiency• GI distress

– Diarrhea, nausea, vomiting, stomatitis, dyspepsia• Skin discoloration• Fatigue

SORAFENIB(Nexavar)• MOA: Inhibits the VEGFR and PGDFR• Indications: - RCC - HCC• Dosage: 400 mg BD• Toxicities: - Hand-foot syndrome, alopecia, rash - Diarrhea or constipation - Nausea/vomiting, abdominal pain - High blood pressure - Bleeding - Neuropathy, joint pain - Dyspnea• Half life – 20-40 hrs

VATALANIB

• MOA: Inhibits all VEGFR but most selective for VEGFR-2

• It is being studied as a single agent and in combination with chemotherapy in patients with

1. Colorectal cancer and liver metastases,2. Advanced prostate cancer3. Renal cell cancer4. Relapsed/refractory Glioblastoma multiforme

PAZOPANIB(Votrient)• MOA: VEGFR and PDGFR inhibitor• Dose : 800 mg OD• Indications : - RCC - Soft tissue sarcoma• Toxicites: - Increased liver enzymes - Malaise

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