II. Mechanism
- Targeted to Protein kinases (esp. Tyrosine Kinase), interfering with various markers (e.g. EGFR, HER2-neu and VEGF)
- Protein kinases targeted are active in promoting cell growth and exploited by cancers
- Primarily oral agents (contrast with other Chemotherapy which is primarily intravenous)
- Small molecules that principally act intracellularly
- Less specific than monoclonal antibodies
- Small molecules also effect healthy tissue, and therefore have systemic effects
III. Pharmacokinetics
- Oral agents
- Very short half life (hours)
IV. Advantages
- Much less expensive than monoclonal antibodies, but still >$5000 for a course of Chemotherapy
V. Efficacy
- Widely variable efficacy depending on tumor type
- Highly effective agents
- Osimertinib is highly effective in metastatic EGFR Lung Cancer
- Alectinib is highly effective in advanced ALK Lung Cancer
- Poor efficacy agents
- PARP agents (e.g. Olaparib) do not appear to affect survival in BRCA Ovarian Cancer
VI. Preparations
- Non-specific intracellular kinase
- Sunitinib (Sutent)
- Non-specifically targets many kinases
- Sunitinib (Sutent)
- ALK (CD246, Anaplastic Lymphoma Kinase): Alectinib (Alecensa), Brigatinib (Alunbrig), Ceritinib (Zykadia), Crizotinib (Xalkori), Loratinib (Lobrena)
- Indications
- Lung Adenocarcinoma (ALK+ fusion, metastatic)
- Efficacy
- Alectinib is highly effective in advanced ALK Lung Cancer
- Adverse Effects
- Bradycardia
- Hepatotoxicity
- Nausea or Vomiting
- Ocular Toxicity
- QTc Prolongation
- Indications
- BCL2 (B-Cell Leukemia/Lypmphoma 2): Venetoclax (Venclexta)
- Indications
- Chronic Lymphocytic Leukemia (17p deletion)
- Adverse Effects
- Pancytopenia (severe)
- Tumor Lysis Syndrome
- Indications
- BCR-ABL: Bosutinib (Bosulif), Dasatinib (Sprycel), Nilotinib (Tasigna), Ponatinib (Iclusig)
- Indications
- Precautions
- Ponatinib is associated with serious cardiovascular events (CVA, MI, PVD) in 20-30% (1% death rate)
- Adverse Effects
- Congestive Heart Failure
- Diarrhea (Bosutinib)
- Edema
- Effusions (Dasatinib)
- Hematologic Effects
- Pancreatitis
- Prolonged QTc (Nilotinib)
- Thrombosis (Ponatinib)
- BRAF (B-raf proto-oncogene): Dabrafenib (Tafinlar), Vemurafenib (Zelboraf), Encorafenib (Braftovi)
- Indications
- Lung Adenocarcinoma (V600E Mutation, metastatic)
- Anaplastic Thyroid Cancer (V600E mutation, advanced or metastatic)
- BRAF agent and MEK agent (Dabrafenib PLUS Trametinib)
- Melanoma (V600E or V600k mutation, metastatic)
- BRAF agent and MEK agent (e.g. Vemurafenib PLUS Cobimetinib, Encorafenib PLUS Binimetinib)
- Adverse Effects
- Colitis
- Congestive Heart Failure
- Fever
- Hepatotoxicity
- Hyperglycemia
- Rash
- Squamous Cell Skin Cancer
- Thrombosis
- Indications
- BTK (Bruton Tyrosine Kinase): Ibrutinib (Imbruvica)
- Indications
- Chronic Lymphocytic Leukemia (17p deletion)
- Adverse Effects
- Indications
- c-KIT (Tyrosine Kinase KIT gene): Imatinib (Gleevec)
- Indications
- Gastrointestinal Stromal Tumor (c-KIT+, adjuvant after complete tumor resection)
- Adverse Effects
- Congestive Heart Failure
- Edema
- Hematologic Effects
- Indications
-
EGFR (Epidermal Growth Factor Receptor): Afatinib (Gilotrif), Dacomitinib (Vizimpro), Erlotinib (Tarcerva), Gefitinib (Iressa), Osimertinib (Tagrisso)
- Indications
- Lung Adenocarcinoma (EGFR exon 19 deletion, exon 21 substitution)
- Efficacy
- Osimertinib is highly effective in metastatic EGFR Lung Cancer
- Adverse Effects
- Diarrhea
- Hepatotoxicity
- Prolonged QTc
- Rash
- Trichiasis
- Indications
- FLT3 (FMS-like Tyrosine Kinase 3 or CD135): Gilteritinib (Xospata), Midostaurin (Rydapt)
- Indications
- Acute Myelogenous Leukemia (FLT3+ new or advanced/refractory)
- Adverse Effects
- Hepatotoxicity
- Prolonged QTc
- Rash
- Vomiting
- Indications
- FGR2/3 (Fibroblast Growth Factor Receptor 1/2): Erdafitinib (Balversa)
- Indications
- Bladder Cancer (FGR2/3+, advanced or metastatic)
- Adverse Effects
- Central Serous Retinopathy
- Hand-Foot Syndrome
- Hyperphosphatemia
- Oncholysis
- Indications
- IDH1/2 (Isocitrate Dehydrogenase 1/2): Enasidenib (Idhifa), Ivosidenib (Tibsovo)
- Indications
- Acute Myelogenous Leukemia (IDH1/2+ new or advanced/refractory)
- Adverse Effects
- Edema
- Hepatotoxicity
- Prolonged QTc
- Indications
- MEK (MAP Kinase-ERK Kinase): Binimetinib (Mektovi), Trametinib (Mekinist), Cobimetinib (Cotellic)
- Indications
- Anaplastic Thyroid Cancer (V600E mutation, advanced or metastatic)
- BRAF agent and MEK agent (Dabrafenib PLUS Trametinib)
- Melanoma
- BRAF agent and MEK agent (e.g. Vemurafenib PLUS Cobimetinib, Encorafenib PLUS Binimetinib)
- Anaplastic Thyroid Cancer (V600E mutation, advanced or metastatic)
- Adverse Effects
- Papulopustular rash
- Diarrhea
- Peripheral Edema
- Hypertension
- Ocular toxicity (uveal, Retinal)
- Indications
- NTKR (Neurotrophic Tyrosine Kinase Receptor): Larotrectinib (Vitrakvi), Entrectinib (Rozlytrek, also targets ROS1)
- NTKR is also known as TRK (tropomyosin kinase receptor)
- Indications
- NTKR Fusion Solid Tumors
- Adverse Effects
- Cardiotoxicity
- Cognitive Impairment
- Fractures
- Hepatotoxicity
- Ocular Toxicity
- PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha): Alpelisib (Piqray)
- Indications
- Breast Cancer (PIK3CA mutation, metastatic)
- Adverse Effects
- Indications
- PARP (Poly ADP Ribose Polymerase): Olaparib (Lynparza), Talazoparib (Telzenna), Niraparib (Zejula), Rucaparib (Rubraca)
- Indications
- Breast Cancer (BRCA mutation, metastatic)
- Ovarian Cancer (BRCA mutation, advanced or metastatic)
- Efficacy
- PARP agents (e.g. Olaparib) do not appear to affect survival in BRCA Ovarian Cancer
- Adverse Effects
- Acute Myelogenous Leukemia (rare)
- Pneumonitis
- Pancytopenia
- Myelodysplastic Syndrome or Macrocytosis
- Indications
- ROS1 (Receptor Tyrosine Kinase encoded by ROS1 gene): Crizotinib (Xalkori, also targets ALK), Entrectinib (Rozlytrek, also targets NTKR)
- Indications
- Lung Adenocarcinoma (ROS1+, metastatic)
- Adverse Effects (based on Entrectinib)
- Cardiotoxicity
- Cognitive Impairment
- Fractures
- Hepatotoxicity
- Ocular Toxicity
- Indications
VII. Labs: Monitoring
- Adverse Effects vary widely among agents (see preparations above)
- Typical monitoring
- Electrolytes, Glucose and Renal Function (e.g. basic chemistry panel, Chem8)
- Complete Bound Count (CBC)
- Liver Function Tests (esp. for agents with hepatotoxicity risk)
- Alkaline Phosphatase
- Total Bilirubin
- Alanine Transaminase (ALT)
- Aspartate Transaminase (AST)
VIII. Diagnostics
- Agents with risk of Cardiomyopathy, Congestive Heart Failure
- Agents with risk of QTc Prolongation or Atrial Fibrillation
- Agents with ocular toxicity
- Dilated Eye Exam by ophthalmology
IX. Drug Interactions
- Multiple Drug Interactions related to Cytochrome P450 enzymes
- Many Cytochrome P-450 3A3/4 Isoenzyme interactions (inducers and inhibitors)
-
Histamine Blockers (H2 Blocks) and Proton Pump Inhibitors impact absorption
- Bosutinib
- Crizotinib
- Dabrafenib
- Dasatinib
- Erlotinib
- Gefitinib
- Nilotinib
- Ponatinib
-
Warfarin Drug Interactions
- Dabrafenib
- Erlotinib
- Gefitinib
- Imatinib
- Vemurafenib
- Venetoclax
Images: Related links to external sites (from Bing)
Related Studies
sprycel (on 4/6/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
SPRYCEL 100 MG TABLET | $510.80 each | |
imatinib (on 6/22/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
IMATINIB MESYLATE 100 MG TAB | Generic | $0.81 each |
IMATINIB MESYLATE 400 MG TAB | Generic | $2.46 each |
sutent (on 1/1/2023 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
SUTENT 12.5 MG CAPSULE | $215.93 each | |
SUTENT 25 MG CAPSULE | $435.98 each |