Hematology and Oncology Book

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Small Molecule Inhibitor-Mediated Chemotherapy

Aka: Small Molecule Inhibitor-Mediated Chemotherapy, Enasidenib, Idhifa, Ivosidenib, Tibsovo, Gilteritinib, Xospata, Midostaurin, Rydapt, Dabrafenib, Tafinlar, Trametinib, Mekinist, Olaparib, Lynparza, Talazoparib, Telzenna, Erdafitinib, Balversa, Venetoclax, Venclexta, Ibrutinib, Imbruvica, Bosutinib, Bosulif, Dasatinib, Sprycel, Nilotinib, Tasigna, Ponatinib, Iclusig, Imatinib, Gleevec, Afatinib, Gilotrif, Dacomitinib, Vizimpro, Erlotinib, Tarcerva, Gefitinib, Iressa, Osimertinib, Tagrisso, Alectinib, Alecensa, Brigatinib, Alunbrig, Ceritinib, Zykadia, Crizotinib, Xalkori, Loratinib, Lobrena, Binimetinib, Mektovi, Cobimetinib, Cotellic, Vemurafenib, Zelboraf, Encorafenib, Braftovi, Larotrectinib, Vitrakvi, Niraparib, Zejula, Rucaparib, Rubraca, Sunitinib, Sutent
  1. See Also
    1. Targeted Cancer Therapy
    2. Monoclonal Antibody-Mediated Chemotherapy
    3. Immune Checkpoint Inhibitor
    4. CAR T-Cell Therapy
    5. Chemotherapy
  2. Mechanism
    1. Targeted to protein kinases (esp. Tyrosine Kinase), interfering with various markers (e.g. EGFR, HER2-neu and VEGF)
      1. Protein kinases targeted are active in promoting cell growth and exploited by cancers
    2. Primarily oral agents (contrast with other Chemotherapy which is primarily intravenous)
    3. Small molecules that principally act intracellularly
    4. Less specific than monoclonal antibodies
    5. Small molecules also effect healthy tissue, and therefore have systemic effects
  3. Pharmacokinetics
    1. Oral agents
    2. Very short half life (hours)
  4. Advantages
    1. Much less expensive than monoclonal antibodies, but still >$5000 for a course of Chemotherapy
  5. Efficacy
    1. Widely variable efficacy depending on tumor type
    2. Highly effective agents
      1. Osimertinib is highly effective in metastatic EGFR Lung Cancer
      2. Alectinib is highly effective in advanced ALK Lung Cancer
    3. Poor efficacy agents
      1. PARP agents (e.g. Olaparib) do not appear to affect survival in BRCA Ovarian Cancer
  6. Preparations
    1. Non-specific intracellular kinase
      1. Sunitinib (Sutent)
        1. Non-specifically targets many kinases
    2. ALK (CD246, Anaplastic Lymphoma Kinase): Alectinib (Alecensa), Brigatinib (Alunbrig), Ceritinib (Zykadia), Crizotinib (Xalkori), Loratinib (Lobrena)
      1. Indications
        1. Lung Adenocarcinoma (ALK+ fusion, metastatic)
      2. Efficacy
        1. Alectinib is highly effective in advanced ALK Lung Cancer
      3. Adverse Effects
        1. Bradycardia
        2. Hepatotoxicity
        3. Nausea or Vomiting
        4. Ocular Toxicity
        5. QTc Prolongation
    3. BCL2 (B-Cell Leukemia/Lypmphoma 2): Venetoclax (Venclexta)
      1. Indications
        1. Chronic Lymphocytic Leukemia (17p deletion)
      2. Adverse Effects
        1. Pancytopenia (severe)
        2. Tumor Lysis Syndrome
    4. BCR-ABL: Bosutinib (Bosulif), Dasatinib (Sprycel), Nilotinib (Tasigna), Ponatinib (Iclusig)
      1. Indications
        1. Chronic Myelogenous Leukemia
      2. Precautions
        1. Ponatinib is associated with serious cardiovascular events (CVA, MI, PVD) in 20-30% (1% death rate)
      3. Adverse Effects
        1. Congestive Heart Failure
        2. Diarrhea (Bosutinib)
        3. Edema
        4. Effusions (Dasatinib)
        5. Hematologic Effects
        6. Pancreatitis
        7. Prolonged QTc (Nilotinib)
        8. Thrombosis (Ponatinib)
    5. BRAF (B-raf proto-oncogene): Dabrafenib (Tafinlar), Vemurafenib (Zelboraf), Encorafenib (Braftovi)
      1. Indications
        1. Lung Adenocarcinoma (V600E Mutation, metastatic)
        2. Anaplastic Thyroid Cancer (V600E mutation, advanced or metastatic)
          1. BRAF agent and MEK agent (Dabrafenib PLUS Trametinib)
        3. Melanoma (V600E or V600k mutation, metastatic)
          1. BRAF agent and MEK agent (e.g. Vemurafenib PLUS Cobimetinib, Encorafenib PLUS Binimetinib)
      2. Adverse Effects
        1. Colitis
        2. Congestive Heart Failure
        3. Fever
        4. Hepatotoxicity
        5. Hyperglycemia
        6. Rash
        7. Squamous Cell Skin Cancer
        8. Thrombosis
    6. BTK (Bruton Tyrosine Kinase): Ibrutinib (Imbruvica)
      1. Indications
        1. Chronic Lymphocytic Leukemia (17p deletion)
      2. Adverse Effects
        1. Atrial Fibrillation
        2. Diarrhea
        3. Edema
        4. Bleeding Diathesis
    7. c-KIT (Tyrosine Kinase KIT gene): Imatinib (Gleevec)
      1. Indications
        1. Gastrointestinal Stromal Tumor (c-KIT+, adjuvant after complete tumor resection)
      2. Adverse Effects
        1. Congestive Heart Failure
        2. Edema
        3. Hematologic Effects
    8. EGFR (Epidermal Growth Factor Receptor): Afatinib (Gilotrif), Dacomitinib (Vizimpro), Erlotinib (Tarcerva), Gefitinib (Iressa), Osimertinib (Tagrisso)
      1. Indications
        1. Lung Adenocarcinoma (EGFR exon 19 deletion, exon 21 substitution)
      2. Efficacy
        1. Osimertinib is highly effective in metastatic EGFR Lung Cancer
      3. Adverse Effects
        1. Diarrhea
        2. Hepatotoxicity
        3. Prolonged QTc
        4. Rash
        5. Trichiasis
    9. FLT3 (FMS-like Tyrosine Kinase 3 or CD135): Gilteritinib (Xospata), Midostaurin (Rydapt)
      1. Indications
        1. Acute Myelogenous Leukemia (FLT3+ new or advanced/refractory)
      2. Adverse Effects
        1. Hepatotoxicity
        2. Prolonged QTc
        3. Rash
        4. Vomiting
    10. FGR2/3 (Fibroblast Growth Factor Receptor 1/2): Erdafitinib (Balversa)
      1. Indications
        1. Bladder Cancer (FGR2/3+, advanced or metastatic)
      2. Adverse Effects
        1. Central Serous Retinopathy
        2. Hand-Foot Syndrome
        3. Hyperphosphatemia
        4. Oncholysis
    11. IDH1/2 (Isocitrate Dehydrogenase 1/2): Enasidenib (Idhifa), Ivosidenib (Tibsovo)
      1. Indications
        1. Acute Myelogenous Leukemia (IDH1/2+ new or advanced/refractory)
      2. Adverse Effects
        1. Edema
        2. Hepatotoxicity
        3. Prolonged QTc
    12. MEK (MAP Kinase-ERK Kinase): Binimetinib (Mektovi), Trametinib (Mekinist), Cobimetinib (Cotellic)
      1. Indications
        1. Anaplastic Thyroid Cancer (V600E mutation, advanced or metastatic)
          1. BRAF agent and MEK agent (Dabrafenib PLUS Trametinib)
        2. Melanoma
          1. BRAF agent and MEK agent (e.g. Vemurafenib PLUS Cobimetinib, Encorafenib PLUS Binimetinib)
      2. Adverse Effects
        1. Papulopustular rash
        2. Diarrhea
        3. Peripheral Edema
        4. Hypertension
        5. Ocular toxicity (uveal, Retinal)
    13. NTKR (Neurotrophic Tyrosine Kinase Receptor): Larotrectinib (Vitrakvi), Entrectinib (Rozlytrek, also targets ROS1)
      1. NTKR is also known as TRK (tropomyosin kinase receptor)
      2. Indications
        1. NTKR Fusion Solid Tumors
      3. Adverse Effects
        1. Cardiotoxicity
        2. Cognitive Impairment
        3. Fractures
        4. Hepatotoxicity
        5. Ocular Toxicity
    14. PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha): Alpelisib (Piqray)
      1. Indications
        1. Breast Cancer (PIK3CA mutation, metastatic)
      2. Adverse Effects
        1. Stevens-Johnson Syndrome
        2. Hyperglycemia
        3. Severe Diarrhea
    15. PARP (Poly ADP Ribose Polymerase): Olaparib (Lynparza), Talazoparib (Telzenna), Niraparib (Zejula), Rucaparib (Rubraca)
      1. Indications
        1. Breast Cancer (BRCA mutation, metastatic)
        2. Ovarian Cancer (BRCA mutation, advanced or metastatic)
      2. Efficacy
        1. PARP agents (e.g. Olaparib) do not appear to affect survival in BRCA Ovarian Cancer
      3. Adverse Effects
        1. Acute Myelogenous Leukemia (rare)
        2. Pneumonitis
        3. Pancytopenia
        4. Myelodysplastic Syndrome or Macrocytosis
    16. ROS1 (Receptor Tyrosine Kinase encoded by ROS1 gene): Crizotinib (Xalkori, also targets ALK), Entrectinib (Rozlytrek, also targets NTKR)
      1. Indications
        1. Lung Adenocarcinoma (ROS1+, metastatic)
      2. Adverse Effects (based on Entrectinib)
        1. Cardiotoxicity
        2. Cognitive Impairment
        3. Fractures
        4. Hepatotoxicity
        5. Ocular Toxicity
  7. Labs: Monitoring
    1. Adverse Effects vary widely among agents (see preparations above)
    2. Typical monitoring
      1. Electrolytes, Glucose and Renal Function (e.g. basic chemistry panel, Chem8)
      2. Complete Bound Count (CBC)
      3. Liver Function Tests (esp. for agents with hepatotoxicity risk)
        1. Alkaline Phosphatase
        2. Total Bilirubin
        3. Alanine Transaminase (ALT)
        4. Aspartate Transaminase (AST)
  8. Diagnostics
    1. Agents with risk of Cardiomyopathy, Congestive Heart Failure
      1. Echocardiogram
    2. Agents with risk of QTc Prolongation or Atrial Fibrillation
      1. Electrocardiogram
    3. Agents with ocular toxicity
      1. Dilated Eye Exam by ophthalmology
  9. Drug Interactions
    1. Multiple Drug Interactions related to Cytochrome P450 enzymes
      1. Many Cytochrome P-450 3A3/4 Isoenzyme interactions (inducers and inhibitors)
    2. Histamine Blockers (H2 Blocks) and Proton Pump Inhibitors impact absorption
      1. Bosutinib
      2. Crizotinib
      3. Dabrafenib
      4. Dasatinib
      5. Erlotinib
      6. Gefitinib
      7. Nilotinib
      8. Ponatinib
    3. Warfarin Drug Interactions
      1. Dabrafenib
      2. Erlotinib
      3. Gefitinib
      4. Imatinib
      5. Vemurafenib
      6. Venetoclax
  10. References
    1. Imai (2006) Nat Rev Cancer 6:714-27 [PubMed]
    2. Pathak (2018) Vivechan Int J Res 9(1): 36-49 +PMID:30853755 [PubMed]
      1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407887/
    3. Smith (2021) Am Fam Physician 103(3): 155-63 [PubMed]
Medication Costs
sprycel (on 1/1/2017 at Medicaid.Gov Pharmacy Drug pricing)
SPRYCEL 100 MG TABLET $385.51 each
SPRYCEL 50 MG TABLET $215.83 each
imatinib (on 11/23/2016 at Medicaid.Gov Pharmacy Drug pricing)
IMATINIB MESYLATE 100 MG TAB Generic $68.17 each
IMATINIB MESYLATE 400 MG TAB Generic $173.87 each
gleevec (on 5/17/2017 at Medicaid.Gov Pharmacy Drug pricing)
GLEEVEC 100 MG TABLET Generic $68.17 each
GLEEVEC 400 MG TABLET Generic $173.87 each
sutent (on 6/1/2017 at Medicaid.Gov Pharmacy Drug pricing)
SUTENT 12.5 MG CAPSULE $160.37 each
SUTENT 25 MG CAPSULE $323.80 each
FPNotebook does not benefit financially from showing this medication data or their pharmacy links. This information is provided only to help medical providers and their patients see relative costs. Insurance plans negotiate lower medication prices with suppliers. Prices shown here are out of pocket, non-negotiated rates. See Needy Meds for financial assistance information.

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