Table 1.
Small molecule TKIs approved by US FDA for use in cancer therapy, their indications, and common adverse effects
| Receptor targets | Drugs | Applications | Cardiovascular Adverse Effects | Extra-Cardiac Adverse Effects | |
|---|---|---|---|---|---|
| ALK family (Anaplastic lymphoma kinase) | First-generation: Crizotinib (Type Ia c-MET inhibitor) | ALK+, ROS1 + NSCLC | Arrhythmia, QT Prolongation, Bradycardia | Visual disturbances (flashes, light columns, blurred vision), Neutropenia | |
| Second-generation: | Ceritinib | ALK + NSCLC as first-line treatment or after crizotinib resistance | QT Prolongation Arrhythmia, MI, Bradycardia | GI disorders | |
| Alectinib | ALK + NSCLC | QT Prolongation, Arrhythmias | Anemia | ||
| Brigatinib | ALK+ NSCLC after crizotinib | Arrhythmia, Bradycardia, HTN | ILD | ||
| Ensartinib | ALK+ NSCLC | – | Rash, Elevated transaminase levels (AST/ALT), Pruritus, GI disorders, Edema, Anemia, Increased levels of blood ALP blood creatinine, GGT, Increased bilirubin level, Increased CPK level, and Hyponatremia | ||
| Third-generation: | Lorlatinib | ALK + NSCLC | MI, PR interval prolongation, AV block | Fatigue, Increased ALT, Cough, Anemia, Decreased neutrophil count, Mental disorders, Mood, speech, and sleep disorders | |
| Entrectinib | ROS1 + NSCLC; solid tumors with NTRK fusion proteins | QT Prolongation | Dysgeusia, Dizziness, Weight Gain, Paresthesia, Fatigue, GI Disorders, Peripheral edema, Myalgia, Anemia, Increased Blood Creatinine, and Arthralgia. | ||
| Repotrectinib (Next- Generation ROS1/TRK/ALK Inhibitor | ROS1+ advanced NSCLC | – | Dizziness | ||
| BCR–ABL family [Fusion protein of ABL1 (Abelson murine leukemia viral oncogene homolog 1) and Breakpoint cluster region protein (BCR)-cytoplasmic fusion tyrosine kinase] | First-generation: Imatinib (also targets VEGFR and PDGFR) | Ph+ CML or ALL, CEL, DFSP, HES, GIST, MDS/MDP | HF, LVD |
Nausea, Vomiting, Diarrhea, Edema, Myelosuppression, Immunosuppression, Fatigue, Insomnia, Depression, Dizziness, URTI, influenza, Pyrexia, Cough, Abdominal pain, Myalgia, Arthralgia, Skin rash, Hemorrhage Rare association with appendiceal carcinoma |
|
| Second-generation: | Nilotinib | Ph+ ALL | MI, QT prolongation, HTN | Myelosuppression, Hyperbilirubinemia, Pancreatitis, Fatigue, Headache, Nausea, Vomiting, Diarrhea, Constipation, Skin rash, Pruritis, Edema | |
| Dasatinib [also targets Src (cytoplasmic tyrosine kinase)] | Ph+ CML and ALL | Pleural/Pericardial Effusion, QT prolongation, HF, LVD, MI |
Myelosuppression, Panniculitis, Bleeding, Fatigue, Headache, Dyspnea, Infection, Fluid retention, Abdominal pain, Nausea, Diarrhea, Edema Myalgia, Arthralgia, Skin rash, Hemorrhage |
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| Bosutinib (also targets Src) | CML resistant or intolerant to prior TKI therapy | QT prolongation, PHTN, Pericardial Effusion | Myelosuppression, Fatigue, Headache, Dyspnea, Cough, Pyrexia, GI disorders, Edema, Increased ALT, Arthralgia, Skin rash | ||
| Third-generation: Ponatinib | Ph+ CML or ALL | HTN, HF, Arrhythmias |
Myelosuppression, Fatigue, Headache, Dyspnea, Pyrexia, Pancreatitis, Pyrexia, Abdominal pain, Nausea, Vomiting, Diarrhea, Constipation, Increased ALT, Myalgia, Arthralgia, Skin rash, Dry skin, Hepatotoxicity, Liver failure, and Death |
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| B-Raf family (B-rapid accelerating fibrosarcoma/v-raf murine sarcoma viral oncogene homolog B1) | Vemurafenib | Melanoma with BRAFV600E mutation, and ECD | LVD, QT prolongation, AF | Photosensitivity, Skin rash, Increased LFTs, Arthralgia, Nausea, Fatigue, Edema, Cutaneous squamous- cell carcinoma, Pruritus, Palmar–plantar dysesthesia | |
| Dabrafenib | Melanoma and NSCLC with BRAF mutations | LVD | Fever, Neutropenia, Arthralgia, Fatigue, Headache, Peripheral edema | ||
| Encorafenib | BRAF V600E/K mutant melanoma with binimetinib | QT prolongation, LVD | Anemia, Transient Bell’s palsy, Myalgia, Nausea, Palmoplantar erythrodysesthesia, Arthralgia, Alopecia, Hyperkeratosis. | ||
| BTK family (Bruton’s tyrosine kinase) | Ibrutinib | MCL, CLL, WM, GVD, MZL | Arrhythmia, HTN | Hemorrhage, Cytopenias Diarrhea, Increased risk of Infections, Arthralgia, Fatigue, Muscle Spasms or Myalgias, Pyrexia, Skin Rash, Headaches | |
| Acalabrutinib | MCL | Arrhythmia | Hemorrhage, Headache, Diarrhea, Fatigue, Myalgias, Cough, Neutropenia, Nausea, Skin Rash, and Infections. | ||
| Zanubrutinib | Refractory MCL and WM | Arrhythmia | Neutropenia, Increased Risk of Infections | ||
| c-MET family (Hepatocyte Growth Factor (HGF)/Mesenchymal al-Epithelial Transition Factor Receptor) | Capmatinib (Type Ib inhibitor) | NSCLC with METex1 4 (MET exon 14 skipping mutation) | – | ILD/Pneumonitis, Peripheral Edema, Fatigue, GI Disorders, Grade 3 hepatotoxicity, Elevated Creatinine clearance, Photosensitivity | |
| Tepotinib (Type Ib inhibitors) | NSCLC) with METex14 | – | Peripheral edema, Nausea, Diarrhea, Increased blood creatinine, Upper abdominal pain, Hypoalbuminemia, Increased ALT/AST, amylase and lipase levels, Asthenia, Decreased appetite, Pleural effusion, Alopecia, Fatigue, General edema | ||
| EGFR/ERBB family ErbB1 [EGFR (human epidermal growth factor receptor) or HER1 (erythroblastic leukemia viral oncogene B), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) [EGFR family receptor tyrosine kinase] | First-generation (Competitive and Reversible) | Gefitinib | NSCLC | MI | Skin rash, Diarrhea, Nausea, ILD, Dry Skin, Pruritus, Stomatitis, Anorexia |
| Erlotinib | NSCLC and Pancreatic Cancer | Edema | Skin rash, Diarrhea, Fatigue, Appetite loss, Nausea, ILD, Hematologic, Alopecia, Arthralgia, Neuropathy | ||
| Lapatinib (reversible dual inhibitor- EGFR and HER2) | Breast Cancer | HF, LVD, QTProlongation | Skin rash, Diarrhea | ||
| Second-generation (Covalent and Irreversible) | Vandetanib (also targets Src/VEGFR 2/RET) | MTC | Asymptomatic QT prolongation, Torsades de pointes, Arrhythmia, HF, HTN | Rash, Diarrhea, Proteinuria | |
| Afatinib | NSCLC | HTN | Severe Diarrhea, Rash-Acne, Stomatitis, Paronychia, Dry Skin, Appetite loss | ||
| Dacomitinib | EGFR-mutated NSCLC | – | Diarrhea, Paronychia, Rash-Acne, Stomatitis, Dry Skin, Appetite loss, Weight Loss, Alopecia, Cough, Hemorrhoids, Wound, Back pain, Headache | ||
| Neratinib | HER2+ breast cancer | Low rates of symptomatic decline in LVEF and QT prolongation | Diarrhea, GI disorders, Fatigue, Headache | ||
| Third-generation (Irreversible): Osimertinib | NSCLC | QT prolongation, LVD, HF, Arrhythmia, MI, Pericardial Effusion | Diarrhea, Rash, Dry Skin, Paronychia, Stomatitis, Fatigue | ||
| Mobocertinib (Irreversible) | EGFR exon 20 insertions (EGFRex20i ns) mutation-driven NSCLC | – | GI Disorders, Rash, Dry skin, Stomatitis, Fatigue, Maculopapular Rash, Paronychia, Anemia, Dermatitis acneiform, Increased lipase, Pruritus | ||
| Pyrotinib (Irreversible dual pan-ErbB receptor inhibitor) | HER2- positive | Diarrhea, Hand-foot syndrome, Leukopenia, Neutropenia, GI disorders, Increased ALT, Anemia, Asthenia | |||
| FGFR family (fibroblast growth factor receptor) | Erdafitinib | Urothelial carcinoma | MI | Ocular disorders (central retinopathy), Hyperphosphatemia, Embryo-fetal toxicity, Fatigue, Dysgeusia, Paronychia, Alopecia, HFSR, Xerosis | |
| Flt3 family (Fms-like tyrosine kinase 3) | Gilteritinib | AML with FLT3 mutation5 | QT prolongation | Arthralgia/myalgia, Dizziness, Dyspnea, Edema, Fatigue, Noninfectious diarrhea, Pneumonia, Rash, Transaminitis | |
| Midostaurin | ALL Flt3 mutation+ | HTN, Pericardial Effusion | Nausea, Vomiting, Diarrhea, Fatigue, Headaches | ||
| JAK family (Janus Kinase) | Ruxolitinib | MF and PV | MI, Venous thromboembolism | Myelosuppression, Hematological toxicity particularly thrombocytopenia, anemia - dose-limiting toxicity, ecchymosis, Dizziness, and Fatigue | |
| Fedratinib | Primary or secondary myelofibrosis | HF, Cardiogenic Shock | Anemia, GI symptoms, Increased levels of liver transaminases, serum creatinine, and pancreatic enzymes, Encephalopathy | ||
| MAPKK family/ MEK ½ (Mitogen-activated protein kinase kinase) | Trametinib | Melanoma (2013) and NSCLC (2017) with BRAF mutations | LVD | Rash, Diarrhea, Central Serous Retinopathy, Papulopustular Exanthema, Peripheral edema, | |
| Binimetinib | BRAF V600E/Kmelanoma with encorafenib | QT prolongation, LVD | Papulopustular rash, Central Serous-like Retinopathy, GI Disorders | ||
| Cobimetinib | Melanoma with BRAF V600E/K mutations with vemurafenib | LVD, QT prolongation | Rash, Fatigue, Edema, GI Disorders | ||
| NTRK family (Neurotrophic Tyrosine Receptor Kinase) | Larotrectinib | Solid tumors with NTRK gene fusion proteins | – | Anemia, Increased AST/ALT, Weight increase, Decreased neutrophil count, Fatigue, Cough | |
| PDGFR family (PDGFR α/β, KIT [CD117, stem cell factor receptor, Colonial stimulating factor-1 receptor (CSF1R), the stem cell growth factor receptor (SCGFR), FLK2/FLK3][Receptor tyrosine kinase] & VEGFR family (VEGFR1, VEGFR2, VEGFR3) [Receptor tyrosine kinase] | Sorafenib (also targets CDK, B-RAF, KIT, FLT-3, RET, c-MET) | RCC, DTC, and HCC | HTN, ACS, HF, Arterial thromboembolism, QT prolongation | Skin rash, Hemorrhage, HFSR, Mucositis, Hypothyroidism, Fatigue, Renal toxicities, including proteinuria and acute renal failure, Dyspnea, Diarrhea | |
| Sunitinib (also targets Src) | HES, GIST, MDS/MDP | HTN, MI, HF, Reduced LVEF, LVD, Arterial thrombosis, QT prolongation, Torsades de pointes | Hemorrhage, Hypothyroidism, Adrenal Dysfunction | ||
| Ponatinib (also targets Src and FGFR) | Ph+ CML or ALL | HF, Arrhythmia, HTN, Cardiomyopathy, Vascular occlusion, Arterial, and Venous thrombosis | Rash, Abdominal pain, Nausea, Constipation, Headaches, Dry skin, Fatigue, Fever, Myalgia. Dyspnea, Arthralgia, Increased ALT/ lipase, Pancreatitis and amylase increase, Hematologic adverse effects (thrombocytopenia > neutropenia > anemia), Hepatotoxicity, Liver failure, and Death | ||
| Axitinib (also targets KIT) | RCC |
HTN, HF, Arterial Thrombosis. Hypotension |
Fatigue, Nausea, Diarrhea, Vomiting, Headache, Hemoptysis, Stomatitis, Erythema, Anorexia, Limb Pain, Arthralgia, Myalgia Hand-Foot Syndrome, Dyspnea, Dehydration | ||
| Regorafenib | CRC, GIST | MI, HTN, Arterial thrombosis | HFSR reactions, Diarrhea, Fatigue, Anemia, Thrombocytopenia, Proteinuria | ||
| Pazopanib | RCC, STS | LVD, HTN, HF, Arterial thrombosis, Cardiomyopathy, QT Prolongation, Torsades de pointes | Fatigue, GI disorders, Elevated ALT, Neutropenia, Leukopenia, Lymphocytopenia, Anemia, Asthenia | ||
| Lenvatinib (also targets Src) | DTC | QT Prolongation, LVD, HF, HTN | Hypothyroidism, Diarrhea, Fatigue, Decreased appetite | ||
| Cabozantinib (Type II c-MET inhibitor) (also targets Src and) | Metastatic MTC, advanced RCC, and HCC | HTN, Arterial thrombosis | Palmar–plantar erythrodysesthesia, GI disorders, Fatigue, Stomatitis. | ||
| Praseltinib (also inhibits RET, DDR1, TRKC, FLT3, JAK1–2, TRKA, VEGFR2, PDGFRb, and FGFR1) |
Metastatic RET fusion + NSCLC Advanced or metastatic RET-mutant MTC Advanced or metastatic RET fusion + thyroid cancer |
HTN | Rash, Anemia, Cough, Fatigue, Pyrexia, GI disorders, Edema, Musculoskeletal pain, Decreased WBCs, Hyperphosphatemia, Increased AST/ALT, Pneumonitis, Headache, Peripheral neuropathy, Dizziness, Dysgeusia | ||
| RET family | Alectinib | ALK + NSCLC | QT Prolongation, Bradycardia | GI disorders, Myalgia, Peripheral edema, Elevated liver enzymes, Elevated blood bilirubin, Anemia | |
| Selpercatinib | Metastatic RET fusion-positive NSCLC, advanced or metastatic RET-mutant MTC | HTN, QT prolongation, | Hepatotoxicity, Hemorrhagic events, Hypersensitivity, risk of impaired wound healing, and Embryo-fetal toxicity. | ||
ACS Acute Coronary Syndrome, AF Atrial Fibrillation, ALL Acute lymphocytic leukemia, ALP, Alkaline Phosphatase, ALT Alanine Transaminase, AST Aspartate Transaminase, AV Atrioventricular, CEL Chronic Eosinophilic Leukemia, CLL Chronic lymphocytic leukemia, CML, Chronic myeloid leukemia, CPK Creatine Phosphokinase, CRC Colorectal cancer, DFSP Dermatofibrosarcoma protuberans, DTC Differentiated thyroid cancer, ECD Erdheim-Chester Disease, GGT Gamma Glutamyl Transference, GI Gastrointestinal, GIST Gastrointestinal Stromal Tumor, GVD graft versus host disease, HCC Hepatic Cell Carcinoma, HES Hyper eosinophilic syndrome, HF Heart Failure, HFSR hand–foot skin reaction, HTN Hypertension, ILD Interstitial Lung Disease, LFT Liver function test, LVD Left Ventricular Dysfunction, LVEF Left ventricular ejection fraction, MCL Mantle cell lymphoma, MDP Myeloproliferative Disorders, MDS Myelodysplastic syndromes, MF Myelofibrosis, MI Myocardial Infarction, MTC Medullary thyroid cancer, MZL Marginal zone lymphoma, NSCLC Non-Small Cell Lung Cancer, PDGFR Platelet-Derived Growth Factor Receptor, Ph+ Philadelphia chromosome, PHT Pulmonary hypertension, PV Polycythemia vera, RCC Renal Cell Carcinoma, ROS Reactive Oxygen Species, STS Soft tissue sarcoma, TKI Tyrosine Kinase Inhibitor, URTI Upper Respiratory Tract Infection, VEGFR Vascular Endothelial Growth Factor Receptor, WBC White Blood cell, WM Waldenstrom macroglobulinemia