Table 2.
Receptor tyrosine kinase inhibitors that have been clinically used for cancer treatment.
| Target | Generic name (Code name) | Brand name (Company) | First approved indication (Year) | Additional indication | Drug resistance mechanism (selected) | Side effects/toxicity (selected) | References |
|---|---|---|---|---|---|---|---|
| EGFR1 |
Gefitinib (ZD1839) |
Iressa (AstraZeneca) |
Advanced NSCLC2 after failure of both platinum-based and docetaxel chemotherapies (2003) | Metastatic NSCLC harboring EGFR mutations (first-line therapy, 2015) |
EGFR T790M mutation MET amplification HER2 amplification Small-cell lung cancer transformation |
Skin rash, nausea, diarrhea, transaminitis, ILD3-like disorders, hematuria | 8,52,63,195–197 |
| EGFR |
Erlotinib (OSI-744) |
Tarceva (Roche/Astellas) |
Locally advanced or metastatic NSCLC after failure of prior chemotherapy regimen (2004) | Metastatic NSCLC harboring EGFR mutations (first-line therapy, 2013) |
EGFR T790M mutation HGF overexpression MET amplification HER2 amplification Small-cell lung cancertransformation |
Skin rash, diarrhea, ocular toxicity | 8,50,52,64,195–197 |
| EGFR |
Afatinib (BIBW2992) |
Gilotrif (Boehringer Ingelheim) |
Metastatic NSCLC with kinase activating mutations (2013) | Advanced squamous cell carcinoma of the lung after treatment with platinum-based chemotherapy (2016) |
EGFR T790M mutation MET amplification EGFR V843I mutation |
Skin rash, diarrhea | 196,198,199 |
| EGFR |
Dacomitinib (PF-00299804) |
Vizimpro (Pfizer) |
Metastatic NSCLC with kinase activating mutations (2018) | EGFR T790M/C797S mutation | Skin toxicity, dermatitis acneiform, paronychia, diarrhea | 67,200,201 | |
| EGFR |
Osimertinib (AZD9291) |
Targrisso (AstraZeneca) |
1st- or 2nd-generation EGFR-TKI-refractory NSCLC (2015) | Advanced NSCLC with mutated EGFR, regardless of T90M mutation (2018) |
Loss of EGFR T790M mutation EGFR C797S mutation MET amplification Wild-type EGFR amplification |
Skin rash, diarrhea, mucositis/stomatitis, paronychia, pneumonitis, cardiac failure | 8,79,195,202–204 |
| EGFR | Lazertinib4 (YH25448) |
Leclaza (Yuhan/Janssen) |
Advanced or metastatic NSCLC (2021) |
Loss of EGFR T790M mutation EGFR activating mutation/amplification EGFR C797S mutation |
Skin rash, itchiness, paresthesia, muscle spasm, headache, diarrhea, anorexia | 72 | |
| EGFR | Cetuximab |
Erbitux (ImClone) |
Metastatic CRC5 (2004) | Head and neck squamous cell carcinoma (2006) |
RAS/BRAF mutation EGFR S492R mutation MET amplification PTEN loss |
Infusion reactions, acneform skin rash, nail disorder | 87–89,205–208 |
| EGFR | Panitumumab |
Vectibix (Abgenix/Amgen) |
Metastatic CRC (2006) |
RAS/BRAF mutation MET amplification PTEN loss |
Integument toxicity, skin toxicity, diarrhea | 88,89,206,208 | |
| EGFR |
Amivantamab (JNJ-61186372) |
Rybrevant (Janssen Biotech) |
Advanced NSCLC with EGFR exon 20 insertion mutations progressing after platinum-based chemotherapy (2021) |
Infusion reactions ocular toxicity, peripheral edema, hypoalbuminemia |
79,80 | ||
| EGFR |
Mobocertinib (TAK-788) |
Exkivity (Takeda Pharmaceuticals) |
Advanced NSCLC with EGFR exon 20 insertion mutations progressing after platinum-based chemotherapy (2021) | Diarrhea, skin toxicity | 79,81 | ||
| HER2 | Trastuzumab |
Herceptin (Genentech/Roche) |
Metastatic breast cancer (1998) | Locally advanced unresectable or metastatic HER2+ gastric or gastroesophageal junction (GEJ) adenocarcinoma in combination with pembrolizumab (2021) |
Truncation of HER2 extracellular domain (p95 HER2) PTEN loss IGF-1R expression PIK3CA mutation |
Cardiotoxicity | 8,56,90,209 |
| HER2 | Pertuzumab |
Perjeta (Genentech/Roche) |
HER2+ early breast cancer (EBC) with high risk of recurrence (2017) | Diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, vomiting | 8,90,210 | ||
| HER2 |
Zanidatamab (ZW25) |
(Zymeworks) | Advanced/metastatic HER2-expressing biliary tract cancers | Diarrhea, infusion-related reactions | 91 | ||
| HER2 |
Lapatinib (GW-572016) |
Tykerb (GlaxoSmithKline/ Novartis) |
HER2+ metastatic breast cancer progressing with prior therapy (in combination with capecitabine, 2007) | Triple-positive metastatic breast cancer (in combination with letrozole, 2010) |
Crosstalk with ER HER2 mutation PIK3CA mutation AXL elevation HER2 L755S mutation |
Diarrhea, skin rash, asymptomatic cardiotoxicity | 82,83,209,211 |
| HER2 |
Neratinib (HKI-272) |
Nerlynx (Puma Biotechnology) |
Extended adjuvant therapy for HER2+ breast cancer (2017) | Advanced or metastatic HER2+ breast cancer progressing with prior therapy (in combination with capecitabine, 2020) |
TORC1 hyperactivation RAS upregulation |
Diarrhea | 56,84,209,211,212 |
| HER2 |
Tucatinib (ONT-380) |
Tukysa (Seattle Genetics) |
Advanced or metastatic HER2+ breast cancer (in combination with trastuzumab and capecitabine, 2020) | HER2 L755S mutation |
Diarrhea cardiotoxicity |
85,211 | |
|
ALK ROS1 MET |
Crizotinib (PF-02341066) |
Xalkori (Pfizer) |
Locally advanced or metastatic ALK+ NSCLC (2011) | ROS1-positive NSCLC (2016) | ALK mutation (G1269A, C1156Y, E1210K, I1171T, S1206C/Y, I1151T/N/S, 1174 C/L/V, V1180L, L1196M) | Nausea, vomiting, diarrhea, visual disturbance, sinus bradycardia, liver enzyme abnormalities | 79,96,98,99,213 |
| ALK |
Ceritinib (LDK378) |
Zykadia (Novartis) |
ALK+ metastatic NSCLC after failure of crizotinib therapy (2014) | ALK+ metastatic NSCLC (first-line therapy, 2017) | ALK mutation (G1202R, F1174C/L/V, 1151Tins, L1152P, C1156Y) | Diarrhea, nausea, vomiting, fatigue, elevated level of transaminase | 95,96,213 |
| ALK | Alectinib (CH5424802) |
Alecensa (Chugai Pharmaceutical/ Roche |
ALK-rearranged advanced/recurrent NSCLC with crizotinib resistance (2015) | ALK+metastatic NSCLC (first-line therapy, 2017) |
ALK mutation (G1202R, V1180L and I1171T/N/S) MET amplification |
Photosensitivity, dysgeusia, myalgia, upregulated creatinine phosphokinase | 79,96,213 |
|
ALK EGFR |
Brigatinib (AP26113) |
Alunbrig (ARIAD Pharmaceuticals) |
ALK-rearranged metastatic NSCLC (2017) | ALK double mutation (G1202R, E1210K and S1206C or D1203N) | Pneumonitis, nausea, diarrhea, fatigue | 79,101,102,213 | |
|
ALK ROS1 |
Lorlatinib (PF-6463922) |
Lorbrena (Pfizer) |
ALK-rearranged metastatic NSCLC (2018) (second/third-line treatment, accelerated approval) |
ALK+ metastatic NSCLC (2021) (regular approval) |
Compound ALK mutation including G1202R, I1171N/T/S, and L1198F ALK L1256F mutation MET amplification |
Edema, cholesterolemia, peripheral neuropathy, hypertriglyceridemia, CNS effects | 8,92,203. |
| MET | Capmatinib (INC280) |
Tabrecta (Novartis) |
Metastatic NSCLC harboring MET exon 14 skipping (2020) | MET mutation at D1228 and Y1230 (D1228 A/E/G/H/N/V/Y, Y1230 C/D/H/N/S) | Nausea, diarrhea, peripheral edema, hypoalbuminemia, increased blood creatinine | 79,99,214 | |
| MET |
Tepotinib (EMD 1214063) |
Tepmetko (Merck) |
Metastatic NSCLC harboring MET exon 14 skipping (2021) | MET mutation at D1228 and Y1230 (D1228 A/E/G/H/N/V/Y, Y1230 C/D/H/N/S) | Nausea, vomiting, peripheral edema, hypoalbuminemia, increased blood creatinine | 79,99,214 | |
| TRK | Larotrectinib (LOXO-101) |
Vitrakvi (Loxo Oncology/Bayer) |
Locally advanced or metastatic solid tumors with NTRK gene fusion (2018) | TRKA F589L/G595R/G667C, TRKC G623R/G696A mutation | Upregulation of serum AST/ALT, dizziness, fatigue, nausea, constipation | 106,107 | |
|
TRK ALK ROS1 |
Entrectinib (RXDX-101) |
Rozlytrek (Genentech) |
Solid tumors with NTRK gene fusion and NSCLC harboring ROS1 rearrangement (2019) | TRKA G595R/G667C, TRKC G623R mutation | Fatigue, dysgeusia, nausea, vomiting, paresthesia, myalgia, diarrhea | 106,107 | |
|
FLT3 c-Kit PDGFR Src VEGFR |
Midostaurin (PKC412, CGP 41251) |
Rydapt (Novartis) |
AML6 harboring FLT3 mutations (2017) |
FLT3 N676K, F691L mutation FLT3 ligand overexpression RAS/MAPK mutation JAK, PI3K/Akt activation |
Nausea, febrile neutropenia, mucositis, vomiting, headache, petechiae, fever | 109,215–217 | |
|
FLT3 AXL |
Gilteritinib (ASP2215) |
Xospata (Astellas Pharma) |
FLT3-mutated refractory AML (2018) |
FLT3 F691L mutation RAS/MAPK mutation JAK, PI3K/Akt activation |
upregulation of hepatic transaminase/creatine phosphokinase, edema, cytopenia, febrile neutropenia | 109,215–217 | |
|
VEGFRs PDGFR-β c-Kit FLT3 RET RAFs |
Sorafenib (BAY 43-9006) |
Nexavar (Bayer/Onyx Pharmaceuticals) |
Advanced RCC7 (2005) |
HCC8 (2008) Locally recurrent or metastatic, progressive DTC9 refractory to radioactive iodine treatment (2013) |
FLT3 F691L, Y842C/H, D835F/V/Y mutation FLT3 ligand overexpression JAK, PI3K/Akt activation |
Hand-foot syndrome, asthenia, gastrointestinal irritation, cytopenia, infection, diarrhea, cardiovascular toxicity, fatigue | 109,215–217 |
|
PDGFR-α/β VEGFR1/2/3 CSF-1R c-Kit, RET FLT3 |
Sunitinib (SU11248) |
Sutent (Pfizer) |
Advanced RCC (2006) Imatinib-resistant GIST10 (2006) |
Pancreatic neuroendocrine tumor (2011) |
Angiogenic factor upregulation Autophagy Metabolic adaptation Stromal cell recruitment |
Mucositis, diarrhea, skin abnormality, taste alteration | 8,126,218,219 |
|
VEGFR1/2/3 PDGFR-α/β FGFR1 FGFR3 c-Kit |
Pazopanib (GW786034) |
Votrient (GlaxoSmithKline/Novartis) |
Advanced/metastatic RCC (2009) | Advanced soft-tissue sarcoma previously treated with chemotherapy (2012) |
Angiogenic factor upregulation Stromal cell recruitment |
Hepatic injury, fatigue, hand-food syndrome, myelosuppression | 220 |
|
VEGFR1/2/3 PDGFR-α FGFRs c-Kit RET |
Lenvatinib (E7080) |
Lenvima (Eisai/Merck) |
Progressive radioactive iodine-refractory thyroid cancer (2015) |
Advanced RCC (recurrent or metastatic) (2016) Unresectable HCC (2018) Advanced RCC in combination with pembrolizumab (2021) |
Angiogenic factor upregulation Stromal cell recruitment |
Hypertension, diarrhea, fatigue/asthenia | 220 |
|
MET VEGFR2 c-Kit RET AXL Tie2 FLT3 |
Cabozantinib (XL184) |
Cometriq (capsule) Cabometyx (tablet) (Exelixis) |
Cometriq: medullary thyroid cancer (2012) Cabometyx: RCC (2016) |
Cabometyx: HCC (second-line, 2019) |
Angiogenic factor upregulation Stromal cell recruitment |
Diarrhea, palmar-plantar erythrodysesthesia syndrome | 220 |
| VEGFRs |
Axitinib (AG 013736) |
Inlyta (Pfizer) |
Advanced or metastatic RCC (2012) |
Angiogenic factor upregulation Stromal cell recruitment |
Hypertension, diarrhea, fatigue | 220 | |
|
VEGFR2 EGFR3 GFR ET |
Vandetanib ZD6474) |
Zactima aprelsa AstraZeneca) |
Medullary thyroid cancer (2011) |
RET V804M/L mutation Activation of RAS/ RAF/MEK pathway |
Diarrhea, skin rash, folliculitis, nausea, fatigue, hypertension, QT interval prolongation | 221 | |
|
VEGFR1/2/3 Tie2 PDGFR-α/β FGFR1/2 c-Kit RET RAFs |
Regorafenib BAY 73-4506) |
Stivarga (Bayer) |
Metastatic CRC (2012) |
Advanced GIST (2013) Advanced HCC (2018) |
KIT V654A, D816V mutation | Hypertension, hand-food skin reaction, diarrhea, fatigue | 220,222 |
|
VEGFR1/2/3 PDGFR-β c-Kit |
Tivozanib (AV-951, KRN-951) |
Fotivda (AVEO Pharmaceuticals /Kyowa Kirin) |
Relapsed or refractory RCC (2021) | Infiltration of myeloid cells | Hypertension, hoarseness, fatigue, headache, diarrhea, rash | 223 | |
|
PDGFR-α c-Kit |
Avapritinib (BLU-285) |
Ayvakit (Blueprint Medicines) |
Unresectable or metastatic GIST harboring PDGFRA exon 18 mutations, including D842V (2020) | Memory impairment, cognitive disorder, intracranial bleeding | 222 | ||
|
PDGFR-α c-Kit |
Ripretinib (DCC-2618) |
Qinlock (Deciphera Pharmaceuticals) |
Advanced GIST treated with three or more kinase inhibitors, including imatinib (2020) | Alopecia | 222 | ||
| FGFR |
Erdafitinib (JNJ‑42756493) |
Balversa (Janssen Pharmaceuticals) |
Metastatic urothelial cancer (2018) | Metastatic or locally advanced bladder cancer with an FGFR3 or FGFR2 alteration (2019) |
FGFR1 V561M/F mutation FGFR2 N549H mutation p.E565A and p.L617M single-nucleotide variants |
Hyperphosphatemia, dry mouth, diarrhea, fatigue, stomatitis | 91,224,225 |
| FGFRs |
Pemigatinib (INCB054828) |
Pemazyre (Incyte Corporation) |
Previously treated, unresectable, locally advanced, or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangements (2020) |
FGFR1 V561M/F mutation FGFR2 N549H mutation |
Hyperphosphatemia, dry mouth, diarrhea, fatigue, stomatitis | 91,224–226 | |
| FGFRs |
Futibatinib (TAS-120) |
(Taiho Pharmaceutical) | Locally advanced/metastatic cholangiocarcinoma with FGFR2 gene rearrangement (2021) |
p.E565A and p.L617M single-nucleotide variants FGFR2 V564F mutation |
Hyperphosphatemia, dry mouth, diarrhea, paronychia, | 91,224,225 | |
| FGFRs |
Infigratinib (BGJ398) |
Truseltriq (QED Therapeutics /Helsinn) |
Locally advanced/metastatic cholangiocarcinoma with FGFR2 gene rearrangement (2021) | FGFR2 N549H, N550H/K, V564F, E565A, K660M, L618V, K641R mutation | Hyperphosphatemia, dry mouth, diarrhea, fatigue, stomatitis | 91,224,225 | |
| FGFRs |
Derazantinib (ARQ 087) |
(Basilea Pharmaceutica /Merck) |
Intrahepatic cholangiocarcinoma (2021) | Hyperphosphatemia, dry mouth, diarrhea, fatigue, stomatitis | 91,224,225 | ||
| RET |
Selpercatinib (LOXO-292) |
Retevmo (Eli Lilly/Loxo Oncology) |
Metastatic RET fusion-positive NSCLC (2020) Advanced or metastatic thyroid cancer with RET alterations (2020) |
RET mutation at G810, Y806 | AST/ALT elevation, hypertension | 227,228 | |
| RET |
Pralsetinib (BLU-667) |
Gavreto (Blueprint Medicines) |
Metastatic RET fusion-positive NSCLC (2020) | RET mutation at G810, L730 | AST/ALT elevation, anemia, hypertension | 227,228 |
1EGFR: epidermal growth factor receptor.
2NSCLC: non-small cell lung cancer.
3ILD: interstitial lung disease.
4Approved in Republic of Korea.
5CRC: colorectal cancer.
6AML: acute myeloid leukemia.
7RCC: renal cell carcinoma.
8HCC: hepatocellular carcinoma.
9DTC: differentiated thyroid carcinoma.
10GIST: gastrointestinal stromal tumor.