Table 2 Receptor tyrosine kinase inhibitors that have been clinically used for cancer treatment.

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

^{8,52,63,195,196,197}

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

^{8,50,52,64,195,196,197}

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

^{8,79,195,202,203,204}

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

^{87,88,89,205,206,207,208}

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

^{109,215,216,217}

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

^{109,215,216,217}

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

^{109,215,216,217}

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

^{91,224,225,226}

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