TKI: Growth Factor Receptor Antagonist

ado-trastuzumab emtansine

TKI: Growth Factor Receptor Antagonist

TKI: Tropomysin receptor kinase inhibitor

TKI: Rearranged during transfection

TKI: Mesenchymal Epithelial Transition Inhibitor

TKI: Bruton's Tyrosine Kinase Inhibitor

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Oncology Exam 2

Smith: Tyrosine Kinase Inhibitors (Drug List)

Drug	TKI Class	MOA	Target Role/ PK	indication	Adverse Rxns	Resistance	DI/ BBW/Fatal	Unique Info
Gefitinib	TKI: Growth Factor Receptor Antagonist	-Reversible inhibitor of EGFR tyrosine kinase activity -Competes with ATP binding to cytoplasmic tyrosine kinase domain -Causes cell cycle arrest at the G0/G1 boundary	EGFR; 250 mg PO Q Day with or without food Metabolized primarily by CYP3A4	-Treat NSCLC patients who failed standard chemo -NSCLC patients whose tumors have EGFR activating mutation	-Most common: Diarrhea, rash, acne, pruritus, dry skin, nausea, vomiting, anorexia; Asymptomatic increase in liver transaminases, so monitor liver function -Interstitial lung disease seen in some patients, rare, but may be fatal	Primary res: (lower than-expected response rate; other mech. poor tumor penetration, drug efflux, drug metab. mutations; -2nd: develop new mutation T790M; *EGFRs with both an activating mutation and T790M resistance mutation have reduced sensitivity gefitinib -Newer EGFR antagonists that are irreversible inhibitors that crosslink the receptor do not have seem to have secondary resistance develop		-Had lower response rate than hoped for (primary resistance) -But a subset of NSCLC patients respond dramatically -Secondary resistance is known to occur; *Asian, NS, broncho, NSCLC pts responded well--> due to SNP variant in exon 21 (L858R) and in-frame deletion spanning positions 746 to 753 (EGFR exon 19 deletion)--> prevent hyperactive
Lapatinib	TKI: Growth Factor Receptor Antagonist	-Reversible inhibitor of both EGFR and HER-2 -Developed to enhance efficacy of small molecule EGFR inhibitors like Gefitinib	EGFR and HER2; -Metabolized mostly by CYP3A4 and CYP3A5	-In combination with capecitabine for advanced or metastatic breast cancer overexpressing HER2 and progressed on prior therapy	BBW for hepatoxicity		avoid graperuit; good at causing hepatotoxicity; get LFT	*made it to target both EGFR and HER2 (still reversible); though was to stop some of the pathophys; BBW good at causing hepatotoxicity
Tucatinib	TKI: Growth Factor Receptor Antagonist	-Small molecule HER2 antagonist -highly selective for HER2; minimal inhibition of EGFR -Tucatinib with trastuzumab improves outcomes probably due to targeting intracellular and extracellular domains of HER2	HER2; -metabolized mostly by CYP2C8, some metabolism by CYP3a	-patients with unresectable or metastatic HER2-positive breast cancers, including patients with brain metastases and pretreated patients -Tucatinib and Trastuzumab together have increased anti-tumor activity compared to either drug alone	Serious: diarrhea and hepatotoxicity			more selective for HER2 and minimal inhibition of EGFR;
Neratinib	TKI: Growth Factor Receptor Antagonist	-Irreversible inhibitor of EGFR, HER2, and HER4 -covalently binds to the intracellular kinase domain	EGFR; HER2; HER4; -metabolized mostly by CYP3A4	-Early stage HER2-overexpressed/amplified breast cancer following adjuvant trastuzumab based therapy; indication for breast cancer	Diarrhea, skin reactions	Not seen yet	PPIs due to change in the pH	IRREVERSIBLE; targeting EGRF, HER2, and HER4 first irriversible
Afatinib	TKI: Growth Factor Receptor Antagonist	Irreversible inhibitor of EGFR, HER2, and HER4 it covalently binds to the intracellular kinase domain	EGFR; HER2; HER4; -P-gp substrate and inhibitor	EGFR mutation-positive NSCLC and previously treated squamous NSCLC	Common - Gastrointestinal and dermatologic toxicities		SE not as bad as other meds	*indicaiton was for non-small lung cell cancers
Osimertinib	TKI: Growth Factor Receptor Antagonist	-Irreversible EGFR antagonist for variant forms of EGFR including T790M, L858R, and exon 19 deletion -9-fold more potent for variant EGFR compared to wild-type	EGFR	-Metastatic NSCLC whose tumors have EGFR exon 19 deletion or the exon 21 L858R mutations detected by an FDA-approved test -EGFR T790M mutation-positive NSCLC after disease progression on or after an EGFR inhibitor	-Common - Gastrointestinal and dermatologic toxicities -Serious - interstitial lung disease/pneumonitis, pneumonia, and pulmonary embolism			good at hitting the variants L858R and exon 19 deletion are activationg mutation variants *T790M variant (confers resistance)
Cetuximab	TKI: Growth Factor Receptor Antagonist	-High specificity chimeric mouse/human IgG1 against EGFR -Affinity greater than that of physiological ligands	EGFR	-EGFR expressing colorectal cancer; head and neck caners -If want to use in colorectal carcinoma, need to evaluate for KRAS mutation	-Rash and diarrhea; Development of rash is predictive of tumor response		-Infusion reactions; Cardiopulmonary arrest	first monoclonal antibody EGFR antagonist; binds better than the growth factor; indication for colorectal cancer pts * mousy its Chimeric; *KRAS mutation and EGFR + (genotype required) ⭐️
Panitumumab	TKI: Growth Factor Receptor Antagonist	-Human kappa monoclonal antibody against EGFR	EGFR	-Colorectal cancer	Dermatologic, diarrhea		Dermatologic toxicities	*same issue as Cetuximab
Trastuzumab	TKI: Growth Factor Receptor Antagonist	-Humanized monoclonal against ErbB-2 (HER-2); Downregulates HER2, decreases ErbB family receptor signaling -induces antibody-dependent cellular cytotoxicity -inhibits angiogenesis	HER2	Breast tumors expressing HER-2	Cardiotoxicity, especially when combined with anthracyclines		BBW: Cardiomyopathy -Infusion Reactions, Pulmonary Toxicity -Embryo-Fetal Toxicity; DI: with Warfrain, therefore monitor prothrombin time ratio or INR	by binding and preventing dimmerization with another prevent signaling; need baseline cardio test done
ado-trastuzumab emtansine	TKI: Growth Factor Receptor Antagonist	-Trastuzumab covalently linked to the small molecule cytotoxin (DM1) -Binds to HER2, is internalized, DM1 released and interrupts the cell cycle and causes apoptosis	HER2	HER2+ breast cancer	nausea, constipation, headache, musculoskeletal pain, or fatigue		Do not substitute for trastuzumab; BBW: (Hepatotoxicity; Cardiotoxicity (decreaseed LVEF); Embroy-fetal toxicity	*warning: Cannot substitite for Trastuzumab (not equivalent)
fam-trastuzumab	TKI: Growth Factor Receptor Antagonist	-Trastuzumab attached to DXd (a topoisomerase I inhibitor) by a cleavable linker -Binds to HER2, is internalized, DXd released by lysosomal enzymes, DXd causes DNA damage and apoptosis	HER2	-HER2+ tumors including breast -Other HER2+ tumors such as gastrointestinal and NSCLC	-nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, and diarrhea		BBW: -Interstitial lung disease (ILD) and pneumonitis; -Embryo-fetal toxicity	*As a TopI inhibitor--> stops DNA replication
pertuzumab	TKI: Growth Factor Receptor Antagonist	-humanized monoclonal antibody targeting HER2 -mediates antibody-dependent cellular cytotoxicity -Used with trastuzumab, as they target different regions on HER2 receptor	HER2	HER2+ breast cancer	-diarrhea, nausea, alopecia, rash, headache, fatigue, and peripheral neuropathy		BBW: -Left Ventricular Dysfunction -Embryo-fetal toxicity
Alectinib	TKI: ALK Inhibitor	Second generation ALK inhibitors, which have better blood brain barrier penetration; also inhibits RET	ALK; inhibits RET	Metastatic ALK+ NSCLC	General: visual disturbances, photosensitivity, potential for fetal harm; Specific AE: fatigue, bradycardia, hepatotoxicity, anemia, constipation, edema, myalgia			*take with food
Brigatinib	TKI: ALK Inhibitor	Second generation ALK inhibitors, which have better blood brain barrier penetration; Also inhibits ROS1, FLT-3, and variant forms of EGFR	ALK; inhibits ROS1, FLT-3, and variant forms of EGFR; Metabolized by CYP3A4	Metastatic ALK+ NSCLC	General: visual disturbances, photosensitivity, potential for fetal harm; Specific AE: pulmonary toxicities and bradycardia; dose escalation approach used to decrease risk of pulmonary toxicities		DI: Metabolized by CYP3A4
Crizotinib	TKI: ALK Inhibitor	-Binds to the intracellular side of ALK, preventing phosphorylation -Also inhibits other kinases: -ROS1, MET, and other kinases ROS physiological role is poorly understood, may be involved during embryonic development for the differentiation of epithelial tissues	ALK; ROS1; MET and other kinases; -Metabolized by CYP3A4/5	ALK+ non small cell lung cancer and anaplastic large cell lymphoma	-Common: vision disturbances, GI distress -Serious: interstitial lung disease/pneumonitis, hepatotoxicity, QT interval prolongation, bradycardia	*Drug resistance often develops	DI: CYP3A inhibitors -QT-interval prolonging drugs -Avoid grapefruit	Drug resistance often develops
Lorlatinib	TKI: ALK Inhibitor	-A third-generation ALK inhibitor (efficacious even against ALK-resistant mutations) -Also targets ROS1	Targets ROS1; -Metabolized by CYP3A4/5	-Approved for ALK+ NSCLC Seems to be effective when disease has progressed on one or more ALK inhibitors	Common: hepatotoxicity, interstitial lung disease/pneumonitis May cause fetal harm		DI: Metabolized by CYP3A4/5; Contraindicated with strong CYP3A inducers because of risk of hepatotixicty	*designed as a 3rd gen for an ALK (+) tumor
Midostaurin	TKI: FLT3 inhibitor	Inhibits FLT3, including the ITD and TKD variants ⭐️ results in apoptosis of leukemic cells;	FLT3; ITD; TKD variants		pulmonary toxicity, febrile neutropenia, gastrointestinal toxicities, fatigue, and hyperglycemia Fetal harm		DI: Metabolized by CYP3A4, so interactions with CYP3A4 inhibitors and grapefruit	Mido hits ITD and TKD; Quizartinib is more potent
Quizartinib	TKI: FLT3 inhibitor	-Inhibits FLT3; more potent for the ITD variant ⭐️ -Has an active metabolite AC886 -Results in apoptosis of leukemic cells	FLT3; more potent for the ITD variant	Adult with newly diagnosed AML that is FLT3 ITD+	Myelosuppression, GI distress, respiratory infection, headache		⭐️BBW: QT Prolongation, Torsades de Pointes, and Cardiac Arrest; ⭐️CI: Severe hypokalemia, Severe hypomagnesemia, Long QT syndrome; ⭐️DI: -Metabolized by CYP3A4, so interactions with CYP3A4 inhibitors and grapefruit -QT prolonging drugs	*active metabolute of AC886 and contributes to its efficacy; BBW of meds that have cardiac effects
Entrectinib	TKI: Tropomysin receptor kinase inhibitor	Inhibitor of TRKA, TRKB, TRKC, ROS1, and ALK kinases	TRKA; TRKB, TRKC, ROS1; ALK kinases -Metabolized by CYP3A4, so interactions with CYP 3A4 inhibitors	-tumors with TRK gene fusions -metastatic NSCLC positive for ROS1	-increased risk for congestive heart failure, cognitive impairment, hepatotoxicity, and prolongation of QT interval		-Metabolized by CYP3A4, so interactions with CYP3A4 inhibitors -QT prolonging drugs	*this is an inhibitor of TRKA/B/C, ROS1, and ALK kinases
Larotrectinib	TKI: Tropomysin receptor kinase inhibitor	-Inhibitor of TRKA, TRKB, and TRKC kinases	TRK; TRKB; TRKC -Metabolized by CYP3A4, so interactions with CYP3A4 inhibitors	treatment of adult and pediatric patients with solid tumors that have a NTRK-gene fusion	-fatigue, nausea, dizziness, vomiting, transaminitis, cough, constipation, and diarrhea -Serious: neurotoxicity and hepatotoxicity		-Metabolized by CYP3A4, so interactions with CYP3A4 inhibitors	⭐️ hits all 3 of the TRK kinases (A,B,C)
Repotrectinib	TKI: Tropomysin receptor kinase inhibitor	-Second generation inhibitor of TRKA, TRKB, and TRKC kinases and ROS1 -Second generation have better efficacy due to more selectivity, potency against TRKs and ROS1 as well as variants that have been found in the TRKs	TRKA; TRKB; TRKC kinases; ROS1; -Metabolized by CYP3A4, so interactions with CYP3A4 inhibitors and grapefruit	-solid tumors that are NTRK-gene fusion+ or ROS1+ NSCLC	-fatigue, nausea, dizziness, vomiting, transaminitis, cough, constipation, and diarrhea -Serious: neurotoxicity, hepatotoxicity, pneumonia	-Metabolized by CYP3A4, so interactions with CYP3A4 inhibitors and grapefruit		more selective and potency against TRKs and ROS1 (variants) 2nd gen TRK; lots of AE; ⭐️neurotoxicity, hepatotoxicity, pneumonia for serous AE
Pralsetinib	TKI: Rearranged during transfection	Inhibits wild-type and mutated RET	RET wild-type and mutated RET; -metabolized by CYP3A4	metastatic RET fusion–positive NSCLC and advanced or metastatic RET-mutant medullary thyroid cancer	severe interstitial lung disease ⭐️ /pneumonitis and hypertension		-metabolized by CYP3A	*orally BA
Selpercatinib	TKI: Rearranged during transfection	inhibits wild-type and mutated RET isoforms, VEGFRs and FGFRs	RET; wild-type and mutated RET isoform; VEGFRs; FGFRs; -metabolized by CYP3A4	-metastatic RET fusion–positive NSCLC and advanced or metastatic RET-mutant medullary thyroid cancer	hepatotoxicity that requires close monitoring every 2 weeks; hypertension requiring monitoring; QTc prolongation; impaired wound healing ⭐️; and tumor lysis syndrome		metabolized by CYP3A	orally BA; impaired wound healing (this is due to hitting VEGFR and FGFR--> SE because it hits these receptors involved in angiogenesis
Capmatinib	TKI: Mesenchymal Epithelial Transition Inhibitor	selective MET kinase inhibitior	MET; -metabolized by CYP3A4	for the treatment of metastatic NSCLC with a maturation that leads to MET exon 14 skipping	peripheral edema, dyspepsia, and fatigue		metabolized by CYP3A4	*orally BA; MET specific
Tepotinib	TKI: Mesenchymal Epithelial Transition Inhibitor	MET kinase inhibitor	MET; -metabolized by CYP3A4	for the treatment of metastatic NSCLC with a maturation that leads to MET exon 14 skipping	peripheral edema, dyspepsia, fatigue, and MSK pain		metabolized by CYP3A4	*orally BA; MET specific; -MSK pain
Amivantamab-vmjw	TKI: Mesenchymal Epithelial Transition Inhibitor	-a bispecific antibody that targets both EGFR and MET at the same time -Stops signaling from these receptors -Kills targeted cells by antibody-dependent cellular cytotoxicity -Has affinity for EGFR exon 19 deletions, exon 21 L858R substitutions, and exon 20 insertions	MET; EGFR	-NSCLC with a EGFR exon 19 deletions, exon 21 L858R substitutions, and exon 20 insertions mutations	-Infusion reactions, interstitial lung disease, pneumonitis, blood clots, including deep vein thrombosis, pulmonary embolism, serious skin reactions, eye or vision problems -Fetal harm	---	---	⭐️ Fetal harm; Targets both EGFR and MET; ⭐️ bispecific antibody; remember that EGFR variant exon 19 deletions, exon 21 L858R variant are the “activating mutations of EGFR and exon 20 makes it resistant to those small molecules ⭐️
Acalabrutinib	TKI: Bruton's Tyrosine Kinase Inhibitor	-second generation BTK inhibitors: Are more selective for BTK (doesn’t inhibit other receptors like EGFR) -developed to improve toxicity – have less cardiovascular adverse effects -Developed to deal with resistance of the first generation BTK inhibitors because they irreversible BTK inhibitors -Prevent signaling from the B cell antigen receptor	BTK (Irreversible inhibitor)	-approved for mantle cell lymphoma; more selective (do not inhibit other receptors such as EGFR); Various lymphomas	-Common: myelosuppression (anemia, neutropenia, thrombocytopenia), diarrhea, fatigue, headache, myalgia, and bruising. -Serious: hemorrhaging; Acalabrutinib may have a better adverse effect profile than zanubrutinib	-metabolized by CYP3A4	DI: PPIs, antacids, 3A4 inhibitors	more selective (do not inhibit other receptors such as EGFR); cause bleeding
Zanubrutinib	TKI: Bruton's Tyrosine Kinase Inhibitor	-second generation BTK inhibitors: -Are more selective for BTK (doesn’t inhibit other receptors like EGFR) -developed to improve toxicity – have less cardiovascular adverse effects -Developed to deal with resistance of the first generation BTK inhibitors because they irreversible BTK inhibitors -Prevent signaling from the B cell antigen receptor	BTK (irreversible inhibitor)	-approved for mantle cell lymphoma; more selective (do not inhibit other receptors such as EGFR); Various lymphomas	-Common: myelosuppression (anemia, neutropenia, thrombocytopenia), diarrhea, fatigue, headache, myalgia, and bruising. -Serious: hemorrhaging; Acalabrutinib may have a better adverse effect profile than zanubrutinib	-metabolized by CY{3A4	PPIs, antacids, 3A4 inhibitors	more selective (do not inhibit other receptors such as EGFR); cause bleeding
Ensartinib	TKI: ALK inhibitor	Second generation ALK inhibitors, which have better blood brain barrier penetration; also inhibits ROS1 and MET	-Inhibits ROS1 and MET; Metastatic ALK+ NSCLC		General: visual disturbances, photosensitivity, potential for fetal harm; Specific AE: fatigue, bradycardia, hepatotoxicity, anemia, constipation, edema, myalgia;		-Metabolized by CYP3A4

Created by: Xander635

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