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Onc Exam 1

Targeted Drug Therapy

DrugPharmacological Big CategoryPharmacological Smaller ClassTargetsMOAPKADRs/DDIOther important info
Gefitinig (historical) Tyrosine Kinase Inhibitor Growth factor receptor antagonist EGFR -Reversible inhibitor of EGFR tyrosine kinase activity​ -Causes cell cycle arrest at the G0/G1 boundary​ -Competes with ATP binding to cytoplasmic tyrosine kinase domain Metabolized by CYP3A4 -Asymptomatic increase in liver transaminases, so monitor liver function​ -Interstitial lung disease seen in some patients, rare, but may be fatal -Primary and Secondary resistance occurs -NSCLC pts & Asian female non-smokers responded well
Lapatinib Tyrosine Kinase Inhibitor Growth factor receptor antagonist EGFR, HER2 Reversible inhibitor of both EGFR and HER-2 Metabolized mostly by CYP3A4 and CYP3A5​ -avoid grapefruit Black Box Warning for hepatotoxicity -Developed to enhance efficacy of small molecule EGFR inhibitors like Gefitinib
Tucatinib Tyrosine Kinase Inhibitor Growth factor receptor antagonist HER2 -Reversible HER2 inhibitor​ -highly selective for HER2; minimal inhibition of EGFR metabolized mostly by CYP2C8, some by CYP3A diarrhea and hepatotoxicity Tucatinib (intracellular) with trastuzumab  (extracellular) improves outcomes probably due to targeting intracellular & extracellular domains of HER2​
Afatinib Tyrosine Kinase Inhibitor Growth factor receptor antagonist EGFR, HER2, HER4 -Irreversible inhibitor of EGFR, HER2, and HER4​ -covalently binds to intracellular kinase domain P-gp substrate and inhibitor FYI- Gastrointestinal and dermatologic toxicities​ n/a
Osimertinib Tyrosine Kinase Inhibitor Growth factor receptor antagonist EGFR Irreversible EGFR inhibitor for variant forms of EGFR including T790M, L858R, and exon 19 deletion ​ n/a Serious - interstitial lung disease/pneumonitis, pneumonia, and pulmonary embolism 9-fold more potent for variant EGFR compared to wild-type
Cetuximab Tyrosine Kinase Inhibitor Growth factor receptor antagonist EGFR -High specificity chimeric mouse/human IgG1 against EGFR​ -Affinity greater than that of physiological ligands n/a -Development of rash is predictive of tumor response ​ Black Box warnings​ –Infusion reactions​ –Cardiopulmonary arrest If want to use in colorectal carcinoma, need to evaluate for KRAS mutation
Panitumumab Tyrosine Kinase Inhibitor Growth factor receptor antagonist EGFR Human kappa monoclonal antibody against EGFR n/a Black Box Warning: Dermatologic toxicities n/a
Trastuzumab Tyrosine Kinase Inhibitor Growth factor receptor antagonist HER2 KNOW​ -Humanized monoclonal against ErbB-2 (HER-2)​ -Downregulates HER2, decreases ErbB family receptor signaling​ -induces antibody-dependent cellular cytotoxicity -inhibits angiogenesis n/a Black Box Warnings:​ -Cardiomyopathy​ -Infusion Reactions, Pulmonary Toxicity​ -Embryo-Fetal Toxicity​ -Drug interaction with warfarin, therefore monitor prothrombin time ratio or INR n/a
ado-trastuzumab emtansine Tyrosine Kinase Inhibitor Growth factor receptor antagonist HER2 -Trastuzumab covalently linked to the small molecule cytotoxin (DM1)​ -Binds to HER2, is internalized, DM1 released and interrupts the cell cycle and causes apoptosis n/a Warnings: Do not substitute for trastuzumab​ Black Box Warnings:​ -Hepatotoxicity​ -Cardiotoxicity (decreased LVEF)​ -Embryo-fetal toxicity n/a
fam-trastuzumab deruxtecan-nxki Tyrosine Kinase Inhibitor Growth factor receptor antagonist HER2 -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 n/a Black Box Warnings​ -Interstitial lung disease (ILD) and pneumonitis​ -Embryo-fetal toxicity n/a
Pertuzumab Tyrosine Kinase Inhibitor Growth factor receptor antagonist HER2 -humanized monoclonal antibody targeting HER2​ -mediates antibody-dependent cellular cytotoxicity n/a Black Box Warnings​ -Left Ventricular Dysfunction​ -Embryo-fetal toxicity Used with trastuzumab, as they target different regions on HER2 receptor​
Crizotinib Tyrosine Kinase Inhibitor ALK Inhibitor ALK, ROS1, MET -Binds to intracellular side of ALK, preventing phosphorylation​ -Also inhibits other kinases: ROS1, MET, and others​ Metabolized by CYP3A4/5 Serious ADR: interstitial lung disease/pneumonitis, hepatotoxicity, QT interval prolongation DRUG INTERACTIONS​ -CYP3A inhibitors​ -QT-interval prolonging drugs​ -Avoid grapefruit Drug resistance often develops
Alectinib Tyrosine Kinase Inhibitor ALK Inhibitor ALK, RET Second generation ALK inhibitors, which have better blood brain barrier penetration Also inhibits RET n/a hepatotoxicity Take with food
Brigatinib Tyrosine Kinase Inhibitor ALK Inhibitor ALK, ROS1, FLT-3, EGFR variants Second generation ALK inhibitors, which have better blood brain barrier penetration -Also inhibits ROS1, FLT-3 and variant forms of EGFR Metabolized by CYP3A4 ADRs: pulmonary toxicities and bradycardia; dose escalation approach used to decrease risk of pulmonary toxicities n/a
Ensartinib Tyrosine Kinase Inhibitor ALK Inhibitor ALK, ROS1, MET Second generation ALK inhibitors, which have better blood brain barrier penetration -Also inhibits ROS1 and MET Metabolized by CYP3A4 hepatotoxicity, interstitial lung disease/ pneumonitis, CNS toxicities, hyperlipidemia, and atrioventricular block n/a
Lorlatinib Tyrosine Kinase Inhibitor ALK Inhibitor ALK, ROS1 -A third-generation ALK inhibitor (efficacious even against ALK- resistant mutations)​ -Also targets ROS1 Metabolized by CYP3A4/5 -Common ADRs: hepatotoxicity, interstitial lung disease/ pneumonitis​ -May cause fetal harm Contraindicated with strong CYP3A inducers because of risk of hepatotoxicity n/a
Midostaurin Tyrosine Kinase Inhibitor FLT3 Inhibitor FLT3 -Inhibits FLT3, including the ITD and TKD variants​ -results in apoptosis of leukemic cells Metabolized by CYP3A4 -fetal harm -interactions with CYP3A4 inhibitors and grapefruit n/a
Quizartinib Tyrosine Kinase Inhibitor FLT3 Inhibitor FLT3 -Inhibits FLT3; more potent for the ITD variant​ -Has an active metabolite AC886​ -results in apoptosis of leukemic cells Metabolized by CYP3A4 BlackBox Warning:​ QT Prolongation​ Torsades de Pointes​ Cardiac Arrest​ Contraindications:​ Severe hypokalemia​ Severe hypomagnesemia​ Long QT syndrome DDIs: -CYP3A4 inhibitors and grapefruit​ -QT prolonging drug n/a
Entrectinib Tyrosine Kinase Inhibitor Tropomysin receptor Kinase inhibitor TRK, ROS1, ALK Inhibitor of TRKA, TRKB, TRKC, ROS1, and ALK kinases Metabolized by CYP3A4 prolongation of QT interval n/a
Larotrectinib Tyrosine Kinase Inhibitor Tropomysin receptor Kinase inhibitor TRK Inhibitor of TRKA, TRKB, and TRKC kinases Metabolized by CYP3A4 neurotoxicity and hepatotoxicity interactions with CYP3A4 inhibitors ​ n/a
Repotrectinib Tyrosine Kinase Inhibitor Tropomysin receptor Kinase inhibitor TRK, ROS1 Second generation inhibitor of TRKA, TRKB, and TRKC kinases and ROS1 Metabolized by CYP3A4 neurotoxicity, hepatotoxicity, pneumonia 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
Pralsetinib Tyrosine Kinase Inhibitor Rearranged during transfection RET inhibits wild-type and mutated RET metabolized by CYP3A severe interstitial lung disease/pneumonitis and hypertension n/a
Selpercatinib Tyrosine Kinase Inhibitor Rearranged during transfection RET, VEGFR, FGFR Inhibits wild-type and mutated RET isoforms, plus VEGFRs and FGFRs Metabolized by CYP3A4 hepatotoxicity that requires close monitoring every 2 weeks; QTc prolongation; impaired wound healing; and tumor lysis syndrome​ n/a
Amivantamab-vmjw Tyrosine Kinase Inhibitor Mesenchymal Epithelial Transition inhibitor MET, EGFR -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 n/a -Infusion reactions, interstitial lung disease, pneumonitis, blood clots, including deep vein thrombosis, pulmonary embolism, serious skin reactions, eye or vision problems​ -Fetal harm EGRF: when drug binds, it will call in NK cell to attach. NK cell will kill CA by antibody dep. cell cytotoxicity C-MET: calls macrophage over to interact with Fc region of antibody and it will eat away the CA cell, which exposes it to more antibodies
Capmatinib Tyrosine Kinase Inhibitor Mesenchymal Epithelial Transition inhibitor MET selective MET kinase inhibitor metabolized by CYP3A4 peripheral edema for the treatment of metastatic NSCLC with a mutation that leads to MET exon 14 skipping (may be FYI idk)
Tepotinib Tyrosine Kinase Inhibitor Mesenchymal Epithelial Transition inhibitor MET MET kinase inhibitor metabolized by CYP3A4 peripheral edema for the treatment of metastatic NSCLC with a mutation that leads to MET exon 14 skipping (may be FYI idk)
Acalabrutinib Tyrosine Kinase Inhibitor Bruton's Tyrosine Kinase inhibitor BTK -2nd gen BTK inhib: -Are more selective for BTK ​ -developed to improve toxicity– less CV effects​ -Developed to deal with resistance of the first gen BTK inhib-> now IRREVERSIBLE BTK inhibitors​ -Prevent signaling from the B cell antigen receptor n/a Adverse effects Common: myelosuppression (anemia, neutropenia, thrombocytopenia) Serious: hemorrhaging Drug interactions:​ -PPIs, antacids​ -3A4 inhibitors Acalabrutinib may have a better adverse effect profile than Zanubrutinib
Zanubrutinib Tyrosine Kinase Inhibitor Bruton's Tyrosine Kinase inhibitor BTK -2nd gen BTK inhib: -Are more selective for BTK ​ -developed to improve toxicity– less CV effects​ -Developed to deal with resistance of the first gen BTK inhib-> now IRREVERSIBLE BTK inhibitors​ -Prevent signaling from the B cell antigen receptor n/a Adverse effects Common: myelosuppression (anemia, neutropenia, thrombocytopenia) Serious: hemorrhaging Drug interactions:​ -PPIs, antacids​ -3A4 inhibitors Acalabrutinib may have a better adverse effect profile than Zanubrutinib
Asciminib Signal Transduction Antagonists BCR-ABL antagonist BCR-ABL an allosteric BCR-ABL inhibitor that binds the myristoyl pocket of ABL, locking the kinase in an inactive conformation. Unlike traditional TKIs, it does not bind the ATP site, allowing activity against many resistant CML mutations. n/a n/a -targets wildtype and mutated BCR-ABL, including the T315I variant Has US FDA Breakthrough Therapy designation (BTD)
Bosutinib Signal Transduction Antagonists BCR-ABL antagonist BCR-ABL Bcr-Abl and Src-family kinase inhibitor​ -will inhibit most imatinib-resistant BCR-ABL genetic variants except the T315I mutant n/a n/a n/a
Dasatinib Signal Transduction Antagonists BCR-ABL antagonist BCR-ABL -greater efficacy than imatinib against wild- type BCR-ABL and will inhibit some imatinib- resistant BCR-ABL genetic variants​ -Also inhibits sarcoma (Src) kinases that also seem to cause some cancers n/a n/a n/a
Imatinib Signal Transduction Antagonists BCR-ABL antagonist BCR-ABL, PDGFR, KIT -Inhibits ABL and its activated variant BCR-ABL​ -Targets BCR-ABL’s ATP binding site when activation loop is closed; stabilizes BCR-ABL in inactive conformation -Also inhibits PDGFR and KIT Metabolized primarily via CYP3A4​ Neutropenia and thrombocytopenia Secondary resistance occurs​
Nilotinib Signal Transduction Antagonists BCR-ABL antagonist BCR-ABL -has the highest affinity for wild type BCR-ABL and will inhibit some imatinib-resistant BCR-ABL genetic variants n/a n/a n/a
Ponatinib Signal Transduction Antagonists BCR-ABL antagonist BCR-ABL -Inhibits T315I mutant of BCR-ABL, which is associated with resistance in the other ABL inhibitors n/a n/a n/a
Dabrafenib Signal Transduction Antagonists B-RAF inhibitor BRAF -Inhibit BRAF variants n/a QT prolongation, severe dermatologic reactions and photosensitivity -Combination therapy with a BRAF and MEK inhibitor has been associated with improved outcomes -Monitor for new cutaneous malignancies and non- cutaneous squamous cell carcinoma​ -Resistance can develop as a result of reactivation of the MAPK pathway
Encorafenib Signal Transduction Antagonists B-RAF inhibitor BRAF -Inhibit BRAF variants and several other kinases in other signaling pathways Metabolized by CYP3A4 QT prolongation, severe dermatologic reactions and photosensitivity, fetal risk -Combination therapy with a BRAF and MEK inhibitor has been associated with improved outcomes -Resistance is being observed
Binimetinib Signal Transduction Antagonists Mitogen-activated extracellular signal regulated protein kinase kinases MEK, BRAF -Inhibits MEK1 and 2 as well as BRAF V600E n/a Rare but serious ADRs: Rhabdomyolysis, retinal vein occlusion, interstitial lung disease -Given with a BRAF inhibitor Secondary resistance due to​ –Activation of alternative signaling pathways​ –mutations in the allosteric binding pocket and activation loop of MEK1 can inhibit the binding of the inhibitor ​ –occurs within 6 to 7 months
Trametinib Signal Transduction Antagonists Mitogen-activated extracellular signal regulated protein kinase kinases MEK, BRAF Inhibits MEK1 and 2 as well as BRAF V600E n/a -Serious ADRs : skin toxicity, cardiomyopathy, interstitial lung disease, and ocular toxic effects, fetal harm -Given with a BRAF inhibitor Secondary resistance due to​ –Activation of alternative signaling pathways​ –mutations in the allosteric binding pocket and activation loop of MEK1 can inhibit the binding of the inhibitor ​ –occurs within 6 to 7 months
Abemaciclib Cyclin dependent kinase (CDK) Inhibitors n/a CDK selectively inhibits cyclin-dependent kinase 4 (CDK4) and 6 (CDK6); arresting cells in G1 Cyp3A4 Neutropenia, pulmonary embolism, avoid pregnancy Counseling:​ -Take with food to increase absorption​ -Abemaciclib may prove to be most efficacious; otherwise these meds are comparable
Palbociclib Cyclin dependent kinase (CDK) Inhibitors n/a CDK selectively inhibits cyclin-dependent kinase 4 (CDK4) and 6 (CDK6); arresting cells in G1 Cyp3A4 Neutropenia, pulmonary embolism, avoid pregnancy Counseling:​ -Take with food to increase absorption
Ribociclib Cyclin dependent kinase (CDK) Inhibitors n/a CDK selectively inhibits cyclin-dependent kinase 4 (CDK4) and 6 (CDK6); arresting cells in G1 Cyp3A4 Neutropenia, pulmonary embolism, avoid pregnancy -avoid other GT interval elongating drugs Counseling:​ -Take with food to increase absorption
Bevacizumab Angiogenesis inhibitors n/a VEGF-A Induction of tumor hypoxia and starvation n/a Risk of bleeding, proteinuria, hypertension​ May increase delivery of other chemotherapeutics, potentiating their effects
Thalidomide (historical) Angiogenesis inhibitors n/a bFGF, Others -Inhibits bFGF-induced angiogenesis; this was the first MOA discovered​ -More recently discovered mechanisms: Inhibits NK cell production & functionality, adhesion, angiogenesis, and antiapoptosis cell growth n/a teratogenicity, thrombosis -Lenalidomide is a second generation analog of thalidomide used for thalidomide refractory multiple myeloma.
Lenalidomide Angiogenesis inhibitors n/a bFGF, Others -Enhanced inhibition of TNF-alpha and co- stimulation of T cells​ -Direct antitumor activity by inducing apoptosis n/a –Thrombosis, neuropathy, constipation, and somnolence less than with thalidomide​ –Primarily causes myelosuppression and thrombocytopenia -Effective in thalidomide refractory multiple myeloma
Atezolizumab Immune checkpoint inhibitor n/a PD-L1 humanized monoclonal targeting PD-L1 n/a -Patients with urothelial carcinoma: risk of urinary tract infection​ -Possible immune-related adverse effects: hepatitis, colitis -myasthenia gravis, Guillain- Barré syndrome -Potential embryofetal toxicity maybe FYI (idk): Treats various advanced or metastatic cancers; these cancers usually need to have high PD-L1 expression; expression >50% = works well
Cemiplimab-rwlc Immune checkpoint inhibitor n/a PD-1 -Fully human monoclonal antibody targeting PD-1​ -blocks PD-1 interaction with PD-L1 and PD-L2 (which is a second ligand for PD-1) n/a -monitor for immune related adverse events (irAEs) including pneumonitis, colitis, dermatologic conditions, hepatitis, nephritis, and endocrine dysfunction. n/a
Durvalumab Immune checkpoint inhibitor n/a PD-L1 Fully human monoclonal antibody targeting PD-L1 n/a urinary tract infection, upper respiratory tract infections n/a
Nivolumab Immune checkpoint inhibitor n/a PD-1 Fully human monoclonal antibody targeting PD-1 n/a upper respiratory tract infection n/a
Pembrolizumab Immune checkpoint inhibitor n/a PD-1 Humanized monoclonal antibody targeting PD-1 n/a Fatigue, pruritus, rash, decreased appetite, and dyspnea -Seems to have long-term response Indications: not sure if testable.. But she did point it out​ -Metastatic NSCLC with >50% PD-L1 expression after progression on platinum-based therapy​ -Head and neck squamous cancer after platinum chemo
Blinatumomab Cell surface antigen monoclonal antibody n/a CD19/CD3 -An anti-CD19/CD3 MoAb targets at the same time​ -Binds to CD19 on malignant B-cells and CD3 on T- cells, physically linking the T cells and tumor cells. The two cell membranes touch, triggering a signaling cascade in the T-cell for target cell lysis n/a Monitor patients for cytokine release syndrome, neurological toxicities, and infections (need to pretreat) Category: BiTE therapy​ Bispecific T-cell Engager​ -Links CA with cell and it will fold​ Which brings them together​ -T-cell can kill CA cell by target ​Cell lysis
Obinutuzumab Cell surface antigen monoclonal antibody n/a CD20 -humanized anti-CD20, but binds CD20 in a different orientation compared to Rituximab​ -Fc portion has been glycoengineered to reduce fucosylation resulting in improved receptor affinity and enhanced ADCC potency​ -Kills the B-cell by causing PCD & ADCC n/a -infusion reactions, myelosuppression -HBV reactivation and Progressive Multifocal Leukoencephalopathy (PML) have also been reported n/a
Rituximab Cell surface antigen monoclonal antibody n/a CD20 -chimeric IgG1 MoAb against the CD20 antigen found on normal mature B-cells and cancerous B-cells​ -The Fab domain binds to the CD 20 antigen; the Fc domain recruits the immune system to kill the cells by ADCC and complement-dependent cytotoxicity​ n/a -Immunosuppression due to targeting of normal mature B cells​ -Hypersensitivity related to chimeric nature of Ab n/a
Venetoclax BCL2 Inhbitor n/a BCL2 A selective inhibitor of BCL-2, allowing apoptosis n/a myelosuppression & upper respiratory tract infection​ -Weekly dose escalation over the first 5 weeks is required to reduce risk of tumor lysis syndrome (TLS) -Oral; take with food
Asparaginase Asparaginase n/a asparagine -Leukemic cells cannot synthesize L-asparagine for protein synthesis; they must acquire it from plasma​ -Asparaginase hydrolyzes circulating asparagine, depriving malignant cells of the asparagine needed for protein synthesis n/a -Hypersensitivity in 5-20% of patients -Coma (rare) may be due to ammonia toxicity from asparagine hydrolysis​ -Pancreatitis -Need to give this med in the proper order -Patient can develop antibodies that may inactivate the enzyme
Asparaginase erwinia chrysanthemi (recombinant)-rywn Asparaginase n/a asparagine -Leukemic cells cannot synthesize L-asparagine for protein synthesis; they must acquire it from plasma​ -Asparaginase hydrolyzes circulating asparagine, depriving malignant cells of the asparagine needed for protein synthesis n/a -Hypersensitivity -Coma (rare) may be due to ammonia toxicity from asparagine hydrolysis​ -Pancreatitis for patients hypersensitive to the E. coli prep -Patient can develop antibodies that may inactivate the enzyme
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