My Patient is on a –mab or –nib. What Should I know? Oncology Therapy for the Generalist Joseph Bubalo PharmD, BCOP, BCPS Assistant Professor of Medicine OHSUOncology Clinical Pharmacy Specialist OHSU Hospital and Clinics Disclosure OHSU• I have nothing to disclose vladimirkorsakov.blogspot.com Objectives • Discuss commonly prescribed oral chemotherapy agents, their respective drug classes, and issues associated with care • Discuss common antineoplastic monoclonal antibodies, their respective drug classes, and issues associated with care • Describe the intersection of these medication groups with OHSUgeneral care and management of associated events and expected side effects Patient Cases – Oral Chemotherapy • Wife and husband • Her (Breast cancer) and (Him) adult Ph + ALL – Breast Cancer = Capecitabine + lapatinib chemotherapy – Ph+ ALL = Allogeneic HSCT + dasatinib maintenance • Both are having side effects from their oral chemotherapy – Wife has been having nausea and severe diarrhea for 2 days. She has OHSUbeen taking loperamide 2 mg PO Q4H. – Husband is having mild edema managed by diuretics. However, he has developed neutropenia and thrombocytopenia. What About the Nibs? Wife: Lapatinib Husband: Dasatinib • Inhibitor: HER2 receptor tyrosine • Inhibitor: BCR-ABL tyrosine kinase kinase • Dose: 100 mg PO Daily • Dose: 1250 mg PO daily • Food: with or without food • Food: without food • Adverse effects: fatigue, rash, edema, • Adverse effects: fatigue, hand-foot N/V, diarrhea, increased LFT’s, syndrome, diarrhea, mucositis, cytopenias cytopenias • Drug Interactions: 3A4 OHSU• Drug Interactions: 3A4 inhibitors/inducers; avoid PPI’s inhibitors/inducers Targeted Therapy • Molecularly Targeted Drugs – Interfere with cell growth (signal transduction inhibitors) – Modify function of proteins that regulate gene expression – Interfere with tumor blood vessel development (angiogenesis) – Induce cancer cell apoptosis – Stimulate the immune system to destroy cancer cells – Deliver toxic drugs to cancer cells • OHSUMonoclonal antibodies targets outside the cell or on the cell surface • Conjugated small molecule drugs diffuse into cells and act on targets within cell OHSU OHSU Tyrosine Kinase Inhibitors (Nibs) OHSU OHSU Ther Clin Risk Manag. 2017 Feb 21;13:223-236. Tyrosine Kinase Inhibitors (TKIs) • Bind on cell surface or intracellularly and affect a variety of targets Bcr-Abl tyrosine kinase Mammalian target of (Philadelphia chromosome rapamycin Mixed kinase inhibitors translocation) (mTOR) * EGFH/HER2 Epidermal growth factor Human epidermal growth * EGFR/VEGFR receptor factor receptor (EGFR) (HER2) Vascular endothelial growth Platelet-derived growth factor receptor factor receptor (VEGFR) (PDGFR) Multi-kinase inhibitors OHSUIncluding VEGFR, PDGFR, cKIT, Raf kinase and more Cytokine receptor Janus associated kinases (cKIT) (JAK) General TKI Class Side Effects Myelosuppression Dermatologic issues Panniculitis Acneiform dermatitis Hand foot reaction Diarrhea Cardiotoxicity Cardiomyopathy, CHF Hepatoxicity QTcOHSU Prolongation Edema Pleural effusions, periorbital Current Drug Metabolism. 2009; 10:470-481. As seen in Chronic Myelogenous Leukemia BCR-ABL Inhibitors Drug Food Acid reducers Major Substrate Major Major Inhibitor Inducer Bosutinib With food Use caution CYP3A4 N/A N/A Dasatinib +/- Use caution CYP3A4* N/A N/A Imatinib With food Ok CYP3A4* N/A N/A Nilotinib Empty Stomach Use caution CYP3A4* N/A N/A Ponatinib +/- Ok CYP3A4 (minor)* N/A N/A *RequireOHSU dose adjustment with certain inhibitors/inducers Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. BCR-ABL Inhibitors Side Effects Drug Side Effect Management Imatinib Fluid retention Diuretics Muscle cramps Tonic water, calcium Dasatinib Fluid retention Diuretics Nilotinib QT prolongation EKG monitoring ↑ Lipase or Amylase Hold until recovery OHSUHepatotoxicity LFT monitoring, Hold until recovery Curr Treat Options Oncol. 2013 Jun;14(2):127-43. BCR-ABL Inhibitors Side Effects Drug Side Effect Management Bosutinib Hepatotoxicity LFT monitoring, Hold until recovery Diarrhea Loperamide, hold therapy Ponatinib Hepatotoxicity LFT monitoring, Hold until recovery Ischemic reactions, vascular occlusion, Permanently hold therapy heart failure ↑ Lipase or Amylase Hold until recovery OHSUCommon to all: Myelosuppression, rash Curr Treat Options Oncol. 2013 Jun;14(2):127-43. Bcr-Abl tyrosine kinase Drug Interactions All TKIs have HIGH potential for drug interactions requiring DOSE ADJUSTMENTS Imatinib and nilotinib Affected by azole inhibition of 3A4 Fluconazole < Voriconazole < Posaconazole Dasatinib solubility pH dependent AVOID acid suppressanting medications OHSU If absolutely necessary – H2 blockers may be given 2 hrs. AFTER dasatinib Food-drug interactions Each TKI is different Nilotinib taken with high fat foods exceeds 80% absorption (empty stomach) Current Drug Metabolism. 2009; 10:470-481. As seen in Non-small cell EGFR Inhibitors Lung Cancer Drug Food Acid reducers Major Substrate Major Major Inducer Inhibitor Gefitinib +/- Use caution CYP2D6 N/A N/A CYP3A4* Erlotinib Empty Use caution CYP3A4* N/A N/A stomach CYP1A2 (minor)* Afatinib Empty Ok N/A N/A N/A stomach OsimertinibOHSU+/- Ok CYP3A4* N/A N/A *Require dose adjustment with certain inhibitors/inducers Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. EGFR Inhibitors Side Effects • EPIDERMAL GFR: Dermatologic side effects Fingertip fissure OHSUAcneiform rash Mucositis Paronychia Asia Pac J Clin Oncol. 2017 May 2. Support Care Cancer. 2011 Aug; 19(8): 1079–1095. EGFR Inhibitors Side Effects – Acneiform Rash • Hydrocortisone 1% cream with moisturizer and sunscreen twice daily Prevention • Minocycline 100 mg PO daily OR Doxycycline 100 mg PO BID • Alclometasone 0.05% cream • Fluocinonide 0.05% cream BID • Clindamycin 1% cream Treatment OHSU• Doxycycline 100 mg BID • Minocycline 100 mg daily • Isotretinoin 20-30 mg daily Support Care Cancer. 2011 Aug; 19(8): 1079–1095. EGFR Inhibitors Side Effects Mucositis Paronychia Xerosis/Fissures • Oral Care • Diluted bleach soaks • Moisturizing creams/soaps • Pain management • Steroids • Avoid extreme • Nutritional support • Calcineurin Inhibitors temperatures and direct • Magic mouthwash • Antimicrobials sunlight • Silver nitrate • Emollients (fragrance free): urea, petroleum-based, • Nail avulsion ammonium, salicylic acid, zinc oxide, etc. • Severe: Medium to high OHSUpotency steroids Support Care Cancer. 2011 Aug; 19(8): 1079–1095. EGFR Inhibitors Side Effects • Other side effects – Diarrhea • Increase fluid intake • Loperamide 4 mg initially then 2 mg after each loose stool until free of diarrhea for 12 hours – Interstitial Lung Disease OHSU• PERMANENTLY DISCONTINUE Asia Pac J Clin Oncol. 2017 May 2. Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. As seen in Renal Cell Carcinoma, other solid tumors VEGF Inhibitors Drug Food Acid reducers Major Substrate Major Major Inhibitor Inducer Axitinib +/- Ok CYP3A4* N/A N/A Cabozantinib Empty Stomach Ok CYP3A4* N/A N/A Lenvatinib +/- Ok N/A N/A N/A Pazopanib Empty Stomach Use caution CYP3A4* N/A N/A Regorafenib After low-fat meal Ok CYP3A4 N/A N/A (<600 calories and <30% fat) Sorafenib Empty Stomach Ok N/A N/A N/A SunitinibOHSU+/- Ok CYP3A4* N/A N/A Vandetanib +/- Ok CYP3A4 N/A N/A *Require dose adjustment with certain inhibitors/inducers Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. VEGF Inhibitors Side Effects • VASCULAR EGF – Vascular side effects OHSUHypertension Impaired wound healing Clotting Bleeding Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; March 11, 2021. Hypertension (HTN) with Oral Anticancer Treatments Agent Indication Total Severe (%) Incidence (%) • Seen Primarily with VEG-F inhibitors, worse in renal cancer Axitinib Renal cell 40 16 • Can be seen in those without prior HTN Cabozantanib Thyroid 33 8 and worsen those with pre-existing HTN Lenvatinib Thyroid, renal, 45-73 24-44 • Most common in first month of therapy hepatic, • Can occur in first week endometrial • Dose dependent Pazopanib Renal cell, sarcoma 40-42 4-7 • Mechanism • Inhibition of vasodilation via nitric oxide Ponatinib CML 53-71 26-39 synthesis Regorafenib Colorectal, GIST 30-59 8-28 • Rarefaction of resistance blood vessels • Monitoring • First cycle – weekly visits or preferably Sorafenib Renal cell, hepatic 9-17 4-5 OHSUhome monitoring daily (preferred) to 3 times/week minimum Sunitinib Renal cell, GIST 15-24 4-13 • Subsequent cycles Q 2weeks 2nd and 3rd, then monthly Vandetanib Thyroid 33 9 VEGF Inhibitors Side Effects • Other warnings – GI perforation – Proteinuria • Management – Hold VEGF inhibitor around major surgery • Time held depends on the agent – Hold on hospital admission if potential significant procedure – Treatment of hypertension – ACEI, ARB, dihydropyridine Calcium channel blockers OHSU– No routine DVT prophylaxis Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. As seen in Non-small Cell Lung Cancer ALK Inhibitors Drug Food Acid reducers Major Substrate Major Major Inhibitor Inducer Alectinib With food Ok N/A N/A N/A Brigatinib +/- Ok CYP3A4* N/A N/A Ceritinib Empty Stomach Use caution CYP3A4* CYP3A4 N/A Crizotinib Empty Stomach Ok CYP3A4 N/A N/A *RequireOHSU dose adjustment with certain inhibitors/inducers Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. ALK Inhibitors Side Effects Common Unique • Vision changes • Hyperglycemia • Hepatotoxicity • Brigatinib • Bradycardia • Ceritinib • Interstitial Lung Disease