sign in sign up
<<
Home , Atezolizumab, Axitinib, Blinatumomab, Bosutinib, Brentuximab vedotin, Ceritinib

My Patient is on a –mab or –nib. What Should I know? 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 agents, their respective drug classes, and issues associated with care • Discuss common antineoplastic monoclonal , their respective drug classes, and issues associated with care • Describe the intersection of these groups with OHSUgeneral care and management of associated events and expected side effects Patient Cases – Oral Chemotherapy

• Wife and husband • Her () and (Him) adult Ph + ALL – Breast Cancer = + chemotherapy – Ph+ ALL = Allogeneic HSCT + maintenance • Both are having side effects from their oral chemotherapy – Wife has been having and severe for 2 days. She has OHSUbeen taking loperamide 2 mg PO Q4H. – Husband is having mild edema managed by diuretics. However, he has developed and . What About the Nibs?

Wife: Lapatinib Husband: Dasatinib • Inhibitor: HER2 tyrosine • Inhibitor: BCR-ABL kinase • Dose: 100 mg PO Daily • Dose: 1250 mg PO daily • Food: with or without food • Food: without food • Adverse effects: , 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

• Molecularly Targeted Drugs – Interfere with cell growth ( inhibitors) – Modify function of that regulate gene expression – Interfere with tumor blood vessel development () – Induce cancer cell – Stimulate the 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 ( rapamycin Mixed kinase inhibitors translocation) (mTOR) * EGFH/HER2 Epidermal Human epidermal growth * EGFR/VEGFR receptor factor receptor (EGFR) (HER2)

Vascular endothelial growth -derived 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 . 2009; 10:470-481. As seen in Chronic Myelogenous BCR-ABL Inhibitors

Drug Food Acid reducers Major Substrate Major Major Inhibitor Inducer With food Use caution CYP3A4 N/A N/A Dasatinib +/- Use caution CYP3A4* N/A N/A With food Ok CYP3A4* N/A N/A Empty Stomach Use caution CYP3A4* N/A N/A +/- 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 ↑ or 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 ↑ 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 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

Drug Food Acid reducers Major Substrate Major Major Inducer Inhibitor +/- Use caution CYP2D6 N/A N/A CYP3A4* Empty Use caution CYP3A4* N/A N/A stomach CYP1A2 (minor)* 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 • 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 • 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 OHSU• PERMANENTLY DISCONTINUE

Asia Pac J Clin Oncol. 2017 May 2. Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. As seen in , other solid tumors VEGF Inhibitors

Drug Food Acid reducers Major Substrate Major Major Inhibitor Inducer +/- Ok CYP3A4* N/A N/A Empty Stomach Ok CYP3A4* N/A N/A +/- Ok N/A N/A N/A Empty Stomach Use caution CYP3A4* N/A N/A 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 +/- 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 Renal cell, hepatic 9-17 4-5 OHSUhome monitoring daily (preferred) to 3 times/week minimum 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 With food Ok N/A N/A N/A +/- Ok CYP3A4* N/A N/A Empty Stomach Use caution CYP3A4* CYP3A4 N/A 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 • • Hepatotoxicity • Brigatinib • Bradycardia • Ceritinib • Interstitial Lung Disease • Increased CPK • Alectinib • QT prolongation OHSU• Crizotinib and Ceritinib

Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. ALK Inhibitors Side Effects • Vision changes – Brief trails or flashes of light in the periphery, typically when moving from a dark room to a light room – Management: No clinical intervention typically needed • Hyperglycemia – Related to IGF-1R inhibition – Possible management strategies: OHSU• • Thiazolidinediones • Sodium- linked transporter 2 • Likely ineffective: and insulin secretagogues Curr Oncol. 2014 Feb;21(1):19-26. Oncologist. 2016 Jul 29. pii: theoncologist.2015-0519. As seen in , Non- small Cell Lung Cancer BRAF/MEK Inhibitors

Drug Food Acid reducers Major Substrate Major Major Inhibitor Inducer MEK Inhibitors Empty Ok N/A N/A N/A Stomach +/- Ok CYP3A4* N/A N/A BRAF Inhibitors Empty Use caution CYP2C8, CYP3A4 N/A N/A OHSUStomach +/- Ok CYP3A4* N/A N/A *Require dose adjustment with certain inhibitors/inducers

Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. BRAF/MEK Inhibitors Side Effects

BRAF MEK - Rash (+SCC) - Rash (-SCC) - - Diarrhea - Arthralgia - Edema - Pyrexia (D>V)* - Dermatitis - Photosensitivity (V>D) - Decrease LVEF

SCC: Combination OHSUsquamous Fewer skin toxicities cell carcinoma *D = dabrafenib; V = vemurafenib

Ther Adv Med Oncol. 2015 Mar;7(2):122-36. BRAF/MEK Inhibitors Side Effects

• Grade 2: Antihistamines, emollients • Grade 3: Hold med, initiate topical and/or oral steroids Rash • Grade 4: Permanently discontinue

• Refer to dermatology urgently SCC

• Sunscreen SPF >30 OHSUPhoto- sensitivity

Ther Adv Med Oncol. 2015 Mar;7(2):122-36. BRAF/MEK Inhibitors Side Effects

• Rule out neutropenic • If , be mindful of DDIs with antibiotics Pyrexia • If not infection, APAP or low dose

• Negative cardiac history: ECHO not necessary Cardio- • Edema: Cardiac work-up with ECHO and EKG myopathy

OHSU• Loperamide Diarrhea • “BRAT” diet

Ther Adv Med Oncol. 2015 Mar;7(2):122-36. As seen in Breast Cancer CDK Inhibitors

Drug Food Acid reducers Major Major Major Inducer Substrate Inhibitor +/- Ok CYP3A4* N/A N/A With Food Ok CYP3A4* N/A N/A +/- Ok CYP3A4* N/A N/A *RequireOHSU dose adjustment with certain inhibitors/inducers

Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. CDK Inhibitors

• Side Effects – Myelosuppression! CBC Monitoring Key • Palbociclib~Ribociclib>Abemaciclib – Diarrhea: Abemaciclib > Palbociclib, Ribociclib – Hepatotoxicity: Warning – Ribociclib, Abemaciclib – Others: fatigue, headache, alopecia, N/V, etc. – Typically given in combination with hormonal therapy – Palbociclib + OR OHSU– Ribociclib + letrozole – Abemaciclib + fulvestrant

Nat Rev Clin Oncol. 2016 Jul;13(7):417-30. As seen in Many tumor types Multikinase Inhibitors

• Examples – Regorafenib – Sorafenib – Sunitinib – Etc. OHSU• Side Effects: – Dependent on the target (VEGFR, EGFR, etc.) – Typically harder to tolerate

Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. Oral Tyrosine Kinase Inhibitors

• Multikinase targets (EGFR, VEGFR 1,2,3, PDGFR, FGFR, AXL, FLT-3, KIT, MET, TIE-2, TRKB, CSF-1R, RET, BRK, CRAF, BRAF) – Cabozantinib – medullary – Vandetanib – – Sunitinib – GIST, renal cell, – Sorafenib – renal cell, – Pazopanib – renal cell, soft tissue sarcoma OHSU– Regorafinib – , GIST As seen in Other Therapy Immunomodulators

Drug Food Acid Major Major Major reducers Substrate Inhibitor Inducer +/- Ok N/A N/A N/A +/- Ok N/A N/A N/A At least 1 hour after Ok N/A N/A N/A OHSUevening meal

Lexicomp Online® , Hudson, Ohio: Lexi-Comp, Inc.; October 1, 2017. Other Therapy Immunomodulators – Side Effects • (Pomalidomide least) • Venous thromboembolism – Prophylaxis • ASA 81-325 mg PO daily OR • Enoxaparin 40 mg SQ daily OR • PO, goal INR 2-3 •OHSUMyelosuppression (Pomalidomide worst) • Secondary Malignancy (Lenalidomide worst) • Teratogenicity: REMS Program!

Expert Opin Investig Drugs. 2013 Feb;22(2):207-15. TKI: Drug/Food Interactions

• Absorption can be – Increased Decreased Prolonged Unchanged OHSU• WITHOUT food recommendation: 1 hour before/2 hours after Key Points • Narrow therapeutic index drugs which are not individualized to patient size – Drug Interactions are serious – Absorption and effect of food is serious • Initial patient counseling is extremely important given potential for less frequent follow up – Adverse event reporting is patient initiated • Counseling focus: administration, side effects, drug OHSUinteractions, safe handling and disposal • Counseling on multiple oral agents – Capecitabine 3-4 tablets PO BID with food 2 wks on/1 wk off – Lapatinib 5 tablets PO daily without food continuously Key Points • Adherence and dosing schedules are a big concern – Cycling on and off therapy – Feeling worse on therapy • Medication procurement is difficult – Specialty pharmacy/mail order requirement • Dispensing challenges with REMS programs • Underinsured patient population – Insured patients who lack financial ability to cover out-of pocket expenses – Medicare, Medicaid, commercial insurance with high deductibles/copays, formulary OHSUrestrictions, and specialty tiers Patient Cases – Oral Chemotherapy • Husband is having mild edema managed by diuretics. However, he has developed neutropenia and thrombocytopenia.

• Complete biopsy to determine whether or not the cytopenias are from disease • Hold therapy until ANC > 1000 and > 20K → resume at original dose OHSU→ If recurrence of cytopenia (ANC < 500, Plt < 10K) →Hold therapy again → Resume at reduced dose Patient Cases – Oral Chemotherapy • Wife has been having nausea and severe diarrhea for 2 days. She has been taking loperamide 2 mg PO Q4H.

• Admit to hospital for IV fluids vs clinic hydration? • Schedule loperamide 4 mg after first episode of diarrhea and then 2 mg PO Q2H for at least 12 hours after diarrhea has stopped. OHSU→Switch to diphenoxylate/atropine 5 mg PO Q6H → Add octreotide 100-200 mcg SQ or IV Q8H → Consider switching to alternate agent Summary

• There are many different types of oral chemotherapy including TKIs, hormonal agents and other • A variety of side effects can be seen with oral chemotherapy including hand foot syndrome, diarrhea, rash, etc. • Upon admission to acute care consider holding agents depending on patient problem list OHSU• Pharmacy consult for polypharmacy issues Monoclonal Antibodies • • • • • • Ibritumomab • • • • • • RituximabOHSU • and Iodine I 131 Tositumomab • Origins of monoclonal antibodies Murine Chimeric Human Humanized (- omab) (- ximab) (- umab) (- zumab) -90 ibritumomab Ofatumumab Alemtuzumab tiuxetan Iodine-131 Cetuximab Panitumumab Trastuzumab tositumomab Brentuximab- Ipilimumab Bevacizumab vedotin Gemtuzumab- ozogamicin OHSUPertuzumab Mechanisms of Action

Anti CD20 EGFR HER2 Anti CD52

Rituximab Cetuximab Trastuzumab Alemtuzumab

Ofatumumab Panitumumab Pertuzumab Yttrium 90 Iodine-131 tositumomab

OHSUAnti CD30 Anti CD33 VEGF/R CTLA-4 PD-1 Brentuximab- Gemtuzumab- Bevacizumab Ipilimumab vendotin ozogamicin MAB Effects Class Directed Cytotoxicity by chaperoning Modulate an Immune Targeted cytotoxic molecules mechanism Therapy (immunoconjugates)

Mecha Block or Conjugated to various cytotoxic Exert cytotoxic effects by nism stimulate a molecules including -dependent cell of particular cell radioisotopes, cellular toxins, or mediated cytotoxicity action membrane biologic agents (ADCC) or complement molecule or dependent cytotoxicity ligand and inhibit (CDC) tumor growth or activate effector OHSUcells Examp Trastuzumab, Brentuximab vedotin, ado- Rituximab, , les bevacizumab, , obinutuzumab cetuximab gemtuzumab ozogamicin Efficacy of Unlabeled antibody Enhanced Through the Crossfire Effect of radiolabeled monoclonal antibodies OHSU

Unlabeled “cold” Antibody Radiolabeled Antibody Courtesy of Andrew Zelenetz, MD. Antibody Drug Conjugates

• Gemtuzumab-ozogamicin – For relapse/refractory AML & Salvage APL • Anti CD33 + Ozogamicin – alkylating agent binds and breaks DNA • Common ADE: myelosuppression, hepatotoxic, mucositis

• Brentuximab-vendotin – Anti-CD30 + microtubule disrupting agent (MMAE) OHSU– Metabolized by CYP 3A4 enzyme – Common ADE: peripheral neuropathy Anti-PD1/L1 or CTLA4 Agents

Atezolizumab (PDL-1) (PDL-1) -rwlc (PD-1) (PDL-1) Nivolumab (PD-1) OHSUPembrolizumab (PD-1) Ipilimiumab (CTLA-4) Anti PD1/CTLA4 Mabs

• Most common AE: fatigue, , nausea, pruritis, rash, decreased appetite, constipation, arthralgia, and diarrhea (> 20%) • Others: Immune mediated side effects: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and many others • Corticosteroids and other immune suppressants OHSUcontraindicated are contraindicated – Unless needed for AE management Patient Management

• Immune mediated effects show up in many subtle forms • Skin, GI, pulmonary most common • Any organ, endocrine or exocrine system can be involved • Primarily a process of ruling out immune mediated event vs expression/worsening of a comorbidity OHSU• Condition can change from benign to urgent rapidly Anti-CD20 Agents Rituximab Ofatumumab Obinutuzumab OHSUYttrium 90 ibritumomab tiuxetan Iodine-131 tositumomab Infusion Reactions

• Managed via: – Pre-medications, hold antihypertensives – Split dosing – Rescue meds/fluids – Variable infusion rates • “Interrupt/Hold/Restart at ½ dose” – Rapid infusion ONLY after tolerating standard x 1-2 cycles OHSU– Never IV push – SQ formulations now available (Rituximab) Adverse Effects

• Infusion reactions, , cough, dyspnea, fatigue, pyrexia, diarrhea, rash, thrombocytopenia, neutropenia, , tumor lysis, musculoskeletal symptoms • Hep B activation, PML, not for use if active OHSU• Do not vaccinate until 6 months after the last dose • Do not give live virus vaccines Human Receptor 2 (HER2)

Trastuzumab Ado-trastuzumab emtansine Fam-Trastuzumab deruxetecan-nxki OHSUPertuzumab Oncologic Targets • FDA approved for metastatic HER2+ breast cancer • May see use for HER-2 positive gastric or other HER-2 positive cancers

• Pertuzumab binds different than OHSUtrastuzumab – Can be used in combined therapy Class Adverse Events

– Infusion-related: • , chills, rigors, asthenia, pain, headache, N/V, hypotension, dizziness • Mainly trastuzumab (Up to 40% with 1st infusion) – Ventricular dysfunction and CHF possible • Incidence/severity HIGHER when in combination with and • Monthly monitoring initially then quarterly OHSU– Myelosuppression (rare), dyspnea, rhinitis, rash, diarrhea Conjugated Products

• Adverse effects mainly due to linked compound • Emtansine – Myelosuppression, neuropathy • Deruxetecan OHSU– Myelosuppression, diarrhea, GI Cancer Agents Bevacizumab Ramucirumab OHSUCetuximab Panitumumab Bevacizumab

• Targets vascular endothelial growth factor, preventing angiogenesis • FDA approved metastatic colorectal, NSCLC, glioblastoma, metastatic RCC, ovarian, cervical, breast • Black box warning OHSU– GI perforation, hemorrhage, wound dehiscence Veg-F Inhibiting Mabs

• Class effects: Hypertension, impaired wound healing/GI perforation, proteinurea • DVT- including arterial clots • Increased bleeding (rare), RPLS • Hold for differing periods pre and post surgery OHSU– Bev - 42 days pre and 28 days post surgery

RPLS-reversible posterior leukoencephalopathy syndrome The EGFR/HER Family NRG1

Ligand Binding

Tyrosine Kinase EGFR HER2 HER3 HER4 OHSUHER1 C-erbB2 C-erbB

Mendelsohn and Baselga. Oncogene. 2000;19:6550. Olayioye et al. EMBO J. 2000;19:3159. Prigent and Lemoine. Prog Growth Factor Res. 1992;4:1. Harari and Yarden. Oncogene. 2000;19:6102. Earp et al. Breast Cancer Res Treat. 1995;35:115. HER Family Dimers

4 Homodimers

OHSU6 Heterodimers

Earp et al. Breast Cancer Res Treat. 1995;35:115. Epidermal Growth Factor Receptor

Cetuximab Panitumuab Binds to EGFR to inhibit EGF, blocks phosphorylation, inhibits cell survival MOA

Metastatic KRAS wild -type Refractory metastatic KRAS wild - Metastatic squamous cell lung FDA colorectal cancer, head and neck type colorectal cancer with chemo cancer with chemo Approved cancer Dose Severe skin rash – acneiform rash Dermtologic, Ocular (keratitis) Dermatologic events, VTE (venous limiting Pulmonary toxicity Pulmonary toxicity and arterial) Closely monitor electrolytes Severe skin reactions (>90%) Cardiac arrest 3%, Closely monitor Black Box Mag, K, Ca – during & after tx Infusion reactions electrolytes OHSUMag, K, Ca – during & after tx EGFR Inhibiting MABs

• Infusion reactions (90% with 1st infusion when they occur) – pre-medication for cetuximab only up front – Cetuximab reactions related to antimurine IgE, regionally related around the US OHSU• Electrolyte wasting – hypomagnesemia • Interstitial lung disease Heme Malignancy Mabs Name Alemtuzumab Balantamab Daratumumab -irfc (Campath®) mafodotin-blmf (Empliciti®) (Darzalex®) (Sarclisa®) (Blenrep®)

Origin Humanized Humanized Humanized Human Chimeric FDA Relapsed B-cell R/R MM MM with MM MM with approved CLL lenalidomide after 1- w/chemo/imids/pro pomalidomide and use 3 prior therapies teasome inhibitors. dexamethhasone Varies with line of therapy

Target CD 52 BCMA Slam-F7 CD38 CD-38 Dose 30 mg SQ or IV 2.5 mg/kg every 10 mg/kg weekly x 16 mg/kg dosed 10 mg/kg IV day TIW (Titrate 21 days 8 then Q 2 weeks weekly (1 thru 8), 1, 8, 15, and 22 dose from 3 mg every 2 weeks x 8 C1, then day 1, 15 (IV) or 10 mg doses, then every 4 C2 and beyond. (SQ)) weeks 28 day schedule OHSU(monotherapy) Half-life 14 days 12-14 days 10-11 days 18-23 days Not reported

NHL- NonHodgkin , CLL – Chronic Lymphocytic Leukemia, MM – Multiple Myeloma, HD – Hodgkin Disease Alemtuzumab

• Dose escalation and premeds required for IV & SQ use • AE: infusion related, myelosuppressive, OHSUOpportunistic infections Daratumumab, Isatuximab

• Pre-medicate with corticosteroids, antipyretics, and H1 blockers, methylprednisolone 20 mg/day x 2 after each dose • AE: >20% - infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, muscle spasms, back pain, pyrexia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, and URI • Interferes with blood cross matching, CD38 binding OHSUresults in a + indirect Coombs test • Interferes with response assessment via SPEP Elotuzumab (Empliciti®)

• AE: > 20% - fatigue, diarrhea, pyrexia, cough, constipation, peripheral neuropathy, nasopharyngitis, URI, decreased appetite, pneumonia, hepatic dysfunction • Infusion reactions, infections, secondary malignancies OHSU• May confound SPEP monitoring Heme Malignancy Mabs Name - Polatuzumab – Blinatumomab Brentuximab cxix (Monjuvi) vedotin-piiq (Blincyto®) (Sylvant®) vedotin (Polivy) (Adcetris®)

Origin Humanized Murine Chimeric Chimeric FDA R/R DLBCL R/R DLBCL with CD19 + ALL (adult Multicentric HD: Stage III/IV, approved with and and pediatric). R/R Castleman’s post auto relapse use lenalidomide rituximab or MRD Disease or maint, Anaplastic Lg cell NHL CD30+ MF Target CD-19 CD-79b CD 19 w/ IL-6 CD30 engager Dose 12 mg/kg day 1, 1.8 mg/kg IV very Cycle 1- 9 mcg/day 11 mg/kg IV Q 3 1.8 mg/kg (Max 4, 8, 15, & 22 21 days for 6 days 1-7, followed weeks 180 mg) every C1, then 1, 8, cycles by 28 mcg/day for 21days or 1.2 155, 22 C2/3, days 8-28, mg/kg (max 120 then Day 1, 15 additional cycles at mg) with dC4 and 28 mcg/day all days chemotherapy OHSUbeyond. 28 day every 2 weeks cycles

Half-life 17 days 12 days 2.11 hrs. 20.6 days 4-6 days

DLBCL- Diffuse B-cell lymphoma, ALL – Acute lymphoblastic leukemia, MRD – Minimal residual disease, R/R - relapsed/refractory Blinatumomab (Blincyto®)

• Murine IgG which is a bispecific CD-19-directed T-cell engager that binds CD19 of B-cells and CD3 on the surface of T cells. • Most common AE (>20%): pyrexia, headache, peripheral edema, febrile neutropenia, nausea, , and constipation. • Cytokine release syndrome, neurological toxicity/leukoencephalopathy, infections, TLS, FN, elevated OHSULFTs • Hypogammaglobuminemic Brentuximab vedotin

• AE: Myelosuppression, peripheral; neuropathy, diarrhea, rash, TLS, Infusion reactions, Stevens-Johnson syndrome, OHSUPML Siltuximab

• Do not give live virus vaccines • Hold if infections, • Pruritus, weight gain, rash, hyperuricemia, OHSUURIs Heme Malignancy Mabs Name - Gemtuzumab Inotuzumab - Moxetumomab lzsg (Gamifant) ozogamicin ozogamicin kpkc pseudotox-tdfk (Mylotarg®) (Besponsa®) (Poteligeo®) (Lumoxiti®)

Origin Human Humanized Humanized Humanized Murine FDA Adult and CD33 + AML, RR CD22+ RR B-ALL Adults with RR RR Hairy cell approved pediatric in adults/peds leukemia use primary or Sezary hemophagocytic syndrome 2nd line lymphohistiocyt or later osis (HLH) Target CD33 CD 22 CCR4 CD22 gamma Dose 1 mg/kg IV 3-6 mg/m2, 0.8 mg/m2 day 1, 1 mg/kg on days 1, 0.04 mg/kg days twice weekly, dosing and days 0.5 mg/m2 days 8, 8, 15, & 22 Cycle 1 1, 3, 5 of each 28 dose increases vary by indication 15, then days 1, 8, then days 1 & 15 days to 3 and 6 15 every 21 days every 28 days mg/kg per OHSUguideline

Half-life 22 days 62-90 hrs. 12.3 days 17 days 1.4 hrs.

ALL- Acute Lymphoblastic Leukemia, AML – Acute Myelogenous Leukemia, RR – Relapsed/Refractory Gemtuzumab ozogamicin

• Infusion reactions, hemorrhage, infection, nausea, , constipation, headache, increased AST/ALT, OHSUrash, mucositis

• Myelosuppression, fatigue, fever, nausea, headache, febrile neutropenia, increased transaminases, OHSUhyperbilirubinemia, Qtc Prolongation, Mogamulizumab-kpkc

• Rashes, infusion reactions, fatigue, diarrhea, OHSUmusculoskeletal pain, URI -tdfk

• Infusion reactions, edema, nausea, fatigue, headache, pyrexia, constipation, diarrhea, and anemia. • Increased Scr, AST/ALT, decreased albumin, calcium, OHSUphosphate Solid Tumor Mabs

Name Enfortumab Sacituzumab- (Unituxin®) vedotin-ejfv (Lartruvo®) govitecan-hziy (Padcev) (Trodelvy)

Origin Chimeric Human Human Humanized FDA Peds Locally advanced Adult soft tissue Metastatic triple approved or metastatic Sarcoma w/ negative breast use with GMCSF urothelial cancer cancer (govitecan = and 13 cis Withdrawn from the SN38) retinoic acid market

Target GD2 Nectin-4 PDGF alpha Trop-2

Dose 17.5 mg/m2/day 1.25 mg/kg (max 15 mg/kg days 1& 8 10 mg/kg IV day 1 IV over 10-20 125 mg) on days Q 21 days and Day 8 every 21 hours 1, 8, & 15 of a 28 days OHSUday cycle Half-life 10 days 3.4 days (MMAE 11 days 16 hrs. (18 hr. 2.4) SN38)

GMCSF- Dinutuximab • Premeds: diphenhydramine, Apap, MS • Most common AE: (>25%) pain, pyrexia, thrombocytopenia, lymphopenia, infusion reactions, hypotension, , inc ALT/AST, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, OHSU• Infusion reactions, neuropathic pain (opioid premed and during infusion), neurlogic opthalmic effects, atypical HUS MABs

• Available for bevacizumab, rituximab, trastuzumab • Product of first choice for clinical indications with expired patents on originator product

• No clinically meaningful difference between the biosimilar OHSUand the originator product