Exam 3: Lecture 7, Monoclonal Antibodies in the treatment of Cancer Flashcards by Patryk Lasiuk

3 Mechanisms of MABs….

Block - molecules cancer cells need to grow
Flag - cancer cells for ID by immune system
Deliver - substances to the cancer cell that may kill it

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MAB general comments…

most given IV infusion
some can be admin SQ
Some can cause infusion reactions, some pt should be premeditated

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standard infusion reactions

Fever/shaking chills
flushing/itching
HR or BP change
Chest, back or abdominal pain
Nausea,vomiting,diarrhea
skin rash

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Standard infusion reactions occur within….

30 min, 2 hrs but can delay up to 24 hr

most common with 1st/2nd dose and incidence declines

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Rituximab îs a….

engineered murine/human chimeric monoclonal antibody

1st one approved for cancer

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Rituximab MOA

Apoptosis
ADCC (Antibody-dependent cell mediated cytotoxicity)
CDC (complement-dependent cytotoxicity)

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Rituximab admin

1st dose: start at 50 mg/hr, can increase by 50mg/hr every 30 min to max of 400 mg/hr

2nd dose: can do 100mg/hr, increase by 100mg/hr until 400 mg/hr

detectable in serum 3-6 months after last dose

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Rapid infusion Rituximab

for pt who didn’t experience grade 3/4 infusion-related adverse event during cycle 1, have NHL and BLBCL

used with regimens that include corticosteroid

1st dose = standard dose schedule
subsequent doses 20% over 30 min, then 80% over 1hr

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Rituximab black box warnings

infusion reactions
Hep B reactivation
Mucocutaneous reactions
PML

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examples of Mucocutaneous reactions Rituximab

Stevens Johnson syndrome, Lichenoid dermatitis, TEN

Onset 1-13 weeks

D/C for severe reactions

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PML is a….

rare brain infection with the JC virus that usually causes death/severe disability

no cure/treatment/prevention

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How to detect PML

Brain MRI
Lumbar Puncture
Signs/Symptoms = focal neurologic deficits

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Tumor lysis syndrome usually occurs in patients who have….

lymphomas or leukemias taking Rituximab

management - hydration, supportive care, dialysis, correct electrolyte abnormalities

pretreat - fluids and allopurinol

onset 12-24hrs after 1st infusion

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Other adverse reactions Rituximab….

Myelosuppression
Renal Dysfunction
Do not give live virus vaccine

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Rituximab and Hyaluronidase allows for it to be given….

via SQ injection in 5-7 min instead of Iv infusion

can only be given after patients have received at least 1 IV treatment

approved for some indications that rituximab approved for

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Trastuzumab MOA

Binds HER2 receptors and inhibits cellular proliferation

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Trastuzumab indications

HER2 breast cancer and GI cancer

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Trastuzumab admin

** Loading dose ** both therapies
Adjuvant therapy - contine to 52 weeks of therapy

Metastatic disease - until progression/toxicity

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Trastuzumab Adverse effects

Infusion reactions most common (20-40%)
cardio toxicity
myelosuppression
embryo-fetal toxicity

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Trastuzumab Premedication:

acetaminophen and an antihistamine

for 90 min infusion, glucocortioicd recommended too prior

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Trastuzumab Cardiotoxicity

reduce Ejection fraction, cause HF
<10% as single drug

anthracyclines can potentiate

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Trastuzumab Cardiotoxicity risks

concurrent or prior anthracyclines or cyclophosphamide
preexisting cardiac disease
prior radiation therapy
old age, smoking, diabetes, thyroid disorders

Trastuzumab and Hyaluronidase combo

lets you give drug SB over 2-5 min

Hyaluronidase mechanism

increased permeability of SQ tissue. effects are reversible and permeability restored within 24-48hrs

How many biosimilars of Trastuzumab?

Trastuzumab analog

fam-trastuzumab deruxtecan-nxki (enhertu) Topoisomerase I inhibit attached to antibody. Binds to HER2, internalized and linker breaks and release DXd which causes DNA damage (Top I inhibitors) good response but ILD-13% (black box warning)

Ibritumomab (Zevalin) MOA:

serves as carrier for radiation

Ibritumomab indication

patients previously untreated follicular NHL

Ibritumomab Admin Schedule

Day 1: 250 mg/m2 rituximab infusion (premed Benadryl/tylenol) Day 7,8,or 9: 250mg/m2 rituximab infusion (premed Benadryl/tylenol) Within 4 hrs, give Ibritumomab

Ibritumomab Precautions

minimize radiation exposure contraceptives at least 12 months after treatment wash hands X 3 day universal precautions for bodily fluids X 3 days

Ibritumomab Adverse effects

Myelosuppression * more likely than other MABs* Infusion + Cutaneous reactions Delayed radiation damage

Bevacizumab MOA:

binds to VEGF preventing reaction with cell receptors

Bevacizumab Dosing

Varies with cancer ranging 5-15mg/kg IV 1st dose: 90 min 2nd dose: 60min Later dose: 30 min

Bevacizumab Adverse effects

Impaired wound healing/wound dehiscence (reopening, 28 day precaution) GI perforation/fistulae Hemorrhage Renal injury, proteinuria Hypertension, monitor BP Venous thromboembulsims

Bevacizumab contraindicaiton

Squarmous cell lung cancer, 31% serious or fatal bleeding

How many qbiosimilars of Bevacizumab

Cetuximab (Erbitux)

targets EGFR and binds to EGFR w/ higher affinity than natural ligands leads to blocking of signal transduction, inhibit cell growth and lead to apoptosis

K-RAS

if have Wt then EGFR works | if have mutated, then doesnt

Cetuximab (Erbitux) indications

squamous cell carcinoma of Heasd/Neck | K-RAS mutation neg, EGFR expressing colorectal cancer

Cetuximab (Erbitux) admin

1st dose = loading = 400 mg/m2 over 2hr max rate @ 10mg/min subsequent weekly doses at 250 mg/m2 over 1hr premeditate with diphenhydramine

Cetuximab (Erbitux) Adverse effects

Infusion reactions Severe reactions more common in NC,TN,ARK,MI,VA,FL, due to pt in these states making antibody to galactose-a-1.3 galactose Pulmonary toxicity and skin toxicity (rash) Cardiopulmonary arrest/sudden death (Head/neck cancer more likely) - monitor Mg,K,Ca hypomagnesemia

Immune Checkpoint inhibitors

Newest class of MABs

Immune Checkpoint inhibitors MOA generalities

T cells may be inhibited by a ligand that binds to a specific receptor on the T cell that limits its activation Drugs may target specific immune checkpoints that are affected by cancer cells to reduce immune activity

Atezolizumab MOA

PDL1 binding agent targets PDL1 to restore anti tumor Cell activity

Ipilimumab

only Checkpoint inhibitor that doesn't work on PD1/PDL1 works on CTLA4

Nivolumab major change in indication

Small cell lung cancer removed

Nivolumab admin

30 min IV infusion 240 mg every 2 week or 480 mg every 4

Nivolumab Adverse effects

Infusion reaction | Immune-related adverse effects

Pembrolizumab admin

30 min Iv infusion 200 mg every 3 week until progression or unacceptable toxicity up to 24 months in pt w/o disease progression all indications except melanoma children 2mg/kg (up to 200mg) every 3 week

Pembrolizumab adverse effects

Infusion reaction Immune related adverse effects Embryo-fetal toxicity

Immune related adverse effect (IRAE)

Most common = fatigue, itching, diarrhea, decreased appetite, rash, dyspnea, constipation, nausea can happen with any immune checkpoint inhibitors bc can effect normal cells.

Immune related adverse effect checklist

anytime patient receives medication, checklist going over to see if they've experienced anything

IRAE more common with....

CTLA-4 inhibitors (Ipilimumab)

Main treatment of IRAEs?

Corticosteroids | Early intervention is key