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What are the benefits of Molecular Tumor Boards?
a multidisciplinary team that assesses tumors mutation(s)
reviews and provides recommendations for molecular targeted therapies
track pt outcomes
Small molecular drugs (TKIs) vs Biologic agents (monoclonal antibodies): Route of administration
TKIs: PO
Monoclonal antibodies: IV, SubQ, IM
Small molecular drugs (TKIs) vs Biologic agents (monoclonal antibodies): Absorption and distribution
TKIs: through passive diffusion/permeability and active transporters
Monoclonal antibodies: through lymphatic system due to large size
Small molecular drugs (TKIs) vs Biologic agents (monoclonal antibodies): Target
TKIs: surface and intracellular targets - receptors + proteins
Monoclonal antibodies: membrane proteins + soluble proteins/signaling molecules
Small molecular drugs (TKIs) vs Biologic agents (monoclonal antibodies): Metabolism/clearance
TKIs: mainly through CYP enzymes, renal excretion, biliary excretion; usually linear
Monoclonal antibodies: through proteolysis, hydrolysis; target mediated clearance
Small molecular drugs (TKIs) vs Biologic agents (monoclonal antibodies): Drug interactions
TKIs: PK and PD
Monoclonal antibodies: PD
Name the K-RAS G12C inhibitors
sotorasib (Kumakras)
adagrasib (Krazati)
Class effects of K-RAS inhibitors
hepatotoxicity
pulmonary toxicity
decreased albumin/electrolytes
lymphocytopenia
heart failure (rare)
Unique effects of sotorasib (lumakras)
Decreased Hgb
Unique effects of Adagrasib (Krazati)
GI toxicity
QTc prolongation
increased CPK
AKI
mental status change (rare)
hyperpigmentation
are EGFR mutations likely to occur in the same settings as KRAS mutations
NO due to functional redundancy
Name the ALK rearrangement inhibitors
Alectinib
Brigatinib
Ceritinib
Crizotinib
Ensartinib
Lorlatinib
Class effects of ALK rearrangement inhibitors
bradycardia
pulmonary toxicity
hepatotoxicity (not in lorlatnib)
photosensivitity (not in lorlatnib)
Unique effects of lorlatinib
CNS effects
Hyperlipidemia
Dose modification and medical management for lorlatinib: CNS effects
grading
grade 1: continue at the same sode or withhold until recovery to baseline. Resume at the same or reduced dose
grade 2-3: withhold dose until Grade 0-1. Resume at a reduced dose
Grade 4: D/C
medical management
psych consult
antipsychotic agents
antidepressants agents
agents for sleep
Dose modification and medical management for lorlatinib: Hypercholesterolemia or hypertriglyceridemia
grading
grade 4: withhold until recovery to less than or equal to grade 2. resume at the dose. If severe or recurraence, resume at reduced dose
medical management
Statins (DDI with lorlatinib): ROSUVASTATIN PREFERRED
fibrates (2nd line)
Dose modification and medical management for lorlatinib: HTN
grading
grade 3: withhold until recovery to grade 0-1,t hen resume at same dose. If adequate control cannot be achieved with medical management, D/C
grade 4: withhold until recovery to less than or equal to grade 0-1 and resume at a reduced dose. If grade 4 reoccurs, D/C
medical management
CCB
ACE-I/ARB
thiazide diuretics
Dose modification and medical management for lorlatinib: Hyperglycemia
grading
grade 4: withhold until adequatelly controlled, then resume at the next lower dosage. If controlled cannot be achieved, D/C
medical management
oral agents
injectable agents
insulin
Name the MET exon skipping mutation inhibitors
capmatinib (tabcrecta)
crizotinib (Xalkori)
tepotinib (tepmetko)
Class effects of MET inhibitors
hepatoxicity
pulmonary toxicity
peripheral edema
decreased hemoglobin/lymphocytopenia
Unique effects of capmatinib (tabcrecta)
edema
facial, genital
pancreatic toxicity
Unique effects of tepotinib (tepmetko)
pulmonary embolism (RARE)
Name the RET rearrangement inhibitors
Cabozantinib
Pralsetinib
Selpercatinib
Class effects of RET inhibitors
hemorrhage
hepatotoxicity
HTN
wound healing impairment
pulmonary toxicity (except carbozantinib)
tumor lysis syndrome (except in carbozantinib)
thyroid dysfunction (except in pralsetinib)
Which of the following agents should you monitor for QTc prolongations?
adagradisb
selpercatinib
crizotinib
ceritinib
Which agents are CYP3A4 inhibitors
adagrasib
crizotinib
ceritinib
lorlatinib
Which agents are CYP3A4 substrates
All of them
Which of the K-RAS inhibitors is most likely to prolong the QTc interval?
Adagrasib (Krazati)
What questions would you ask of a patient receiving Sotorasib or Adagrasib to probe for the onset of delayed toxicities?
What lab tests would you follow to monitor for toxicities?
Does better CNS penetration by Adagrasib mean that Sotorasib is not effective upon CNS metastases of cancers?
Tests
Imaging can tell us if its malignant-caused or if its true ADR caused by the medication through inflammation
LFTs
CBC
CNS pentration
sotorasib still have good activity within the CNS