tyrosine kinase inhibitors Flashcards
where are the EGFR mutations that we care about for treatment
exons 19-21
exon 19 deletions, L858R, T790M
first and second generation EGFR TKIs are approved for
exon 19 deletions and exon 21 L858R substitutions
third generation EGFR TKIs are approved for
exon 20 T790M
secondary resistance mutation
develops in about 50% that become resistant to EGFR TKIs
first generation TKIs
erlotinib
gefitinib
reversible
second generation TKIs
afatinib
irreversible
third generation TKIs
osimertinib
mutant-selective
TKIs are associated with _____
skin rashes and diarrhea
what are limitations of 1st and 2nd generation TKIs
on-target, off-tumor inhibition of EGFR leads to rash, diarrhea
resistance inevitably develops
poor blood brain barrier penetration
what is special about osimertinib in terms of ADEs
selective for MUTATED EGFR, so less rash/diarrhea
what causes the acneiform rash
direct inhibition of wild-tupe EGFR
management of mild (Grade 1) rash
continue EGFR inhibitor at current dose
no treatment OR topical hydrocortisone 1-2.5% or clindamycin 1%
management of moderate (Grade 2) rash
continue EGFR inhibitor at current dose
hydrocortisone 2.5 % cream or clindamycin 1% gel or pimecrolimus 1% cream
PLUS
doxycycline 100 mg BID or minocycline 100 mg BID
management of severe (Grade 3-4) rash
reduce EGFR inhibitor dose per label
hydrocortisone 2.5% cream or clindamycin 1% gel or pimecrolimus 1% cream
PLUS
doxycycline 100 mg BID or minocycline 100 mg BID
PLUS
methylprednisolone dose pack
drug interaction with gastric acid reducing drugs
erlotinib
gefitinib
decreases TKI exposure
drugs interaction with CYP inducers
erlotinib
gefitinib
osimertinib
decreases TKI exposure
