Checkpoint inhibitors - CME Flashcards
3 meds approved for advanced melanoma and their classes?
ipilimumab - CTLA4 inhibitor
nivolumab - PD1 inhibitor
pembrolizumab - PD1 inhibitor
why is combo of novo and ipi suggested ?
higher overall survival vs ipi alone
that being said PD1s have better survival compared to ipip
ipilimumab (anti-CTLA4) dosing?
both 10 mg/kg and 3 mg /kg used in trials - 3 has better adverse effect profile
IPI 3x3 - 3 mg/kg Q3 weeks for 4 treatments then every 3 MONTHS for 3 YEARS
nivo indications and dosing?
BRAF + or - ve
first line for adjuvant MM therapy
response rate for ipi + nev0?
60% vs 11 % w/ just ipi
dosing for nivo?
3 mg/kg every 2 weeks (same dose as ipi but Q2 w not Q3 like the other)
if ipi and nivo combined ->
ipi 3 mg /kg and nevo 1 mg /kg Q3 weeks x 4 followed by nivo 3 mg/kg Q3 weeks for 4 doses
pembro dosing ?
pembro 2 mg/kg Q3 weeks
ipi 3 mg/kg Q3 weeks
nivo 3 mg/kg Q2 weeks or Q3 if combined
checkpoint inhibitor approved for cSCC?
cemiplimab
pembro showing some promise in trials
most SCC pts do not respond to immunotx
what 2 checkpoint inhibitors are approved in treatment of Merkel cell carcinoma?
avelumab - anti PD-1L
pembrolizumab - anti - PD1
nivo is in trials - also recommended but not approved
all 3 “first line”
avelumab - 5 adverse effects?
common (from google search) muscle, bone, or joint pain weight loss fatigue headache N/V/ constipation weight loss tiredness
"serious" (from CME) central DI AI hepatitis PNA thrombocytopenia
MA: ave - thirst, EtOH (communion), breathing, bleeding (cross)
what are checkpoint inhibitors approved for BCC, lymphomas, sarcomas ?
none
pembro helpful in some and is best exam guess, esp in BCC - pembro + vismodegib
Which group of checkpoint inhibitors has more severe side effects?
CTLA-4 = cytotoxic t lymphocyte associated PROTEIN 4 inhibitors have more frequent and more severe side effects when compared to PD-1s (programmed cell death)1 and programmed cell death ligand)
90% of CTLA-4
80% of PD-1s
almost all its in combined group
most common life threatening s/e of cytotoxic T lymphocyte protein 4 inhibitors?
colitis -> bowel perforation
CTLA for COLON
MC severe s/e of programmed death-1 inhibitors?
pneumonitis
PNA for PD1
5 MC s/e of checkpoint inhibitors?
maculopapular rash (?morbilliform eruption) PRURITIS eczematous psoriasiform lichenoid BP litiligo-like hypo pigmentation/depigmentation ALOPECIA SJS/TEN, DRESS and others also possible
why not use CS before giving immunotherapy to reduce s/e of these meds?
may blunt anti-tumour resposne
what are the 4 grades of adverse effects in immunotherapy?
Grade 1 - <10% BSA +- symptoms
Grade 2- <30% BSA+- symptoms (pruritis, burning, tightness)
OR LIMITING ADLs or >30 % without limiting self-care ADLs
Grade 3 - >30% BSA, moderate to severe symptoms, limiting self care
Grade 4 + life threatening
5 MC eruptions in immunotherapy?
maculopapular eczematous psoriasiform lichenoid PRURITIS
MC adverse event of cytotoxic Cell lymphocyte protein 4 inhibition? tx?
maculopapular rash (MPR) MC usually 3- 6 weeks into tx trunk and extensors self-limited typically may Koebenrize
superpotent to mid potent topical CS
if grade 3 (>30% limiting ADLs) give pred 1 mg/kg/day and up to 2 mg/kg day if needed
HOLD until grade 1
if grade 4 -> methylpred 2 mg/kg/day
lichenoid eruption in immunotherapy - timing and treatment?
MC in anti-PD1/PD-L1
6-12 weeks post start
(reminder lichenoid eruptions can take up to a year, so well within that timing)
tx: high potency TCS and PO CS if needed
“alternatives: phototherapy and acitretin”
BP in immunotherapy - which class of agents is most likely to cause it? Tx?
PD1-PDL1 inhibitors
DELAYED ONSET typically = 14 weeks +
presents with prodromal non-bulbous phase of pruritis -> generalized or localized tense bullae +- oral mucosa in 10-30%
BP180 and 230 + and correlates with dz severity, can also be used to monitor tx response
Grade 2 and above -> PO CS (some Gr 1 can respond to topical)
Grade 3-4 -> rituzimab
may persist for months post d/c
what class of immunotherapy agents is most responsible for pruritis? Tx?
CTLA 4 s - pruritis and morbilliform
pruritis can come with or without cutaneous eruptions
Tx: TCS, PO antihistamines, “oral neuromodulators like GABA
aprepitant = neurokinin receptor inhibitor if refractory
neurokinin receptors bind both substance P and neurokinin A/B, so may be helpful for both pruritis and vomiting
immunotherapy agent most likely to induce vitiligo like skin hypopigmentation/depigmentation ?
depigmentation risk 10x the general population
vitiligo is PPV for tumour response to CPI
associated with greater anticancer benefit
25% of PD1 and 11% of anti-CTLA4s (think of PD1s as more effective so have better tumour response and more vitiligo)
“in anti-PD-1 treatment, CD8 cytotoxic T cells are activated against melanoma associated antigens (Melan A, gp100, tyrosinase related proteins) shared by normal melanocytes and melanomas”
what is the distinct phenotype of CPI related vitiligo?
multiple flecked aka speckled macules of depigmentation evolving into large plaques on PHOTOEXPOSED SKIN
2-4 x prolonged progression free survival and overall survival
apart from morbilliform and lichenoid and BP /vitiligo changes, name 4 more reactions 2’ CPI use?
psoriasiform = PD1 mostly
- high potency TCS, D3s, narrowband UVB, retinoids, biologics
eczematous
DRESS
SJS - targeting of keratinocytes by activated CD+ cells
TEN
alopecia
what is the clinical presentation of CPI-related alopecia?
similar to AA»_space;» telogen effluvium
possible mucosal toxicity in CPI?
xerostomia (think of it as mucosal pruritis)
mucosal lichenoid reactions
if BP - > mucosal erosions possible
mucosal involvement in SJS/TEN
What is the first drug-related cutaneous eruption to develop post PD1/CTLA 4 use? what is the timing of other drug-adverse events?
psoriasiform rash (0-3 w)
morbilliform “maculopapular rash” 4-6 w
pruritis (can be with morbiliform or solitary) 4-6 w
licehnoid eruption, SJS/TEN, DRESS, vitiligo-like hypo pigmentation 7 w +
bullous pemphigoid, alopecia 13+ weeks
what are MC systemic adverse effects of CTLA4 therapy and their timing?
skin first - starts at 3 weeks
GI - 6 weeks (remember C for colon)
endocrine - 9 weeks
what would you do in CPI-related alopecia?
still need to do full diagnostic workup
hair pull test
biopsy
lab testing for iron studies, THRYOID, ZINC, vitamin D
intralesional triamcinolone and clobetasol foam
poliosis possible
