Checkpoint inhibitors - CME

Question 1

3 meds approved for advanced melanoma and their classes?

Answer 1

ipilimumab - CTLA4 inhibitor
nivolumab - PD1 inhibitor
pembrolizumab - PD1 inhibitor

Question 2

why is combo of novo and ipi suggested ?

Answer 2

higher overall survival vs ipi alone

that being said PD1s have better survival compared to ipip

Question 3

ipilimumab (anti-CTLA4) dosing?

Answer 3

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

Question 4

nivo indications and dosing?

Answer 4

BRAF + or - ve

first line for adjuvant MM therapy

Question 5

response rate for ipi + nev0?

Answer 5

60% vs 11 % w/ just ipi

Question 6

dosing for nivo?

Answer 6

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

Question 7

pembro dosing ?

Answer 7

pembro 2 mg/kg Q3 weeks
ipi 3 mg/kg Q3 weeks
nivo 3 mg/kg Q2 weeks or Q3 if combined

Question 8

checkpoint inhibitor approved for cSCC?

Answer 8

cemiplimab

pembro showing some promise in trials
most SCC pts do not respond to immunotx

Question 9

what 2 checkpoint inhibitors are approved in treatment of Merkel cell carcinoma?

Answer 9

avelumab - anti PD-1L
pembrolizumab - anti - PD1
nivo is in trials - also recommended but not approved

all 3 “first line”

Question 10

avelumab - 5 adverse effects?

Answer 10

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)

Question 11

what are checkpoint inhibitors approved for BCC, lymphomas, sarcomas ?

Answer 11

none

pembro helpful in some and is best exam guess, esp in BCC - pembro + vismodegib

Question 12

Which group of checkpoint inhibitors has more severe side effects?

Answer 12

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

Question 13

most common life threatening s/e of cytotoxic T lymphocyte protein 4 inhibitors?

Answer 13

colitis -> bowel perforation

CTLA for COLON

Question 14

MC severe s/e of programmed death-1 inhibitors?

Answer 14

pneumonitis

PNA for PD1

Question 15

5 MC s/e of checkpoint inhibitors?

Answer 15

maculopapular rash (?morbilliform eruption)
PRURITIS
eczematous
psoriasiform
lichenoid
BP
litiligo-like hypo pigmentation/depigmentation
ALOPECIA
SJS/TEN, DRESS and others also possible

Question 16

why not use CS before giving immunotherapy to reduce s/e of these meds?

Answer 16

may blunt anti-tumour resposne

Question 17

what are the 4 grades of adverse effects in immunotherapy?

Answer 17

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

Question 18

5 MC eruptions in immunotherapy?

Answer 18

maculopapular
eczematous
psoriasiform
lichenoid
PRURITIS

Question 19

MC adverse event of cytotoxic Cell lymphocyte protein 4 inhibition? tx?

Answer 19

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

Question 20

lichenoid eruption in immunotherapy - timing and treatment?

Answer 20

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”

Question 21

BP in immunotherapy - which class of agents is most likely to cause it? Tx?

Answer 21

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

Question 22

what class of immunotherapy agents is most responsible for pruritis? Tx?

Answer 22

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

Question 23

immunotherapy agent most likely to induce vitiligo like skin hypopigmentation/depigmentation ?

Answer 23

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”

Question 24

what is the distinct phenotype of CPI related vitiligo?

Answer 24

multiple flecked aka speckled macules of depigmentation evolving into large plaques on PHOTOEXPOSED SKIN
2-4 x prolonged progression free survival and overall survival

Question 25

apart from morbilliform and lichenoid and BP /vitiligo changes, name 4 more reactions 2’ CPI use?

Answer 25

psoriasiform = PD1 mostly
- high potency TCS, D3s, narrowband UVB, retinoids, biologics
eczematous
DRESS
SJS - targeting of keratinocytes by activated CD+ cells
TEN
alopecia

Question 26

what is the clinical presentation of CPI-related alopecia?

Answer 26

similar to AA&raquo_space;» telogen effluvium

Question 27

possible mucosal toxicity in CPI?

Answer 27

xerostomia (think of it as mucosal pruritis)
mucosal lichenoid reactions
if BP - > mucosal erosions possible
mucosal involvement in SJS/TEN

Question 28

What is the first drug-related cutaneous eruption to develop post PD1/CTLA 4 use? what is the timing of other drug-adverse events?

Answer 28

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

Question 29

what are MC systemic adverse effects of CTLA4 therapy and their timing?

Answer 29

skin first - starts at 3 weeks
GI - 6 weeks (remember C for colon)
endocrine - 9 weeks

Question 30

what would you do in CPI-related alopecia?

Answer 30

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