Toxicities: EGFR Inhibitors Immune Checkpoint Inhibitors Flashcards
EGFR Inhibitors - Diarrhea
– Most likely to occur within the first 4 weeks after initiating treatment
– Mechanism unclear but thought to be primarily secretory
– Usually grade 1-2, but up to 25% of patients will experience grade 3 diarrhea
or higher from EGFR TKIs
mild, grade 1 increase of less than 4 stolls per day over baseline
moderate, increase of 4-6
severe, increase of 7 or more stools
EGFR Inhibitor induced Diarrhea
EGFR Inhibitor diarrhea is managed very similarly to diarrhea
from traditional antineoplastic agents (like capecitabine)
– Drink plenty of fluids
– Avoid high fibre foods
– BRAT diet (bananas, rice, applesauce, toast)
– Avoid dairy (temporary lactose intolerance)
– Loperamide
Management of Diarrhea
from EGFR Inhbitors
for grade 1-4
Grade 1 * Drink clear fluids (maintain good hydration)
* Start loperamide 4 mg asap and 2 mg after each loose bowel movement until
bowel movements cease for 12 hours (maximum debatable, 12-20mg per
day)
Grade 2 * Continue loperamide as above
* If diarrhea does not improve after 48 hours, hold the EGFR TKI. Can restart
EGFR TKI once diarrhea has settled to grade 1 (may consider reduced dose)
Grade 3 * Referral required
* Stool culture to rule out infectious process
* Aggressive fluid replacement (IV fluids)
* Temporarily discontinue EGFR TKI and restart at reduced dose once improved
to grade 1. Permanently discontinue if diarrhea does not improve to grade
within 14 days.
Grade 4 * Life threatening
EGFR Inhibitor TKI and Mab:
Acneiform Rash
- Epidermal growth factor (EGF) and EGF receptor (EGFR) play an essential role
in wound healing through stimulating epidermal and dermal regeneration. - Patients receiving EGFR inhibitors commonly experience an acneiform rash as
an adverse effect - Examples of EGFR inhibitors include: gefitinib, erlotinib, afatinib, osimertinib,
panitumumab, cetuximab
Acneiform rash
– erythema, edema, papulopustular eruptions followed by crusting and
dryness of the skin.
– Looks like “acne” but isn’t like acne in that it can be painful and pruritic
(itchy) and doesn’t respond to OTC acne products
– Very common
* up to 90% of patients on afatinib
* Up to 60% of patients on osimertinib
* Up to 80% of patients on cetuximab
* Up to 50% of patients on panitumumab
– Usually occurs within the first 1-2 weeks of treatment (range 2 days to 6
weeks) peaks after 2–4 weeks, and then slowly regresses with
continuation of therapy
Rash Phases
Phase one Weeks 0-1 Sensory disturbance with erythema and edema
Phase two Weeks 1-3 papulopustular eruptions
Phase three Weeks 3-5 Crusting
Phase four Weeks 5-8 Erythematotelangiectasias (red areas)
- The lesions are usually sterile, however, a secondary bacterial or fungal
infection at the site of the eruption can occur - The severity of the rash waxes and wanes throughout these four phases,
and typically resolves without permanent scarring within two months of
therapy discontinuation
EGFR Inhibitor Acneiform Rash
* Why is this rash so important????
- Positives:
- appearance of a papulopustular rash may be an accurate surrogate marker of the efficacy of
anti-EGFR therapy, as well as for the clinical response of the patient. - Several key clinical trials, along with smaller case series have reported a significant correlation between rash and response to treatment.
if they dont get a rash, doesn’t mean its’ not working - Negatives:
– Can lead to compromised integrity of skin (ie risk of infection from impairment of natural
barrier to infection)
– Patients can experience decreased quality of life
– NON-compliance or therapy discontinuation - Clinicians often want some rash…. But not too much rash!
pt education and monitoring for rash
skin care and hygeine, pat dry
moisturize
avoid sun/heat exposure
don’t pop pustules/rash
avoid OTC anti-acne pdts, benzoyl peroxise ineffective and drying
montior skin closely\
gtade 1 <10% BSA
grade 2 10-30%
grade 3 >30%
grade 4 life threatening
oharmacotx of EGFR inhibitor rash (AB)
what to give fro grade 1-4
Grade 1 (<10% of BSA)
- topical clindamycin 2% + hydrocortisone 1% lotion bid x 4wks
- cannot be hydrocortisone added to Dalacin T solution (contains alcohol and is drying)
- MUST BE CLINDA POWDER + HYDROCORTISONE POWDER
Grade 2 (10-30% of BSA)
- topical clinda + HC AND minocycline/doxycycline 100mg PO BID x 4wks
Grade 3 (>30% of BSA and/or moderate to severe symptoms)
- may need systemic corticosteroids and referral to dermatologist
- may need dose reducation or discontinuation of their EGFR inhibitor tx
Grade 4 (life theratening)
- urgent referral/admission
Patient Education and Monitoring for Acneiform
Rash
- Skin Care and Hygiene
– Wash and clean skin with lukewarm water, gently pat dry
(avoid hot water)
– Apply moisturizers (to intact skin) liberally, gently and
frequently - Avoid perfumed products or alcohol containing products
– Avoid sun exposure and exposure to heat (saunas, steam
rooms hot baths etc) - Avoid popping pimples/pustules/rash
- Avoid topical anti-acne products such as benzoyl
peroxide (doesn’t work and is drying) - Instruct patient to assess their skin daily
- Team to assess patient’s skin at each clinic visit
Immunotherapy Toxicity Management
Background
- Tumors can employ a host of mechanisms to defend themselves
from attack by the immune system
– “Avoiding Immune Destruction” (hallmark of malignancy)
– Tumour cells can take advantage of the “checkpoints” to evade
destruction and death - Modulating these receptors is an approach termed “Immune
Checkpoint Blockade”
– Inhibit the checkpoints Potentiating the bodies own immune system
to act in an anti-tumour fashion
Recap - Immune Checkpoint Inhibitors
Checkpoint Inhibition
- Can cause side effects related to auto-immunity and
inflammatory responses
– Leads to self-reactive T-cells - Although the pharmacologic mechanism of influencing T cell
response is very exciting, it is associated with a different array
of side effects that require close monitoring and different
management strategies
Adverse Effects of Checkpoint Inhibitors
hypophysitis
thyroiditis
adrenal insufficiency enterocolitis
dermatitis
pneumonitis
hepatitis
prancreatitis
motor and sensory neuropathies
arthritis
these are immune mediated adverse effects
immune mediate AE
immune mediated dermatitis
immune mediated enterocolitis
immune mediated organ dysfunction
immune mediated endocrinopathies
Adverse Effects - Checkpoint Inhibitors
- Diverse presentations
- Can be subtle at the beginning
- Can occur at any time
– At beginning, several weeks/months after initiating therapy, after therapy
termination - Can lead to serious autoimmune consequences
- Patients are usually outpatients (ambulatory)
- TAKE HOME MESSAGES:
– Must be vigilant in our patient monitoring to identify and manage these
adverse effects early and quickly
– Patient education is of key importance to empower patients to contact the
team quickly when side effects occur`
5 pillars of immunotx toxicity managmenet
prevent
anticipate - this could happen in time, check up and f/u
detect
treat monitor
Immune Mediated Dermatitis
- Very common but mostly mild
– Approximately 45% with CTLA-4 inhibitors and 35% with PD-1/PD-L1 inhibitors
– Only 3% of patients develop grade 3 or higher dermatologic toxicities
– Occasionally can be severe [stevens-johnson syndrome (SJS) or toxic epidermal
necrolysis (TEN)] - Pruritus that may be associated with a erythema and/or maculopapular
rash
– most commonly on trunk and extremities - Can occur at any time but median time of occurrence is week 3 (early
onset) - Monitoring – instruct patient to report itching (pruritus), rash, redness
(erythema) on skin
Immune Mediated Dermatitis
grade 1-2
grade 3-4
Grade 1-2 Rash ≤ 30% of skin surface * Moisturizers
* Sun safety
* Moderate potency topical
corticosteroids (2.5% hydrocortisone cream or triamincolone 0.1%)
* Oral antihistamines
if persists:
* Consider a skin biopsy
* Consider withholding CI
* Oral prednisone and once
improved taper over 1 month
Grade 3-4 Examples:
* Rash > 30% of skin surface
* treatment resistatant with
high QoL impact
* <10% if skin is starting to
slough
* Refer to oncologist for medical attention asap
* Withhold CI
* Consider skin biopsy/dermatology consult
* High potency topical corticosteroids and/or systemic
corticosteroids (example: Prednisone PO or Methylprednisolone IV
daily until improves to grade 1 and then taper over at least 1
month
Pneumonitis
- Median time to onset is 12 weeks
(range 9-22 weeks) - Monitor for shortness of breath, chest
pain, new/worsening cough - If pneumonitis is suspected, evaluate
with chest X-ray and rule out other
causes
Pneumonitis
grade 1-3
Grade 1 Radiographic Changes only
* Consider withholding CI
* Consider pulmonary/ID consult
* If improves, resume CI
* If worsens, treat as grade 2 or 3
Grade 2 Mild to moderate new or worsening cough, chest pain, SOB
* Refer to oncologist or oncology team
* HOLD the CI
* Prednisone daily
* If improves, taper prednisone over at least 1 month
* If worsens, treat as grade ¾
Grade 3/4 Severe new or worsening cough, chest pain, SOB or hypoxia
**Can be life threatening
**
* HOSPITALIZE
* Discontinue CI
* High dose corticosteroids (e.g. methylprednisolone 1-2 mg/kg/day)
* If improves to baseline, taper prednisone over at least 6 weeks
* If worsens, consider non-steroid immunosuppression
- BL presents to oncology clinic and states for the last 2 days she
has had abdominal pain and 5-6 loose bowel movements per
day (her baseline was once daily). The oncologist states they
have ruled out other causes of the diarrhea and believe it is an
immune mediated adverse effect of nivolumab. The oncologist
asks what to prescribe and if its ok to proceed with her
nivolumab scheduled for tomorrow?
what do you recommend?
– Patient experiencing grade 2 enterocolitis
– Hold the dose of nivolumab
– Initiate loperamide and hydration
– If symptoms persist > 3 days, start prednisone, once improved, taper
prednisone over one month and then restart nivolumab
PG is a 58 year old male and presents to your pharmacy asking
for an over the counter cough and cold preparation. Upon
further questioning, PG states he has malignant melanoma and
started a drug called ipilimumab about 6 months ago. He says
he has developed a very annoying cough and would like
something to suppress it. What do you recommend?
You are concerned that PG may be experiencing signs of
immune mediated pneumonitis related to his ipilimumab. You
refer PG for urgent assessment including chest X-ray
DW is a 48 year old female who comes in to your pharmacy
asking for a medication for an itchy rash. After questioning,
she reveals that she has non-small cell lung cancer and
states she is receiving a new medication called nivolumab.
She shows you her arm and reveals a maculopapular rash.
She says the rash is on her arms and a small portion of her
chest. What do you recommend?
You are concerned that DW may be experiencing an immune
mediated dermatitis
* You recommend the following:
– topical hydrocortisone 2.5% cream (alternative would be triamcinolone
0.1%)
– refer to medical oncology team for further assessment
– Advise patient if it spreads to a larger portion of her body to seek medical
attention asap
– Advise patient if it starts to blister or peel to seek medical attention asap
Immune Mediated Hepatitis
- Manifests as elevated transaminases
- Median time to onset is 14 weeks (range is 2-8
months) - Monitor liver function tests
– AST, ALT, Alkaline Phosphatase, total bilirubin - Monitor for clinical signs of hepatotoxicity
– Jaundice, dark urine, severe nausea/vomiting,
easy bruising/bleeding
Immune Mediated Nephritis
- Median time to onset 1 week to 12 months
- Monitor for changes in renal function
– urine volume, urine color
– Edema
– Serum creatinine
Immune Mediated Endocrinopathies
- Examples:
– Thyroid endocrinopathy (up to 15%) Examples: hypothyroidism,
hyperthyroidism
– Hypopituitarism (hypophysitis)
– Autoimmune diabetes (Diabetes Mellitus, Diabetic Ketoacidosis)
– Adrenal Insufficiency - Patients may present with non specific symptoms
– Fatigue, weight change, headache, mood/behaviour changes, decreased
sex drive, change in bowel habits, vision changes, dizziness - Lab tests done at baseline and regularly through treatment:
– Blood glucose, thyroid function, chemistries
Drug Interactions? Think about it
- Existing autoimmune disorders
– Higher risk of IMAE
– Think about a patient with rheumatoid arthritis, psoriasis, multiple sclerosis,
crohn’s disease - Existing endocrinopathy
– Think about a patient with existing hypothyroidism or existing diabetes - Concomitant medications
– Some medications are already associated with autoimmune disease and it is hypothesized that this could increase risk - Example – some anticonvulsants
Immune Mediated Endocrinopathies tx
see table on 46
Drug Interactions
- Antibiotics?
– Mounting evidence that gut microbiome influences the capacity of ICIs to stimulate the immune system.
– Retrospective analyses have shown a strong association between antibiotic induced dysbiosis and poor ICI efficacy. However, a causal link is not certain.
– Timing of antibiotics seems important. Antibiotics within 1 month of starting ICI may negatively impact efficacy of ICI.
– Length of treatment and spectrum also seem important. Short course and narrow spectrum having less impact on efficacy. - PPIs?
– Seems to be a similar association between PPI use and reduced ICI efficacy.
Theory is also related to PPI impact on microbiome.
Corticosteroids
- Mainstay of treatment for severe IMAE
- Keep in mind the toxicities of high dose corticosteroids and
appropriate supportive care - May need prophylaxis for opportunistic infections
– Example Septra for pneumocystic jiroveci pneumonia (PJP)
