10.1 Immunotherapy Toxicity Management

Ipilimumab (for NSCLC) MOA

• Targets CTLA-4 on the T-cell

• Dendritic cells prime T-cells to recognize cancer cells.

• CTLA-4 is an “off switch” that dendritic cells can activate on the T cell (hence turning off T-cell cancer kill). By blocking CTLA-4 we block that “off switch”

Pembrolizumab and Nivolumab (indicated for NSCLC) MOA

• PD-1 Inhibitors

• Target the off switch (PD-1) on the T-Cell so that tumour cells can’t access the receptor (PD-1) and turn T cells off. (car analogy: stopping the cancer from accessing the “brakes”)

Durvalumab and Atezolizumab (indicated in NSCLC) MOA

• PD-L1 Inhibitors 

• Target the ligand on tumour cells (PD-L1) so they can’t activate the “off switch” on the T-cells (PD-1). (car analogy: stopping the cancer from “braking”)

AEs of Checkpoint Inhibitors

Adrenal insufficiency 

Hypophysitis 

Thyroiditis 

Enterocolitis 

Dermatitis 

Pneumonitis 

Hepatitis 

Pancreatitis 

Motor and sensory neuropathies 

Arthritis 

Initial Immune Mediated Dermatitis Lower grade rash (<30% of skin surface) Treatment

• moisturizers and moderate potency topical corticosteroids (hydrocortisone 2.5% or triamcinolone 0.1%)

• sun safety

• oral antihistamines

Immune Mediated Dermatitis (Higher grade rash (>30% of skin surface, or <10% if skin is starting to slough) Treatment

refer for medical attention asap. May need to hold cancer treatment and initiate systemic corticosteroids

• Ex. Prednisone PO or Methylprednisolone IV daily until improves to grade 1 and then taper over at least 1 month

Immune Mediated Organ Dysfunction: Pneumonitis Symptoms

SOB, chest pain, new or worsening cough - REFERRAL

Immune Mediated Organ Dysfunction: Hepatitis Symptoms

elevated transaminases, severe nausea/vomiting

Immune Mediated Organ Dysfunction: Nephritis Symptoms

elevated creatinine, edema, urine changes

Immune Mediated Enterocolitis Presentation

Presents as any of: diarrhea, increased stools, abdominal pain, changes in stools (tarry, blood, mucus)

Immune Mediated Enterocolitis Treatment

If increase in stool frequency is < 4 stools per day OVER BASELINE, then treat with loperamide once infection is ruled out.

Examples of Immune Mediated Endocrinopathies and monitoring plan

• hypothyroidism, hypopituitarism, diabetes mellitus, adrenal insufficiency

• Close monitoring of relevant laboratory tests (eg. TSH)

• Monitor for fatigue, weight change, mood changes

Immune Mediated Adverse Effects (IMAE): When who do they usually occur 

• 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)

Laboratory test timeline for IMAE Monitoring

• eg. TSH, blood glucose, HgA1c, electrolytes

• Baseline and q4wks for first 6 months and then can extend to q3 months

General Management of Organ Related Grade 1 IMAE

• Temporary stop of ICI (can consider restart if improvement

• Work-up/investigations

• Pharmacologic management of symptoms

• Close monitoring

General Management of Organ Related Grade 2 IMAE

• Temporary or permanent stop of ICI

• Continued pharmacologic management of symptoms

• Initiate Corticosteroids

General Management of Organ Related Grade 3 or 4 IMAE

• Permanent D/C of ICI

• Consider hospital admission (grade 3) and hospitalize (grade 4)

• Higher dose corticosteroids

• Consider additional immunosuppression

General Management of Endocrine Related Grade 1 IMAE

• Work-up/investigations

• Hormone replacement if required

• Close monitoring

General Management of Endocrine Related Grade 2 IMAE

• Consider temporary stop of ICI. If held, restart ICI only after endocrinopathy is stabilized.

• Hormone replacement if required

General Management of Endocrine Related Grade 3 or 4 IMAE

• Stop ICI. Consider restart only if endocrinopathy stabilized

• Consider hospital admission (grade 3) and hospitalize (grade 4)

• Consult endocrinology (for hormone management)

• Consider corticosteroids

Mainstay of treatment for severe IMAE

corticosteroids

What may patient’s need prophylaxis for due to high doses and extended duration of corticosteroids therapy?

• patient may need prophylaxis for opportunistic infections

• Ex. Septra for pneumocystic jiroveci pneumonia (PJP)

Persistent Immune Mediated Dermatitis Lower grade rash (<30% of skin surface) Treatment

• Consider a skin biopsy

• Consider withholding CI

• Oral prednisone and once improved taper over 1 month

Pneumonitis Diagnosis & Time to Onset

• If pneumonitis is suspected, evaluate with chest X-ray and rule out other causes

• Median time to onset is 12 weeks (range 9-22 weeks)

Management of Grade 1 Pneumonitis (radiographic changes only)

Initial:

• Consider withholding CI

• Consider pulmonary/ID consult

Next Steps:

• • If improves, resume CI

• If worsens, treat as grade 2 or 3

Management of Grade 2 Pneumonitis (Mild to moderate new or worsening cough, chest pain, SOB)

Initial:

• Refer to oncologist or oncology team

• HOLD the CI 

• Prednisone daily

Next Steps:

• If improves, taper prednisone over at least 1 month

• If worsens, treat as grade 

Management of Grade 3 or 4 Pneumonitis (Severe new or worsening cough, chest pain, SOB or hypoxia)

Initial:

• HOSPITALIZE

• Discontinue CI

• High dose corticosteroids (e.g. methylprednisolone 1-2 mg/kg/day)

Next Steps:

• If improves to baseline, taper prednisone over at least 6 weeks

• If worsens, consider non-steroid immunosuppression

Enterocolitis Typical Onset

• Can occur at any time including after discontinuation 

• Typical onset is early after therapy

• PD1/PD-L1 - median time to onset is approximately 2-3 months

• CTLA-4 (Ipilimumab) – median time to onset 1-5 months

Immune medicated colitis presentation (may be any of the following)

• severe abdominal pain

• diarrhea

• black/tarry stools

• stool with blood or mucus

• occasionally can have aphthous ulcers, fissures, or extra-intestinal manifestations (skin changes, arthralgias)

Rule out other causes (ex. infection)

Grade 1 Enterocolitis definition

Diarrhea < 4 stools per day over baseline

Grade 1 Enterocolitis Management

Initial:

• Antidiarrheal treatment

• Hydration and simple electrolyte replacement

• Daily follow up

Next Steps:

• If improves, resume CI

• If worsens, treat as grade 2 or 3

Grade 2 Enterocolitis Definition

Diarrhea of 4-6 stools per day over baseline, normal daily activities , abdominal pain, blood or mucus in stool

Grade 2 Enterocolitis Management 

Initial:

• Refer to oncologist or oncology team (will assess need to hospitalize)

• HOLD the CI

• IV fluids for hydration

• Rule out infection.

• Antidiarrheal treatment, if persists > 3 days start prednisone

Next Steps: 

• If improves, taper prednisone over at least 1 month (if used)

Grade 3 or 4 Enterocolitis Definition

Diarrhea of ≥ 7 stools per ay over baseline, incontinence, impaired daily activities, colitis with severe abdominal pain, signs of bowel perforation

Grade 3 or 4 Enterocolitis Management

Initial:

• May need to HOSPITALIZE.

• Gastroenterology consult and consider endoscopy

• Withhold or discontinue CI

• High dose corticosteroids (unless bowel perforation)

• If bowel perforation or septic, will need antibiotics

Next Steps:

• If improves to baseline, taper prednisone over at least 1 month

• If no response or recurs within 5 days, consider non-steroid immunosuppression

Immune Mediated Hepatitis Manifestation and Onset 

• Manifests as elevated transaminases

• Median time to onset is 14 weeks (range is 2-8 months)

Immune Mediated Hepatitis Monitoring

• liver function tests:

  • AST, ALT, Alkaline Phosphatase, total bilirubin

• clinical signs of hepatotoxicity:

  • Jaundice, dark urine, severe nausea/vomiting, easy bruising/bleeding

Immune Mediated Nephritis Onset

Median time to onset 1 week to 12 months

Immune Mediated Nephritis Monitoring

Monitor for changes in renal function:

• urine volume

• urine color

• Edema

• Serum creatinine

Examples of Immune Mediated Endocrinopathies

• Thyroid endocrinopathy (up to 15%) Examples: hypothyroidism, hyperthyroidism

• Hypopituitarism (hypophysitis)

• Autoimmune diabetes (Diabetes Mellitus, Diabetic Ketoacidosis)

• Adrenal Insufficiency

Non specific symptoms of Endocrinopathies

• Fatigue

• weight change

• headache

• mood/behaviour changes

• decreased sex drive

• change in bowel habits

• vision changes

• dizziness