‍Management of Select Overlapping ICI + Oral TKI Toxicities

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General ICI + Oral TKI Toxicity Management Pearls

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• Class specific adverse events (AEs) with oral TKIs and immune related adverse events (irAEs) with ICIs can overlap and act synergistically in certain circumstances, which can make it difficult to attribute toxicity to one specific agent. 
  
  • Other considerations when assessing new symptoms should take into account cancer related symptoms, and symptoms related to established comorbid illnesses.

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• Keep the half-life of oral TKI in mind when delaying TKI and ICI as this may predict when specific toxicity improves. Toxicity related to TKIs with a longer half-life, such as cabozantinib (e.g., 99 hrs), may take longer to improve compared to those with a shorter half-life, such as axitinib (e.g., 6 hrs). 
  
  • If related to TKI, toxicity can typically be managed with appropriate supportive care, dose delay, TKI dose reduction, and/or intermittent dosing strategies.

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• Even though rates of toxicity (e.g., fatigue, asthenia, hypertension, etc.) are higher with oral TKIs, clinicians must always consider irAEs in differential as delays in diagnosis and appropriate management may result in increased morbidity, hospitalization, treatment discontinuation, and mortality.

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• If an AE is suspected to be treatment-related and is severe / life-threatening (e.g., grade 3-4) at the time of onset or is rapidly worsening, both drugs should be interrupted and treatment with a corticosteroid and other supportive care should be initiated promptly.

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• In some cases, it is good practice to cautiously resume treatment with one drug first, even with reduced dose if deemed necessary and feasible, in order to predict tolerance and eventually restart full treatment. 

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Diarrhea Management with ICI + TKI Combinations 

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Grade 1: Obtain information to appropriately grade toxicity, including number of bowel movements in comparison to baseline, impact of diarrhea on iADL or ADL, and presence and severity of colitis symptoms (abdominal pain / cramping, hematochezia, steatorrhea).

• Diarrhea - Increase of < 4 stools per day from baseline; mild increase in ostomy output compared with baseline.
• Enterocolitis irAE - Asymptomatic; clinical or diagnostic observations only; intervention not indicated.

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Management: 

• Rule out other causes of diarrhea, including drug induced (e.g., antimicrobials, PPIs, etc), infection (e.g., Clostridium difficile, bacteria, viral, ova and parasites), recent dietary changes or travel, and sick household contacts.

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• Continue oral TKI and ICI with close monitoring of symptoms. 
  
  • Monitor for new or persistent red flag symptoms of enterocolitis irAE, including abdominal pain / cramping, progressively worsening diarrhea, hematochezia, steatorrhea, and fever.

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• Implement pharmacologic and nonpharmacologic supportive care strategies for diarrhea.
  
  • Therapeutic challenge with loperamide for 24 - 48 hours. 
    
    • Loperamide 4 mg as initial dose, then 2 mg after each episode of diarrhea thereafter up to a maximum of 16 mg per day. Goal is to be diarrhea free for 12 - 24 hours. 
  • Maintain adequate hydration with 2 - 3L of fluids per day.
  • Diet modification with frequent, small means incorporating BRAT (bananas, rice, applesauce, and toast). Avoid foods which may exacerbate diarrhea such as alcohol, caffeine, spicy foods, fatty foods, dairy, and food high in insoluble fiber.

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• If symptoms progress to intolerable grade 2, consider trial dose delay of oral TKI after adequate loperamide challenge.

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Grade 2: Obtain information to appropriately grade toxicity, including number of bowel movements in comparison to baseline, impact of diarrhea on iADL or ADL, and presence and severity of colitis symptoms (abdominal pain / cramping, hematochezia, steatorrhea).

• Diarrhea - Increase of 4 - 6 stools per day from baseline; moderate increase in ostomy output compared with baseline; limiting iADL.
• Enterocolitis irAE - Abdominal pain; mucus or blood in stool.

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Management: 

• Rule out other causes of diarrhea, including drug induced (e.g., antimicrobials, PPIs, etc), infection (e.g., Clostridium difficile, bacteria, viral, ova and parasites), recent dietary changes or travel, and sick household contacts.

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• Dose delay oral TKI for a minimum of 2 - 3 days* and monitor for improvement in symptoms. Delay ICI until assessment confirms causal relationship to TKI.
  
  • * = If toxicity is related to TKI, improvement in symptoms may be delayed for TKIs with a longer half life such as lenvatinib (5 x T_1/2 = 5-6 days; recovery may take up to 4 days) and cabozantinib (5 x T_1/2 = 20-21 days; recovery may take up to 14 days). 
  • If diarrhea improves with dose delay of oral TKI, implement dose reduction or intermittent dosing schedule when re-starting TKI.

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• Implement pharmacologic and nonpharmacologic supportive care strategies for diarrhea as per grade 1 management. 
  
  • If initiating loperamide for isolated grade 2 diarrhea, rule out infectious causes, limit duration to 24 - 48 hrs, and commit to follow-up after oral TKI dose delay to rule out enterocolitis irAE.

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• Monitor for new or persistent red flag symptoms of enterocolitis irAE, including abdominal pain / cramping, progressively worsening diarrhea, hematochezia, steatorrhea, and fever.
  
  • Assess stool inflammatory markers (e.g., stool for calprotectin) to help differentiate TKI diarrhea from enterocolitis irAE if the clinical picture is unclear.

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• If diarrhea severity progresses or new colitis symptoms occur despite appropriate dose delay of oral TKI, delay ICI, start PO corticosteroid (prednisone 1 mg/kg daily or equivalent) as outpatient, and monitor diarrhea / colitis symptoms every 3 days. 
  
  • Taper corticosteroid over at least 4 - 6 weeks once diarrhea and/or colitis symptoms are improved to baseline. 
  • Consider supportive care interventions during corticosteroid pulse and taper as clinically indicated. 
    
    • Infection prophylaxis, bone health measures, gut prophylaxis, and other corticosteroid supportive management (e.g., hyperglycemia management, insomnia management, etc.). 
  • Only restart ICI after a shared decision with the patient once fully recovered from diarrhea / colitis and prednisone ≤ 10 mg per day.

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Grade 3/4: Obtain information to appropriately grade toxicity, including number of bowel movements in comparison to baseline, impact of diarrhea on iADL or ADL, and presence and severity of colitis symptoms (abdominal pain / cramping, hematochezia, steatorrhea).

• Diarrhea - Increase of ≥ 7 stools per day from baseline; severe increase in ostomy output compared with baseline; limiting self-care ADL; hospitalization indicated. 
• Enterocolitis irAE - Severe or persistent abdominal pain; fever; ileus; peritoneal signs; urgent intervention indicated.

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Management: 

• Rule out other causes of diarrhea, including drug induced (e.g., antimicrobials, PPIs, etc), infection (e.g., Clostridium difficile, bacteria, ova and parasites), recent dietary changes or travel, and sick household contacts.

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• Dose delay oral TKI* and hold ICI. 
  
  • * = If toxicity is related to TKI, improvement in symptoms may be delayed for TKIs with a longer half life such as lenvatinib (5 x T_1/2 = 5-6 days; recovery may take up to 4 days) and cabozantinib (5 x T_1/2 = 20-21 days; recovery may take up to 14 days). 
  • If diarrhea improves with dose delay of oral TKI, implement dose reduction or intermittent dosing schedule when re-starting TKI.

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• Isolated diarrhea with no enterocolitis symptoms: For stable patients, monitor for progressively worsening diarrhea and enterocolitis symptoms for 48 hours after oral TKI dose delay. For unstable patients, follow management as per below. 
  
  • Assess stool inflammatory markers (e.g., stool for calprotectin) to help differentiate TKI diarrhea from enterocolitis irAE if the clinical picture is unclear.
  • If diarrhea persists or progresses in severity after 24 - 48 hours of monitoring, start PO corticosteroid (prednisone 1 - 2 mg/kg daily or equivalent) as outpatient once causal relationship to oral TKI has been ruled out. Consider IV route (e.g., methylprednisolone or dexamethasone) if suspecting upper GI inflammation (e.g., nausea, vomiting, anorexia). 
  • If no response to corticosteroids, consult gastroenterology to guide use of pharmacologic therapy (e.g., corticosteroids, additional immunosuppression, etc), endoscopy, and specialized monitoring as clinically indicated.
    
    • Consider additional immunosuppression if no improvement in symptoms after 48 - 72 hours of IV corticosteroids (e.g., infliximab, vedolizumab, etc).
  • Taper corticosteroid over at least 4 - 6 weeks once blood work is improved to baseline. 
  • Consider supportive care interventions during corticosteroid pulse and taper as clinically indicated. 
    
    • Infection prophylaxis, bone health measures, gut prophylaxis, and other corticosteroid supportive management (e.g., hyperglycemia management, insomnia management, etc.). 
  • Only restart ICI after a shared decision with the patient once fully recovered from diarrhea / colitis and prednisone ≤ 10 mg per day.

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• Concurrent diarrhea and enterocolitis symptoms: Start corticosteroid (prednisone 1 - 2 mg/kg daily or equivalent) as inpatient. Consider IV route if suspecting upper GI inflammation (e.g., nausea, vomiting, anorexia). 
  
  • Consult gastroenterology to guide use of pharmacologic therapy (e.g., corticosteroids, additional immunosuppression, etc), endoscopy, and specialized monitoring as clinically indicated.
    
    • Consider additional immunosuppression if no improvement in symptoms after 48 - 72 hours of IV corticosteroids (e.g., infliximab, vedolizumab, etc).
  • Taper corticosteroid over at least 4 - 6 weeks once blood work is improved to baseline. 
  • Consider supportive care interventions during corticosteroid pulse and taper as clinically indicated. 
    
    • Infection prophylaxis, bone health measures, gut prophylaxis, and other corticosteroid supportive management (e.g., hyperglycemia management, insomnia management, etc.). 
  • Discontinue ICI and restart oral TKI at same or reduced dose level once patient is recovered if toxicity was felt to be enterocolitis irAE.

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Hepatotoxicity Management with ICI + TKI Combinations 

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Management Algorithm - Hepatotoxicity with ICI + TKI:

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Grade 1: Obtain information to appropriately grade toxicity, including AST, ALT, total bilirubin, and symptoms related to hepatitis (e.g., RUQ pain, jaundice, anorexia, nausea / vomiting, fever, and fatigue). Always compare to the patient's usual baseline. 

• Transaminitis - AST / ALT < 3.0 x ULN; AST / ALT 1.5-3.0 x baseline if baseline values were abnormal. 
• Hepatitis - Asymptomatic; AST / ALT < 3.0 x ULN and/or total bilirubin (Tbili) < 1.5 x ULN.

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Management: 

• Rule out other causes of transaminitis / hepatitis, including drug induced (e.g., acetaminophen, antimicrobials, etc.), infection (e.g., viral hepatitis), comorbidities (e.g., fatty liver disease), or progression of malignancy.

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• Continue oral TKI and ICI. 
  
  • Monitor liver specific blood work (AST, ALT, Tbili) every 3 days to assess for progression of transaminitis to ≥ grade 2.
  • Monitor for new or persistent red flag symptoms of hepatitis, including right upper quadrant (RUQ) pain, jaundice, anorexia, fever, and nausea / vomiting.

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Grade 2: Obtain information to appropriately grade toxicity, including AST, ALT, total bilirubin, and symptoms related to hepatitis (e.g., RUQ pain, jaundice, anorexia, nausea / vomiting, fever, and fatigue). Always compare to the patient's usual baseline. 

• Transaminitis - AST / ALT > 3.0 - 5.0 x ULN; AST / ALT > 3.0 - 5.0 x baseline if baseline values were abnormal. 
• Hepatitis - Asymptomatic; AST / ALT 3.0 - 5.0 x ULN and/or Tbili < 1.5 x ULN.

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Management: 

• Rule out other causes of transaminitis / hepatitis, including drug induced (e.g., acetaminophen, antimicrobials, etc.), infection (e.g., viral hepatitis), comorbidities (e.g., fatty liver disease), or progression of malignancy.

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• Dose delay oral TKI for a minimum 2 - 3 days* and monitor blood work (AST, ALT and Tbili) every 3 days. Delay ICI until blood work confirms causal relationship to TKI.
  
  • * = If toxicity is related to TKI, improvement in symptoms may be delayed for TKIs with a longer half life such as lenvatinib (5 x T_1/2 = 5-6 days; recovery may take up to 4 days) and cabozantinib (5 x T_1/2 = 20-21 days; recovery may take up to 14 days). 
  • If transaminitis improves with dose delay of oral TKI, implement dose reduction when re-starting TKI.

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• Monitor for new or persistent red flag symptoms of hepatitis, including RUQ pain, jaundice, anorexia, fever, and nausea / vomiting.

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• If transaminitis progresses in severity despite appropriate dose delay of oral TKI, delay ICI, start PO corticosteroid (prednisone 0.5 - 1 mg/kg daily or equivalent) as outpatient, and continue to monitor blood work (AST, ALT and TBili) every 3 days. 
  
  • Taper corticosteroid over at least 4 weeks once blood work (AST, ALT and Tbili) is improved to baseline. 
  • Consider supportive care interventions during corticosteroid pulse and taper as clinically indicated. 
    
    • Infection prophylaxis, bone health measures, gut prophylaxis, and other corticosteroid supportive management (e.g., hyperglycemia management, insomnia management, etc.). 
  • Only restart ICI after a shared decision with the patient once fully recovered from hepatitis and prednisone ≤ 10 mg per day.

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Grade 3 / 4: Obtain information to appropriately grade toxicity, including AST, ALT, total bilirubin, and symptoms related to hepatitis (e.g., RUQ pain, jaundice, anorexia, nausea / vomiting, fever, and fatigue). Always compare to the patient's usual baseline. 

• Transaminitis - AST / ALT 5.0 - 20.0 x ULN (>20x for grade 4); AST / ALT > 5.0 - 20.0 x baseline (>20x for grade 4) if baseline values were abnormal. 
• Hepatitis - Symptomatic liver dysfunction with or without decompensated liver function; AST / ALT > 5.0 - 20.0 x ULN (>20x for grade 4) and/or total bilirubin 3.0 - 10.0 x ULN (>10x for grade 4)

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Management: 

• Rule out other causes of transaminitis / hepatitis, including drug induced (e.g., acetaminophen, antimicrobials, etc.), infection (e.g., viral hepatitis), comorbidities (e.g., fatty liver disease), or progression of malignancy.

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• Dose delay oral TKI* and hold ICI. 
  
  • * = If toxicity is related to TKI, improvement in symptoms may be delayed for TKIs with a longer half life such as lenvatinib (5 x T_1/2 = 5-6 days; recovery may take up to 4 days) and cabozantinib (5 x T_1/2 = 20-21 days; recovery may take up to 14 days). 
  • If transaminitis improves with dose delay of oral TKI, implement dose reduction when re-starting oral TKI.

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• Isolated transaminitis without elevation in Tbili or hepatitis symptoms: Monitor blood work (AST, ALT and Tbili) every 3 days after oral TKI dose delay. 
  
  • If transaminitis progresses in severity after 1-2 blood work assessments, start corticosteroid (prednisone 1 -2 mg/kg daily or equivalent) as outpatient (PO) once causal relationship to oral TKI has been ruled out.
    
    • Consult gastroenterology or hepatology to guide use of pharmacologic therapy (e.g., corticosteroids, additional immunosuppression, etc) and specialized monitoring as clinically indicated if the patient is hospitalized.
      
      • Consider additional immunosuppression if no improvement after 48 - 72 hours of corticosteroids (e.g., mycophenolate mofetil, azathioprine, tacrolimus, etc).
    • Taper corticosteroid over at least 4 -6 weeks once blood work (AST, ALT and Tbili) is improved to baseline. 
    • Consider supportive care interventions during corticosteroid pulse and taper as clinically indicated. 
      
      • Infection prophylaxis, bone health measures, gut prophylaxis, and other corticosteroid supportive management (e.g., hyperglycemia management, insomnia management, etc.). 
    • Discontinue ICI and restart oral TKI at same or reduced dose level once patient is recovered if toxicity was felt to be hepatitis irAE.

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• Concurrent Tbili + transaminitis elevation and/or clinical symptoms of hepatitis: Start IV corticosteroid (prednisone 1 - 2 mg/kg daily or equivalent) as inpatient and continue to monitor blood work (AST, ALT and TBili) every 3 days. 
  
  • Consult gastroenterology or hepatology to guide use of pharmacologic therapy (e.g., corticosteroids, additional immunosuppression, etc) and specialized monitoring as clinically indicated.
    
    • Consider additional immunosuppression if no improvement after 48 - 72 hours of corticosteroids (e.g., mycophenolate mofetil, azathioprine, tacrolimus, etc).
  • Taper corticosteroid over at least 4 - 6 weeks once blood work is improved to baseline. 
  • Consider supportive care interventions during corticosteroid pulse and taper as clinically indicated. 
    
    • Infection prophylaxis, bone health measures, gut prophylaxis, and other corticosteroid supportive management (e.g., hyperglycemia management, insomnia management, etc.). 
  • Discontinue ICI and restart TKI at same or reduced dose level once patient is recovered if toxicity was felt to be hepatitis irAE.

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Thyroid Toxicity Management with ICI + TKI Combinations 

Management Algorithm - Thyroid toxicity with ICI + TKI:

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Grade 1: Obtain information to appropriately grade toxicity, including thyroid function tests (e.g., TSH, free T₄, free T₃), symptoms related to hypo- or hyperthyroidism, and interference with iADL or ADL.

• Hypothyroidism - Asymptomatic; clinical or diagnostic observations only (e.g., TSH ≤ 10 mIU/L); intervention not indicated. 
• Hyperthyroidism / Thyroiditis - Asymptomatic; clinical or diagnostic observations only (e.g., low TSH, elevated free T₄); intervention not indicated.

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Management: 

• Continue TKI and ICI.
  
  • Monitor thyroid function tests (TSH, free T₄ if indicated) every 3-6 weeks with each new cycle of treatment. 
    
    • Rule out central hypothyroidism secondary to hypophysitis (e.g., low TSH, low free T₄). 
  • Monitor for new or persistent red flag symptoms related to hyperthyroid phase of thyroiditis, including throat discomfort, tremors, palpitations, anxiety / emotional lability, diaphoresis, heat intolerance, and hyperdefecation.

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• Hyperthyroid phase of thyroiditis
  
  • If patient has PMHx of hypothyroidism and is at risk of hyperthyroid related complications (e.g., cardiac disease [heart failure, coronary artery disease, arrhythmia], age >60 years of age, etc), hold levothyroxine as clinically indicated until euthyroid or conversion to hypothyroidism. 
  • For hyperthyroid phase of thyroiditis > 6 weeks, consider consultation with endocrinology to guide use of additional pharmacologic therapy (e.g., corticosteroids, thionamide antithyroid medication, etc.) and specialized monitoring.

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Grade 2: Obtain information to appropriately grade toxicity, including thyroid function tests (e.g., TSH, free T₄, free T₃), symptoms related to hypo- or hyperthyroidism, and interference with iADL or ADL.

• Hypothyroidism - Symptomatic or TSH ≥10; thyroid replacement indicated; limiting iADL
• Hyperthyroidism / Thyroiditis - Symptomatic hyperthyroidism; thyroid suppression therapy indicated; limiting iADL

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Management: 

• Continue TKI and ICI.
  
  • Monitor thyroid function tests (TSH, free T₄ if indicated) every 3-6 weeks with each new cycle of treatment. 
    
    • Rule out central hypothyroidism secondary to hypophysitis (e.g., low TSH, low free T₄). 
  • Monitor for new or persistent red flag symptoms related to hyperthyroid phase of thyroiditis, including throat discomfort, tremors, palpitations, anxiety / emotional lability, diaphoresis, heat intolerance, and hyperdefecation.

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• Hypothyroidism
  
  • Clinical suspicion of overt hypothyroidism following episode of thyroiditis from ICI in patients who are not frail, < 60 years of age, and no cardiac comorbidities
    
    • Initiate levothyroxine 1.6 mcg/kg/day. 
    • Adjust dose based on thyroid function blood work at each new cycle. 
  • Clinical suspicion of overt hypothyroidism following episode of thyroiditis from ICI in patients who are frail, > 60 years of age, and/or cardiac comorbidities (e.g., coronary artery disease)
    
    • Initiate levothyroxine 12.5 - 50 mcg once daily. Monitor for the onset of cardiac symptoms (e.g., angina) and decrease dose if required. 
    • Adjust dose based on thyroid function blood work at each new cycle. 
  • Clinical suspicion of TKI induced hypothyroidism or TSH elevation ≥10
    
    • Initiate levothyroxine 25 - 50 mcg once daily.
    • Titrate dose based on thyroid function blood work at each new cycle.

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• Hyperthyroid phase of thyroiditis
  
  • For symptomatic patients, initiate beta blockers and other supportive medicines (e.g., propranolol, lorazepam, etc) as clinically indicated until conversion to hypothyroidism.
  • If patient has PMHx of hypothyroidism and is at risk of hyperthyroid related complications (e.g., cardiac disease [heart failure, coronary artery disease, arrhythmia], age >60 years of age, etc), hold levothyroxine as clinically indicated until euthyroid or conversion to hypothyroidism.
  • For hyperthyroid phase of thyroiditis > 6 weeks or clinical suspicion of Graves’ disease, consider consultation with endocrinology to guide use of additional pharmacologic therapy (e.g., corticosteroids, thionamide antithyroid medication, etc.) and specialized monitoring. 
    
    • If antithyroid or corticosteroids are required, hold ICI until symptom recovery and clinical stability.

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Grade 3 / 4: Obtain information to appropriately grade toxicity, including thyroid function tests (e.g., TSH, free T₄, free T₃), symptoms related to hypo- or hyperthyroidism, and interference with iADL or ADL.

• Hypothyroidism - Severe or life-threatening symptoms; limiting self-care ADL; hospitalization and urgent intervention indicated. 
• Hyperthyroidism / Thyroiditis - Severe or life-threatening symptoms; limiting self-care ADL; hospitalization and urgent intervention indicated.

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Management: 

• Dose delay oral TKI and hold ICI.
  
  • Restart ICI and TKI after conversion to hypothyroidism and thyroid replacement therapy is initiated. Treatment with ICI or TKI does not require discontinuation in most clinical scenarios.

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• Monitor thyroid function tests (TSH, free T₄, free T₃) every 3-6 weeks.
  
  • Rule out central hypothyroidism secondary to hypophysitis (e.g., low TSH, low free T₄). 
  • Consider TSH receptor antibody testing under direction of endocrinology if there is a clinical suspicion of Graves’ disease (e.g., ophthalmopathy, clinical thyrotoxicosis, etc).

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• Hypothyroidism
  
  • If a patient is hospitalized due to hypothyroidism or myxedema (e.g., bradycardia, hypothermia, and altered mental status), consult endocrinology to guide use of additional pharmacotherapy (e.g., IV levothyroxine, corticosteroids, other supportive care) and specialized monitoring. 
  • Follow management as per grade 2 when appropriate to manage patients as an outpatient.

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• Thyrotoxicosis / hyperthyroid phase of thyroiditis
  
  • Hospitalize patients to initiate IV hydration, beta blockers, and other supportive medicines (e.g., propranolol, lorazepam, etc) as clinically indicated for thyrotoxicosis symptoms.
  • Consult endocrinology to guide use of additional pharmacotherapy (e.g., thionamide antithyroid medication, corticosteroids, radioactive iodine, other supportive care), surgery, and specialized monitoring. 
  • If a patient has PMHx of hypothyroidism, hold levothyroxine as clinically indicated until euthyroid or conversion to hypothyroidism.

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Fatigue Management with ICI + TKI Combinations 

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Management Algorithm - Fatigue / Endocrinopathy with ICI + TKI:

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Grade 1: Obtain information to appropriately grade toxicity, including fatigue / asthenia history, onset, pattern, duration, change over time, associated or alleviating factors, and interference with iADL or ADL.

• Fatigue - Fatigue is relieved by rest. 
• Adrenal Insufficiency - Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. 
• Hypophysitis - Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.

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Management: 

• Continue oral TKI and ICI with close monitoring of symptoms. 
  
  • Monitor for new or persistent red flag symptoms of endocrine irAE, including  prolonged and intolerable fatigue / asthenia, unusual headaches, visual disturbances, hypotension, electrolyte changes (e.g., hyponatremia, hypokalemia), mood alteration, anorexia, and nausea / vomiting.

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• Identify reversible, contributing factors and implement supportive care strategies for fatigue / asthenia.
  
  • Maintain adequate diet and fluid intake. Adjust intake of diet and fluids and refer to an oncology dietician as necessary. 
  • Increase activity level, but rest when energy is low. Conserve energy and prioritize daily activities as necessary. 
  • Implement nonpharmacologic sleep hygiene recommendations. If the patient requires pharmacotherapy for insomnia, discuss appropriate options using shared decision making.  
  • Discontinue or change pharmacotherapy contributing to fatigue, asthenia, or insomnia.

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• If symptoms progress to intolerable grade 2, consider trial dose delay of oral TKI and assess endocrine parameters to rule out endocrine irAEs summarized under grade 2 toxicity management.

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Grade 2: Obtain information to appropriately grade toxicity, including fatigue / asthenia history, onset, pattern, duration, change over time, associated or alleviating factors, and interference with iADL or ADL.

• Fatigue - Fatigue not relieved by rest; limiting age-appropriate iADL (e.g., preparing meals, grocery shopping, managing money, using telephone). 
• Adrenal Insufficiency - Moderate symptoms; medical intervention indicated. 
• Hypophysitis - Moderate, minimal, or non-invasive intervention indicated; limiting age-appropriate iADL.

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Management: 

• Identify reversible, contributing factors and implement supportive care strategies for fatigue / asthenia as summarized in grade 1 management.

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• Dose delay oral TKI for a minimum of 2 - 3 days* and monitor for improvement in symptoms. Continue ICI if low suspicion of irAE.
  
  • * = If toxicity is related to TKI, improvement in symptoms may be delayed for TKIs with a longer half life such as lenvatinib (5 x T_1/2 = 5-6 days; recovery may take up to 4 days) and cabozantinib (5 x T_1/2 = 20-21 days; recovery may take up to 14 days). 
  • If fatigue / asthenia improves with dose delay of oral TKI, implement dose reduction or intermittent dosing schedule when re-starting TKI.

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• Monitor for new or persistent red flag symptoms of endocrine irAE during dose delay, including prolonged and intolerable fatigue / asthenia, unusual headaches, visual disturbances, hypotension, electrolyte changes (e.g., hyponatremia, hypokalemia), mood alteration, anorexia, and nausea / vomiting.

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• If intolerable grade 2 fatigue / asthenia is persisting or progressing in severity despite appropriate dose delay of oral TKI, assess blood work for endocrinopathies from ICI, such as hypophysitis, adrenal insufficiency, and thyroid toxicity.
  
  • Endocrinopathy workup may include → AM or random cortisol, adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), free T4, free T3, testosterone, 17-beta-estradiol, prolactin, and insulin-like growth factor-1 (IGF-1).

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• If endocrinopathy from ICI is diagnosed, implement appropriate hormone replacement therapy as outpatient and continue oral TKI and ICI as clinically indicated.
  
  • Consult endocrinology if ongoing follow-up of hormone replacement is required.
  • If grade 2 or higher hypophysitis is diagnosed, ICI should be held until a stable dose of hormone replacement therapy is established.

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Grade 3 / 4: Obtain information to appropriately grade toxicity, including fatigue history, onset, pattern, duration, change over time, associated or alleviating factors, and interference with iADL or ADL.

• Fatigue - Fatigue not relieved by rest; limiting age-appropriate self-care ADL (e.g., bathing, dressing / undressing, feeding self, using toilet, taking medications, ambulating around home). 
• Adrenal Insufficiency - Severe symptoms; hospitalization and urgent intervention indicated.
• Hypophysitis - Severe symptoms (e.g., severe headache, visual disturbance) or severe adrenal insufficiency (e.g., low blood pressure, severe electrolyte disturbance).

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Management: 

• Identify reversible, contributing factors and implement supportive care strategies for fatigue / asthenia as summarized in grade 1 management.

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• Dose delay oral TKI* and hold ICI.
  
  • * = If toxicity is related to TKI, improvement in symptoms may be delayed for TKIs with a longer half life such as lenvatinib (5 x T_1/2 = 5-6 days; recovery may take up to 4 days) and cabozantinib (5 x T_1/2 = 20-21 days; recovery may take up to 14 days). 
  • If fatigue / asthenia improves with dose delay of oral TKI, implement dose reduction or intermittent dosing schedule when re-starting TKI.

‍

• Assess blood work for endocrinopathies from ICI, such as hypophysitis, adrenal insufficiency, and thyroid toxicity.
  
  • Endocrinopathy workup may include → AM or random cortisol, adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), free T4, free T3, testosterone, 17-beta-estradiol, prolactin, and insulin-like growth factor-1 (IGF-1).

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• If endocrinopathy from ICI is diagnosed, implement appropriate hormone replacement therapy and consult endocrinology for ongoing follow-up as clinically indicated.
  
  • Consider hospitalization if a patient has severe symptoms requiring specialized interventions (e.g., monitoring, IV fluid, IV corticosteroids, etc.).

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• Treatment with ICI and oral TKI does not require discontinuation in most clinical scenarios once hormone replacement has been initiated.

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References: 

• BC Cancer - Cancer Drug Manual. Axitinib monograph. Accessed on August 19th, 2024. Available from: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Axitinib_monograph_1March2014.pdf 
• BC Cancer - Cancer Drug Manual. Lenvatinib monograph. Accessed on August 19th, 2024. Available from: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Lenvatinib_monograph.pdf. 
• BC Cancer - Cancer Drug Manual. Cabozantinib monograph. Accessed on August 19th, 2024. Available from: http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Cabozantinib_monograph.pdf. 
• Katsuyama Y, Kawasaki Y, Tanaka K et al. Combination Therapy of Pembrolizumab plus Axitinib for a Patient on Hemodialysis with Metastatic Renal Cell Carcinoma: A Case Report. Case Reports in Oncology. 2022; 14(3): 1522-1529.
• Minami K, Osawa T, Kojima T et al. Efficacy and safety of axitinib for metastatic renal cell carcinoma: Real-world data on patients with renal impairment. Urologic Oncology. 2023; 41(11): 458.e9-458.e19. 
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