Signs, symptoms, grading, and management

Immune-mediated endocrinopathies

Thyroid icon

Signs and symptoms for all immune-mediated endocrine adverse reactions may include new or worsening1,2

  • Headaches that will not
    go away or unusual
    headaches
  • Extreme tiredness
  • Weight loss or weight gain
  • Dizziness or fainting
  • Eye sensitivity to light
  • Eye problems
  • Rapid heartbeat
  • Increased sweating
  • Changes in mood or behavior,
    such as decreased sex drive,
    irritability, or forgetfulness
  • Feeling more hungry or thirsty
    than usual
  • Urinating more often than usual
  • Feeling cold
  • Constipation
  • Voice gets deeper
  • Hair loss

Management considerations for immune-mediated adrenal insufficiency1,2

GRADES BASED
ON CTCAE V5.03
GRADE 1 GRADE 2 GRADE 3 GRADE 4
Dose modification with
OPDIVO, OPDIVO + YERVOY, or OPDIVO Qvantig
Continue treatment Consider withholding depending on clinical severity until symptom improvement with hormone replacement. Resume treatment once acute symptoms 
have resolved.
Withhold treatment until clinically stable or permanently discontinue depending on severity.
Management - Initiate symptomatic treatment, including hormone replacement as clinically indicated. 
Administer 1 to 2 mg/kg/day prednisone or equivalent until improvement to Grade 1 or less if clinically appropriate. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.
Follow-up -

Consider administration of other systemic immunosuppressants, including corticosteroid therapy, if clinically appropriate.
Treatments received by some patients in the clinical trial:

  • For OPDIVO single agent (n=1994): of the patients with adrenal insufficiency (n=20), ~85% received HRT and 90% required systemic corticosteroids
  • For OPDIVO 1 mg/kg + YERVOY 3 mg/kg (mMel and HCC; n=456): of the patients with adrenal insufficiency (n=35), ~71% received HRT, including systemic corticosteroids
  • For OPDIVO 3 mg/kg + YERVOY 1 mg/kg (aRCC and mCRC; n=666): of the patients with adrenal insufficiency (n=48), ~94% received HRT, including 
    systemic corticosteroids
  • For OPDIVO + CABOMETYX (aRCC; n=320): of the patients with adrenal insufficiency (n=15), ~80% received HRT, including systemic corticosteroids
  • In the clinical study of patients receiving OPDIVO Qvantig, systemic corticosteroids were required in 100% (5/5) of patients with adrenal insufficiency

NCI CTCAE V5.0 GRADING OF IMMUNE-MEDIATED ADRENAL INSUFFICIENCY3

  • GRADE 1:  Asymptomatic; clinical or diagnostic observations only; intervention not indicated
  • GRADE 2:  Moderate; medical intervention indicated
  • GRADE 3:  Severe symptoms; hospitalization indicated
  • GRADE 4:  Life-threatening consequences; urgent intervention indicated

In trials that evaluated OPDIVO as a single agent or in combination with YERVOY, toxicity was graded per NCI CTCAE V4 or V5.1  In a trial that evaluated OPDIVO Qvantig, toxicity was graded per NCI CTCAE V5.2

When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld or discontinued, YERVOY should also be withheld or discontinued.1

aRCC=advanced renal cell carcinoma; HCC=hepatocellular carcinoma; HRT=hormone replacement therapy; mCRC=metastatic colorectal cancer; mMel=metastatic melanoma; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

Management considerations for immune-mediated hypophysitis1,2

GRADES BASED
ON  CTCAE V5.03
GRADE 1 GRADE 2 GRADE 3 GRADE 4
Dose modification with
OPDIVO, OPDIVO + YERVOY, or OPDIVO Qvantig
Continue treatment Consider withholding depending on clinical severity until symptom improvement with hormone replacement. Resume treatment once acute symptoms 
have resolved.
Withhold treatment until clinically stable or permanently discontinue depending on severity.
Management - Initiate hormone replacement as clinically indicated. 
Administer 1 to 2 mg/kg/day prednisone or equivalent until improvement to Grade 1 or less if clinically appropriate. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.
Follow-up -

Consider administration of other systemic immunosuppressants, including corticosteroid therapy, if clinically appropriate.
Treatments received by some patients in the clinical trial:

  • For OPDIVO single agent (n=1994): of the patients with hypophysitis (n=12), 67% received HRT, including systemic corticosteroids
  • For OPDIVO 1 mg/kg + YERVOY 3 mg/kg (mMel and HCC; n=456): of the patients with hypophysitis (n=42), 86% received HRT, and 88% required 
    systemic corticosteroids
  • For OPDIVO 3 mg/kg + YERVOY 1 mg/kg (aRCC and mCRC; n=666): of the patients with hypophysitis (n=29), ~72% received HRT, including systemic corticosteroids
  • Hypophysitis was not observed in the clinical study of patients receiving OPDIVO Qvantig

NCI CTCAE V5.0 GRADING OF IMMUNE-MEDIATED HYPOPHYSITIS3

  • GRADE 1:  Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated
  • GRADE 2:  Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental ADL
  • GRADE 3:  Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of existing hospitalization indicated; limiting self-care ADL
  • GRADE 4:  Life-threatening consequences; urgent intervention indicated

In trials that evaluated OPDIVO as a single agent or in combination with YERVOY, toxicity was graded per NCI CTCAE V4 or V5.1 In a trial that evaluated OPDIVO Qvantig, toxicity was graded per NCI CTCAE V5.2

When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld or discontinued, YERVOY should also be withheld or discontinued.1

ADL=activities of daily living; aRCC=advanced renal cell carcinoma; HCC=hepatocellular carcinoma; HRT=hormone replacement therapy; mCRC=metastatic colorectal cancer; mMel=metastatic melanoma; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

Management considerations for immune-mediated type 1 diabetes mellitus that can present with diabetic ketoacidosis1,2,4

GRADES BASED
ON CTCAE V5.0
FOR HYPERGLYCEMIA3
GRADE 1 GRADE 2 GRADE 3 GRADE 4
Dose modification with OPDIVO, OPDIVO + YERVOY, or OPDIVO Qvantig Continue treatment Consider withholding depending on clinical severity until symptom improvement with hormone replacement. Resume treatment once acute symptoms 
have resolved.
Withhold treatment until clinically stable or permanently discontinue depending on severity.
Management Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated.
- Administer 1 to 2 mg/kg/day prednisone or equivalent until improvement to Grade 1 or less if clinically appropriate. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.
Follow-up - Consider administration of other systemic immunosuppressants, including corticosteroid therapy, if clinically appropriate.
Treatments received by some patients in clinical trials:
  • For OPDIVO single agent (n=1994): of the patients who developed type 1 diabetes (n=17), none required systemic corticosteroids
  • For OPDIVO 3 mg/kg + YERVOY 1 mg/kg (aRCC and mCRC; n=666): of the patients who developed type 1 diabetes (n=15), 7% required systemic corticosteroids
  • In the clinical study of patients receiving OPDIVO Qvantig, systemic corticosteroids were not required

NCI CTCAE V5.0 GRADING OF IMMUNE-MEDIATED HYPERGLYCEMIA3

  • GRADE 1: Abnormal glucose above baseline with no medical intervention
  • GRADE 2: Change in daily management from baseline for a diabetic; oral antiglycemic agent initiated; workup for diabetes
  • GRADE 3: Insulin therapy initiated; hospitalization indicated
  • GRADE 4: Life-threatening consequences; urgent intervention indicated

In trials that evaluated OPDIVO as a single agent or in combination with YERVOY, toxicity was graded per NCI CTCAE V4 or V5.1  In a trial that evaluated OPDIVO Qvantig, toxicity was graded per NCI CTCAE V5.2

When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld or discontinued, YERVOY should also be withheld or discontinued.1

aRCC=advanced renal cell carcinoma; mCRC=metastatic colorectal cancer; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

Management considerations for immune-mediated thyroid disorders1,2.4

GRADES BASED
ON CTCAE V5.03
GRADE 1 GRADE 2 GRADE 3 GRADE 4
Dose modification with
OPDIVO, OPDIVO + YERVOY, or OPDIVO Qvantig
Continue treatment Consider withholding depending on clinical severity until symptom improvement with hormone replacement. Resume treatment once acute symptoms 
have resolved.
Withhold treatment until clinically stable or permanently discontinue depending on severity.
Management - Initiate hormone replacement or medical management as clinically indicated.
Administer 1 to 2 mg/kg/day prednisone or equivalent until improvement to Grade 1 or less if clinically appropriate. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.
Follow-up -

Consider administration of other systemic immunosuppressants, including corticosteroid therapy, if clinically appropriate.
Treatments received by some patients in clinical trials:

  • Of patients with thyroiditis:
    • For OPDIVO single agent (n=12): 17% required systemic corticosteroids
    • For OPDIVO 3 mg/kg + YERVOY 1 mg/kg (n=22): 18% required systemic corticosteroids
  • Of patients with hyperthyroidism:
    • For OPDIVO single agent (n=54): 19% received methimazole, 7% received carbimazole, 4% received propylthiouracil, and 9% required systemic corticosteroids
    • For OPDIVO 1 mg/kg + YERVOY 3 mg/kg (n=42): 26% received methimazole, 21% received carbimazole, and 17% required systemic corticosteroids
    • For OPDIVO 3 mg/kg + YERVOY 1 mg/kg (n=80): 16% received methimazole, 3% received carbimazole, and 20% required systemic corticosteroids
  • Of patients with hypothyroidism:
    • For OPDIVO single agent (n=163): 79% received levothyroxine and 3.1% required systemic corticosteroids
    • For OPDIVO 1 mg/kg + YERVOY 3 mg/kg (n=91): 89% received levothyroxine and 2.2% required systemic corticosteroids
    • For OPDIVO 3 mg/kg + YERVOY 1 mg/kg (n=122): 82% received levothyroxine and 7% required systemic corticosteroids
  • In the clinical study of patients receiving OPDIVO Qvantig, systemic corticosteroids were not required

NCI CTCAE V5.0 GRADING OF IMMUNE-MEDIATED THYDROID DISORDERS3

  • GRADE 1:  Asymptomatic; clinical or diagnostic observations only; intervention not indicated
  • GRADE 2:  Symptomatic; limiting instrumental ADL; hyperthyroidism: thyroid suppression therapy indicated; hypothyroidism: thyroid replacement indicated
  • GRADE 3:  Severe symptoms; limiting self-care ADL; hospitalization indicated
  • GRADE 4:  Life-threatening consequences; urgent intervention indicated

In trials that evaluated OPDIVO as a single agent or in combination with YERVOY, toxicity was graded per NCI CTCAE V4 or V5.In a trial that evaluated OPDIVO Qvantig, toxicity was graded per NCI CTCAE V5.2

When OPDIVO is administered in combination with YERVOY, if OPDIVO is withheld or discontinued, YERVOY should also be withheld or discontinued.1

ADL=activities of daily living; aRCC=advanced renal cell carcinoma; mCRC=metastatic colorectal cancer; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

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Dosing Information

Find the appropriate dosing information for your patients in any approved regimen.

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OPDIVO Dosing Guide

A guide to dosing across all indications.
 

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Patient Monitoring Checklist

A convenient, printable tool to help nurses identify signs and symptoms of immune-mediated adverse reactions. 

References:

  1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
  2. OPDIVO Qvantig [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
  3. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Published November 27, 2017. Accessed July 19, 2024. https://ctep.cancer.gov/protocoldevelopment/‌electronic_applications/docs/CTCAE_v5_ Quick_Reference_8.5x11.pdf.
  4. YERVOY [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.


1506-US-2400610  11/24