What are the guidelines for initiating nivolumab (Opdivo) in adults, including indications, dosing schedule, eligibility criteria, baseline labs, monitoring, and management of immune‑related adverse events?

Nivolumab (Opdivo) Recommendations for Adults

Indications and Patient Selection

Nivolumab is FDA-approved for multiple oncologic indications including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, and other malignancies, with specific patient selection criteria varying by indication. 1

• For metastatic NSCLC in combination with ipilimumab, select patients based on PD-L1 expression using FDA-approved companion diagnostic tests 1
• For melanoma, nivolumab is indicated as monotherapy or in combination with ipilimumab for unresectable or metastatic disease 2
• For microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer in adults and pediatric patients ≥12 years after progression on fluoropyrimidine, oxaliplatin, and irinotecan 1

Dosing Schedules

Monotherapy Dosing

The FDA-approved dosing for nivolumab monotherapy is 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks, administered over 30 minutes. 2, 1

• Historical pivotal trial dosing was 3 mg/kg every 2 weeks, but flat dosing regimens (240 mg Q2W or 480 mg Q4W) are now standard based on pharmacokinetic modeling 2
• For pediatric patients ≥12 years weighing <40 kg: 3 mg/kg every 2 weeks 1
• Continue treatment until disease progression or unacceptable toxicity 1

Combination Dosing with Ipilimumab

For nivolumab plus ipilimumab combination therapy, the NCCN-preferred regimen is nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks (or 480 mg every 4 weeks) as maintenance. 2

• The FDA-approved regimen is nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 doses, then nivolumab maintenance, but this has higher toxicity (55-59% grade 3-4 treatment-related adverse events) 2
• The lower-dose ipilimumab regimen (nivolumab 3 mg/kg + ipilimumab 1 mg/kg) significantly reduces grade 3-5 toxicity to 33% while maintaining efficacy 2
• Administer nivolumab first, followed by ipilimumab on the same day using separate infusion bags 1

Treatment Duration

Continue nivolumab until disease progression, unacceptable toxicity, or completion of protocol-specified duration depending on indication. 1

• For adjuvant melanoma: treat for up to 1 year 1
• For metastatic disease: treat until progression or toxicity; maximum treatment duration in pivotal trials was often 24 months 2
• Responses can persist for years after treatment discontinuation, and 75% of 5-year survivors in NSCLC received no subsequent therapy 3
• Treatment beyond progression may be considered in highly selected patients with clinical benefit, provided no substantial adverse events occur 2

Baseline Laboratory Requirements

Obtain baseline liver enzymes (AST, ALT, total bilirubin, alkaline phosphatase), creatinine, and thyroid function (TSH, free T4) before initiating nivolumab. 1

• Evaluate for active or chronic infections, particularly hepatitis B and C 1
• Obtain complete blood count to assess for baseline cytopenias 4
• Consider morning cortisol and ACTH if fatigue is present to exclude adrenal insufficiency 5

Monitoring During Treatment

Monitor liver enzymes, creatinine, and thyroid function periodically during treatment, with increased frequency if immune-related adverse events develop. 1

• For patients on combination therapy, check AST, ALT, total bilirubin, and alkaline phosphatase every 3-5 days during active hepatitis 6, 5
• Transition to weekly monitoring once liver enzymes are improving 6
• Monitor for clinical manifestations of immune-related adverse events at each visit, including rash, diarrhea, dyspnea, and neurologic symptoms 1

Management of Immune-Related Adverse Events

General Principles

For grade 3-4 immune-related adverse events, immediately discontinue nivolumab (permanently for most grade 4 events) and initiate high-dose corticosteroids (methylprednisolone 1-2 mg/kg/day IV or prednisone equivalent orally). 5, 1

• For grade 2 immune-related adverse events, withhold nivolumab until resolution to grade 0-1, then consider resuming 1
• For grade 1 immune-related adverse events, continue treatment with close monitoring 4
• Permanently discontinue if unable to reduce corticosteroids to ≤10 mg prednisone daily (or equivalent) within 12 weeks of initiating steroids 1

Hepatotoxicity Management

For grade 3-4 hepatotoxicity (AST/ALT >5× ULN or total bilirubin >3× ULN), permanently discontinue nivolumab and ipilimumab, initiate methylprednisolone 1-2 mg/kg/day IV, and monitor liver function tests every 3-5 days. 6, 5, 1

• Rule out alternative causes including viral hepatitis, drug-induced liver injury, and metastatic disease 6
• Consider liver biopsy if diagnosis is uncertain and would alter management 6, 5
• Continue high-dose corticosteroids until liver enzymes improve to grade 1 or baseline 6
• Taper corticosteroids over minimum 4-6 weeks with weekly liver function monitoring during taper 6, 5
• Expected time to resolution is 4-8 weeks with appropriate treatment 6
• For refractory hepatotoxicity (no improvement after 3-5 days), add mycophenolate mofetil or azathioprine in consultation with hepatology 5
• Median time to onset of grade 3-4 hepatic toxicity with nivolumab/ipilimumab is 7.4 weeks (range 2.1-48.0 weeks) 5

Colitis Management

For grade 2 colitis, withhold nivolumab and ipilimumab; for grade 3-4 colitis, permanently discontinue both agents. 1

• Initiate corticosteroids for grade 2 or higher colitis 1
• Resume treatment only after complete or partial resolution to grade 0-1 following corticosteroid taper 1

Pneumonitis Management

For grade 2 pneumonitis, withhold nivolumab and initiate corticosteroids; for grade 3-4 pneumonitis, permanently discontinue nivolumab. 1

• Pneumonitis occurred in 3-4% of patients in pivotal trials 7
• Obtain chest imaging and pulmonary consultation for suspected pneumonitis 1

Endocrinopathies

Monitor for hypothyroidism, hyperthyroidism, adrenal insufficiency, and hypophysitis throughout treatment. 5

• For symptomatic hypothyroidism, initiate thyroid hormone replacement and continue nivolumab 1
• For grade 3-4 endocrinopathies, withhold nivolumab until controlled with hormone replacement 1
• Obtain TSH and free T4 for fatigue; obtain morning cortisol and ACTH to exclude adrenal insufficiency 5

Fever Management

For grade 1 fever (<38.5°C), continue nivolumab with antipyretics as needed; for grade 2 fever (38.5-40°C), withhold nivolumab until resolution and rule out infection. 4

• For grade 3-4 fever (>40°C or with complications), immediately withhold nivolumab, initiate high-dose corticosteroids, and consider hospitalization 4
• Fever may signal onset of serious immune-related adverse events including pneumonitis, nephritis, or encephalitis 4
• Rule out infection with appropriate cultures and imaging before attributing fever to immunotherapy 4

Critical Safety Considerations

The nivolumab plus ipilimumab combination produces immune-related adverse events in approximately 95% of patients, with grade 3-4 toxicity in 55% of cases, substantially higher than ipilimumab monotherapy (10-27% grade 3-4 events). 5

• Immune-related adverse events can occur at any time during treatment or up to one year after discontinuation 5
• Early identification and prompt management with corticosteroids are essential to prevent serious complications 1
• Avoid anti-PD-1/PD-L1 agents in patients with solid organ transplantation due to risk of graft rejection 2
• Use with caution in patients with autoimmune disease after discussion of risks and benefits 2, 4
• Do not reduce nivolumab dose; management relies on withholding or discontinuing treatment and using corticosteroids 1