What are the side effects and adverse effects of nivolumab (Opdivo)?

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Nivolumab Side Effects and Adverse Events

Nivolumab causes immune-related adverse events (irAEs) in 74-85% of patients, with severe (grade 3-4) toxicity occurring in 12-20% when used as monotherapy, and the most common side effects include fatigue, rash, diarrhea, and endocrine dysfunction. 1

Frequency and Severity of Adverse Events

Monotherapy Profile

When nivolumab is used alone, treatment-related adverse events occur in approximately 74-85% of patients, with 12-20% experiencing grade 3-4 toxicity across various cancer types including melanoma, non-small cell lung cancer, and renal cell carcinoma. 1 The incidence varies by indication, with metastatic melanoma showing 74-85% any-grade events and 12-20% severe events, while NSCLC demonstrates 58-69% any-grade and 7-10% severe toxicity. 1

Combination Therapy Risks

Combining nivolumab with ipilimumab dramatically increases toxicity, with 95% of patients experiencing treatment-related adverse events and 55-59% developing grade 3-4 toxicity - more than double the rate seen with nivolumab monotherapy. 2, 1 In the CheckMate 067 trial, 39% of patients receiving combination therapy discontinued treatment due to adverse events, compared to only 12% on nivolumab monotherapy. 2

Most Common Adverse Reactions

General and Constitutional Symptoms

  • Fatigue/asthenia: Occurs in 47-62% of patients (3.5-7% grade 3-4) 1, 3
  • Pyrexia (fever): Affects 16-40% of patients, more common with combination therapy 1
  • Decreased appetite: Reported in 22-51% of patients 1, 3

Gastrointestinal Toxicity

  • Diarrhea: Occurs in 29-54% of patients (2.9-11% grade 3-4) 1, 3
  • Nausea: Affects 22-65% of patients 1, 3
  • Colitis: A serious irAE occurring in approximately 10% of combination therapy patients, leading to treatment discontinuation 3
  • Stomatitis: Seen in 44% of patients receiving nivolumab with chemotherapy 3

Dermatologic Reactions

  • Rash: Develops in 16-53% of patients (0.6-6% grade 3-4), significantly more common with combination therapy 1, 3
  • Pruritus: Affects 11-23% of patients 1, 3
  • Vitiligo: Occurs in 9-11% of patients, particularly in melanoma 3, 4

Endocrine Dysfunction

  • Hypothyroidism: Develops in 7-19% of patients, more frequent with PD-1 inhibitors than PD-L1 inhibitors (6.7% vs 4.2%) 2, 1, 3, 4
  • Hyperthyroidism: Occurs in 6-14% of patients, often preceding hypothyroidism 1, 3
  • Adrenal insufficiency: A serious but less common endocrine toxicity 3

Hepatotoxicity

  • Elevated transaminases (ALT/AST): Occurs in 20-55% of patients (2.1-16% grade 3-4), with combination therapy showing substantially higher rates 1, 3
  • Hepatitis: Develops in 1-5% of patients as an immune-mediated adverse event 1

Pulmonary Toxicity

  • Pneumonitis: Occurs in approximately 4% of patients on PD-1 inhibitors versus 2% on PD-L1 inhibitors, with 1.1% being high-grade 2
  • Cough: Reported in 13-28% of patients 1, 3

Musculoskeletal Effects

  • Musculoskeletal pain: Affects 11-42% of patients 1, 3
  • Myositis/myopathy: Rare but serious, can present with elevated creatine kinase without muscle pain 4

Renal Toxicity

  • Increased creatinine: Occurs in 15-41% of patients (0.7-2.7% grade 3-4) 3
  • Renal insufficiency: Can develop as an immune-mediated adverse event 4

Timing of Adverse Events

irAEs typically occur within weeks to 3 months after initiating treatment, but can develop as late as 1 year after discontinuation. 1 The median time to onset varies by organ system:

  • Skin toxicity: Median 5.6-7.4 weeks 1
  • Gastrointestinal toxicity: Median 12.1-26.3 weeks 1
  • Hepatic toxicity: Median 3.7-7.4 weeks 1
  • Endocrine toxicity: Median 28.6 weeks 1

With combination therapy, grade 3-4 toxicities may develop earlier and over a more prolonged period compared to monotherapy. 1

Serious and Fatal Adverse Events

Serious adverse reactions occur in 21-74% of patients, with higher rates in combination therapy. 2, 5 Fatal irAEs occur in approximately 0.36% of patients receiving anti-PD-1 therapy. 2

The most frequent serious adverse reactions include:

  • Pneumonia (10-13%) 3
  • Diarrhea and colitis (10-13%) 3
  • Pneumonitis (1.9-4.3%) 3

Fatal adverse reactions reported with nivolumab include pneumonitis, myocarditis, hepatitis, neurological disorders (including Guillain-Barré syndrome), and sepsis. 3, 6

Laboratory Abnormalities

Hematologic

  • Lymphopenia: 39-67% (4-23% grade 3-4) 3
  • Anemia: 27-81% (0.8-21% grade 3-4) 3
  • Neutropenia: 13-61% (1.3-18% grade 3-4) 3

Chemistry

  • Hyponatremia: 19-52% (1.7-15% grade 3-4) 3
  • Hyperglycemia: 34-53% (0-5.3% grade 3-4) 3
  • Increased lipase: 32-43% (12-22% grade 3-4) 3

Special Populations and Considerations

Patients with autoimmune disease are at increased risk for worsening of their condition while on immune checkpoint blockade. 1

A critical warning exists for complications of allogeneic hematopoietic stem cell transplantation after nivolumab, including severe or hyperacute graft-versus-host disease and transplant-related mortality. 5

Management Requirements

Approximately 25-72% of patients require systemic corticosteroids for management of irAEs, with 25% requiring additional immunosuppression with infliximab or mycophenolate for steroid-refractory toxicity. 7 Emergency department visits occur in 50% of patients and hospitalizations in 36% related to immune-related adverse events. 7

References

2
Guideline

management of immunotherapy-related toxicities, version 1.2019.

Journal of the National Comprehensive Cancer Network : JNCCN, 2019

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.