Nivolumab is a fully human IgG4 monoclonal antibody that targets the programmed death-1 (PD-1) receptor. By modulating immune checkpoints, nivolumab enhances the body’s antitumor immune response and has transformed the therapeutic landscape for various advanced malignancies.
Mechanism of Action
The PD-1 receptor, expressed on activated T cells, binds its ligands PD-L1 and PD-L2, typically upregulated in tumor microenvironments. This interaction inhibits T-cell activation, allowing tumors to escape immune surveillance.
Nivolumab binds to PD-1, blocking its interaction with PD-L1/PD-L2, thereby:
- Reactivating cytotoxic T lymphocytes,
- Restoring tumor-specific immune responses,
- Promoting antitumor activity.
FDA-Approved Indications (2025)
Nivolumab is approved as monotherapy or in combination therapy for multiple solid and hematologic malignancies:
✅ Approved Indications:
- Melanoma (adjuvant and metastatic)
- Non-small cell lung cancer (NSCLC) (including resectable disease in the neoadjuvant setting)
- Renal cell carcinoma (RCC) (in combination with cabozantinib or ipilimumab)
- Classical Hodgkin lymphoma (relapsed/refractory)
- Esophageal squamous cell carcinoma (advanced and after chemoradiotherapy)
- Gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma
- Hepatocellular carcinoma (in select second-line settings)
- Head and neck squamous cell carcinoma (HNSCC)
- Urothelial carcinoma (in specific settings)
- Colorectal cancer (MSI-H/dMMR subtype)
💡 Emerging Indications (2025):
- Ongoing trials (e.g., CheckMate-77T, -9ER, -816) are expanding use to earlier stages and additional tumor types.
- Investigational use includes triple-negative breast cancer (TNBC) and ovarian cancer.
Dosing and Administration
Adult Dosing Regimens (selective):
| Indication | Dosage | Frequency |
|---|---|---|
| Monotherapy (most settings) | 240 mg IV | Every 2 weeks |
| 480 mg IV | Every 4 weeks | |
| In combination with ipilimumab | 3 mg/kg Nivolumab + 1 mg/kg Ipilimumab | Every 3 weeks for 4 doses |
| Adjuvant settings (e.g., melanoma, lung cancer) | 240–480 mg IV | Every 2–4 weeks up to 1 year |
| Neoadjuvant NSCLC (with chemo) | 360 mg IV | Day 1 of each chemo cycle for 3 cycles |
- Infusion time: Administer IV over 30–60 minutes.
- Pediatric use: Not routinely established outside clinical trials.
🔁 Therapy may be continued until disease progression, unacceptable toxicity, or a maximum of 2 years, depending on clinical context.
Adverse Effects and Toxicity
Immune-related adverse events (irAEs) may affect any organ system due to immune activation. Most AEs are manageable with prompt recognition and corticosteroid treatment.
Common AEs:
- Fatigue
- Diarrhea
- Rash
- Pruritus
- Nausea
- Arthralgia
Severe or Immune-Related AEs (irAEs):
| System | Manifestation |
|---|---|
| Dermatologic | Severe rash, Stevens-Johnson syndrome |
| GI | Colitis, diarrhea, bowel perforation |
| Hepatic | Hepatitis, elevated LFTs |
| Endocrine | Hypophysitis, hypothyroidism, adrenal insufficiency |
| Pulmonary | Pneumonitis |
| Renal | Nephritis |
| Neurologic | Guillain-Barré, myasthenia gravis, encephalitis |
🔍 Patients should be monitored for new or worsening symptoms during and after therapy.
Drug Interactions
Potentially Interacting Agents:
Caution with immunosuppressive agents or drugs that may suppress immune function or increase risk of infection:
- Corticosteroids (avoid unless managing irAEs)
- Immunomodulators: fingolimod, siponimod, ozanimod, leflunomide, baricitinib, filgotinib
- Myelosuppressive agents: clozapine, deferiprone
- Checkpoint inhibitors: caution in combining with other PD-1 or CTLA-4 agents (monitor for additive toxicity)
💡 Drug interaction data are limited due to its non-metabolized mechanism (not CYP450 substrate).
Contraindications
- Known hypersensitivity to nivolumab or excipients
- Active autoimmune disease requiring systemic therapy
- Use during pregnancy or lactation unless benefits outweigh risks
- Live vaccines during therapy
Use in Pregnancy and Lactation
- Pregnancy Category: Risk presumed based on mechanism of action and animal studies.
- Placental transfer has been documented.
- May cause fetal harm or immune activation.
- Breastfeeding: Not recommended during treatment and for 5 months after last dose.
Storage and Handling
- Store between 2°C and 8°C (36°F to 46°F)
- Do not freeze or shake
- Protect from light
- Use diluted solution within 24 hours if stored at room temperature
Clinical Pearls (2025)
- Nivolumab has long-term survival data in melanoma and NSCLC, with 5-year overall survival exceeding 30–40% in some settings.
- Biomarkers like PD-L1 expression, TMB, MSI status, and LAG3 co-expression are increasingly used to stratify response.
- Immunotherapy combinations (e.g., with ipilimumab, chemotherapy, or tyrosine kinase inhibitors) are becoming standard of care in many advanced malignancies.
- Use of neoadjuvant nivolumab is growing, particularly in NSCLC and bladder cancer.
Conclusion
Nivolumab has revolutionized cancer therapy through checkpoint inhibition and restoration of antitumor immunity. With expanding indications, durable responses, and tolerability, it plays a central role in the treatment of multiple malignancies. However, clinicians must be vigilant about immune-related toxicities and patient selection to optimize outcomes.
Key Trials & Guidelines (2024–2025)
- CheckMate-067 (Melanoma)
- CheckMate-9LA, 227, 816 (Lung Cancer)
- CheckMate-214 (RCC)
- NCCN, ASCO, ESMO 2025 Guidelines