What is Nivolumab (Opdivo)?
Nivolumab is a fully human IgG4 monoclonal antibody that blocks the programmed death-1 (PD-1) immune checkpoint receptor, thereby releasing PD-1 pathway-mediated inhibition of the immune response and restoring anti-tumor T-cell activity. 1
Mechanism of Action
Nivolumab binds to the PD-1 receptor on T cells and blocks its interaction with PD-L1 and PD-L2 ligands, which are upregulated on many tumor cells. 1
This blockade prevents the inhibitory signaling that normally suppresses T-cell proliferation and cytokine production, allowing the immune system to recognize and attack cancer cells. 1
In preclinical syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. 1
When combined with ipilimumab (anti-CTLA-4), nivolumab produces enhanced T-cell function greater than either antibody alone, resulting in improved anti-tumor responses. 1
Physical and Pharmaceutical Properties
Nivolumab is an IgG4 kappa immunoglobulin with a calculated molecular mass of 146 kDa, expressed in a recombinant Chinese Hamster Ovary (CHO) cell line. 1
It is supplied as a sterile, preservative-free, clear to opalescent, colorless to pale-yellow liquid that may contain light particles. 1
Each mL contains nivolumab 10 mg, along with mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, with pH adjusted to 6. 1
FDA-Approved Indications
Melanoma
Nivolumab was FDA-approved in 2015 for advanced melanoma after prior anti-angiogenic therapy, and in 2018 in combination with ipilimumab for intermediate- or poor-risk, previously untreated advanced melanoma. 2
For adjuvant treatment, nivolumab is approved for resected nodal or metastatic melanoma, with demonstrated improvement in recurrence-free survival (RFS) compared to ipilimumab. 2
The NCCN Guidelines recommend nivolumab as a category 1 option for patients with stage IIIB/C disease with clinically detected lymph nodes. 2
Renal Cell Carcinoma
Nivolumab was approved as monotherapy for advanced RCC after treatment with a VEGF-targeting agent, based on the CheckMate 025 trial showing overall survival benefit compared with everolimus. 2
The response rate to nivolumab monotherapy was 25% (compared to 5% for everolimus), though most patients did not experience significant tumor shrinkage. 2
In 2018, the combination of nivolumab and ipilimumab was approved for intermediate- and poor-risk, previously untreated patients with advanced RCC. 2
Non-Small Cell Lung Cancer
Nivolumab is approved as monotherapy and in combination with ipilimumab plus platinum-doublet chemotherapy for NSCLC. 2
In patients aged 75 years or older receiving nivolumab with ipilimumab and chemotherapy, there was a higher discontinuation rate due to adverse reactions (43%) compared to all patients (24%). 1
Colorectal Cancer
Nivolumab is recommended as a treatment option for patients with metastatic mismatch repair-deficient (dMMR) CRC in second- or third-line therapy. 2
In the CheckMate-142 trial, nivolumab monotherapy achieved an objective response rate of 31.1% in dMMR CRC patients, with 1-year progression-free survival and overall survival of 50% and 73%, respectively. 2
The combination of nivolumab plus ipilimumab showed higher efficacy with an objective response rate of 55% and 1-year overall survival of 85% in dMMR CRC. 2
Microsatellite instability (MSI) is a predictive marker for effectiveness of nivolumab across tumor types. 2
Other Malignancies
- Nivolumab is also approved for esophageal squamous cell carcinoma, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, and urothelial carcinoma in combination with chemotherapy. 1
Pharmacokinetics
Nivolumab exposure increases dose-proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. 1
Steady-state concentrations are reached by 12 weeks when administered at 3 mg/kg every 2 weeks, with systemic accumulation of 3.7-fold. 1
The geometric mean elimination half-life is 25 days. 1
Age (29-87 years), weight (35-160 kg), sex, race, baseline LDH, PD-L1 expression, tumor type, tumor size, renal impairment (eGFR ≥15 mL/min/1.73 m²), and mild to moderate hepatic impairment have no clinically important effect on nivolumab clearance. 1
Safety Profile
Nivolumab is generally associated with a manageable adverse event profile across multiple cancer types. 3, 4
The most common treatment-related adverse event is fatigue (occurring in 24-35% of patients depending on dose). 4
Grade 3-4 treatment-related adverse events occur in approximately 11-20% of patients receiving nivolumab monotherapy. 4, 2
Immune-related adverse events can occur, including pneumonitis (approximately 3-7% of patients), which is one of the most serious side effects. 2
Vitiligo-like depigmentation can occur as a side effect, representing a CD8+ T-cell dependent destruction of melanocytes, and may correlate with improved survival in melanoma patients. 5