Nivolumab is a programmed death receptor-1 (PD-1) blocking monoclonal antibody; it binds with ligands PD-L1 and PD-L2 resulting in immune response inhibition. Nivolumab is indicated for use in adult patients with esophageal cancer, gastric cancer, gastroesophageal junction cancer, head and neck cancer, hepatocellular carcinoma, Hodgkin lymphoma, melanoma, mesothelioma, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, non-small cell lung cancer, renal cell carcinoma, and urothelial carcinoma. In pediatric patients 12 years of age and older, nivolumab is indicated for the treatment of advanced melanoma as a single agent or in combination with ipilimumab, as adjuvant therapy in melanoma following resection, and MSI-H or dMMR metastatic colorectal cancer in combination with ipilimumab. Immune-mediated adverse reactions including colitis, pneumonitis, hepatitis, hypophysitis, nephritis, hypothyroidism/hyperthyroidism, and encephalitis have been reported with nivolumab therapy in clinical trials; treatment with high-dose corticosteroids may be necessary for patients who develop immune-mediated toxicity.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles.
Intravenous Administration
-Nivolumab is available as a clear to slightly opalescent and colorless to pale yellow solution (10 mg/mL) in a single-dose vial; do not shake.
Preparation:
-Withdraw the required volume of drug and transfer into an intravenous container.
-Dilute nivolumab with either 0.9% Sodium Chloride Injection or 5% Dextrose Injection, to prepare an infusion with a final concentration ranging from 1 to 10 mg/mL. The total volume must not exceed 160 mL. For adult and pediatric patients with body weights less than 40 kg, the total volume of infusion must not exceed 4 mL/kg of body weight.
-Mix the diluted solution by gentle inversion. Do not shake.
-Discard partially used or empty vials of nivolumab.
-For combination therapy given on the same day, infuse nivolumab first followed by ipilimumab (followed by platinum-doublet chemotherapy, if applicable) or nivolumab first followed by platinum-doublet chemotherapy.
-Use separate infusion bags and filters for each drug.
-Storage: After preparation, store either at room temperature and room light for no more than 8 hours from the time of preparation to end of the infusion, or under refrigeration (2 to 8 degrees C or 36 to 46 degrees F) and protected from light for no more than 7 days from the time of preparation to end of infusion. Do not freeze.
Intravenous Infusion:
-Administer the diluted infusion over 30 minutes through an intravenous line containing sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 to 1.2 micrometer).
-Do not coadminister with other drugs through the same intravenous line.
-Flush the intravenous line at the end of infusion.
Infection, primarily upper respiratory tract infections, has been reported in 9% to 48% of patients who received nivolumab in clinical trials. Upper respiratory tract infections, generally mild but including some fatalities, occurred in 9% to 23% (grade 3 or 4, 1% or less) of patients treated with nivolumab as monotherapy or in combination with ipilimumab, cabozantinib, mFOLFOX6, or CapeOx including pharyngitis, nasopharyngitis, rhinitis, and sinusitis; at least 2% of patients with head and neck cancer who received nivolumab monotherapy also reported serious upper respiratory tract infections. Upper respiratory tract infection was more common in patients with relapsed or progressive classical Hodgkin lymphoma (44%, grade 3 or 4, 0.8%). Pneumonia occurred in 10% to 13% (grade 3 or 4, 3.8% to 7%) of patients with esophageal cancer, Hodgkin lymphoma, mesothelioma, or NSCLC treated with nivolumab as monotherapy or in combination with ipilimumab; serious cases of pneumonia was reported in 2% or more of patients treated with nivolumab as monotherapy or in combination with ipilimumab, cabozantinib, mFOLFOX6, or CapeOx in several clinical trials. An influenza-like illness occurred in 14% of a small cohort of patients with HCC receiving nivolumab in combination with ipilimumab; influenza occurred in 10% (grade 3 or 4, 2%) of these patients. Nasal congestion was reported in 11% of patients with Hodgkin lymphoma who received nivolumab monotherapy. Urinary tract infection (UTI) occurred in 17% to 22% (grade 3 or 4, 6% to 8%) of patients with urothelial cancer who received nivolumab in clinical trials, including cystitis, pyelonephritis, and urethritis. Serious UTIs occurred in at least 2% of patients with advanced renal cell cancer treated with nivolumab plus cabozantinib. Sepsis occurred in at least 2% of patients with head and neck cancer or urothelial cancer treated with nivolumab.
Cough was reported in 10% to 37% (grade 3 or 4, 0.7% or less) of patients receiving nivolumab either as monotherapy or in combination with ipilimumab, platinum-doublet chemotherapy, cabozantinib, mFOLFOX6, or CapeOx in clinical trials. Dyspnea was additionally reported in 10% to 27% (grade 3 or 4, 4.7% or less) patients receiving nivolumab as monotherapy or in combination with ipilimumab (with or without platinum-doublet chemotherapy) in clinical trials. Dysphonia occurred in 17% (grade 3 or 4, 0.3%) of patients with advanced renal cell cancer treated with nivolumab in combination with cabozantinib in a randomized clinical trial. Respiratory failure occurred in up to 2% of patients treated with nivolumab monotherapy.
Immune-mediated pneumonitis occurred in 3.1% (grade 3 or 4, less than 1%) of patients who received single-agent nivolumab (n = 1,994) and in 9% (grade 3 or 4, 4%; grade 5, 0.7%) of patients who received ipilimumab 1 mg/kg with nivolumab 3 mg/kg combination therapy (n = 576) in clinical trials. The incidence of pneumonitis was higher in patients who had received prior thoracic radiation. Monitor patients for signs and symptoms of pneumonitis. If confirmed, nivolumab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. In clinical studies, all patients who developed pneumonitis following nivolumab therapy received systemic corticosteroids. In patients treated with single-agent nivolumab, pneumonitis resolved in 84% of patients. Of 14 patients who resumed therapy after symptoms improved, 4 patients had a recurrence of pneumonitis. In patients with non-small cell lung cancer who received nivolumab and ipilimumab therapy, pneumonitis resolved in 72% of patients; 2 of 16 patients had a recurrence of pneumonitis after ipilimumab was reinitiated. In individual clinical trials, serious cases of pneumonitis/interstitial lung disease including fatalities occurred in at least 2% of patients treated with nivolumab as monotherapy or in combination with ipilimumab (with and without platinum-doublet chemotherapy), cabozantinib, mFOLFOX6, or CapeOx in various clinical trials. Pneumonitis occurred in 10% (grade 3 or 4, 2%) of patients with hepatocellular cancer receiving nivolumab in combination with ipilimumab 3 mg/kg and in 6% of patients with classical Hodgkin lymphoma who received nivolumab monotherapy.
Immune-mediated musculoskeletal toxicity that was reported in less than 1% of patients who received nivolumab as a single agent or in combination with ipilimumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, and polymyalgia rheumatica; cases may be severe or fatal. Nivolumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Necrotizing myositis was reported in 0.8% of patients with colorectal cancer who nivolumab plus ipilimumab (n = 119) in a nonrandomized, multicohort trial. Musculoskeletal pain occurred in 17% to 42% (grade 3 or 4, 4% or less) of patients who received nivolumab as monotherapy or in combination with other therapies in various clinical trials. Back pain occurred in 21% (grade 3 or 4, 3.4%) of patients with advanced renal cell cancer treated with nivolumab monotherapy (n = 406) in a randomized trial; extremity pain was also reported. Myopathy and myositis/polymyositis were each reported in less than 10% of advanced melanoma patients who received single-agent nivolumab or nivolumab in combination with ipilimumab in a randomized trial. Increased creatine phosphokinase level occurred in 2% of patients with hepatocellular cancer treated with nivolumab plus ipilimumab. Polymyalgia rheumatica and rhabdomyolysis were also each reported in patients with non-small cell lung cancer who received nivolumab in combination with ipilimumab in a randomized trial. The term musculoskeletal pain included terms such as back pain, bone pain, extremity pain, flank pain, joint pain, joint effusion, muscle cramps/spasms, musculoskeletal chest pain/non-cardiac chest pain, musculoskeletal disorder, myalgia, musculoskeletal stiffness, neck pain, osteitis, periarthritis, polymyalgia rheumatica, psoriatic arthropathy, spondylolisthesis, and synovitis.
Electrolyte abnormalities have been reported in patients who received nivolumab in clinical trials, including hyperkalemia (10% to 35%; grade 3 or 4, 5% or less) and hypokalemia (27% or less: grade 3 or 4, 7% or less). Hyponatremia occurred in 13% to 49% of patients receiving nivolumab (grade 3 or 4, 0.6% to 13%); the incidence of severe hyponatremia was higher in patients who received nivolumab in combination with ipilimumab (5% to 32%) compared to those receiving monotherapy or combination therapy with other treatments. Hypocalcemia occurred in 10% to 26% (grade 3 or 4, 1.2% or less) of patients who received nivolumab monotherapy, 16% to 47% of patients treated with nivolumab in combination with ipilimumab, and in 36% to 54% (grade 3 or 4, 1.6% to 2.1%) of patients who received nivolumab in combination with other therapies. Hypomagnesemia occurred in 17% or fewer (grade 3 or 4, less than 1%) patients treated with nivolumab monotherapy, 29% or fewer (grade 3 or 4, 1.2% or less) patients receiving nivolumab in combination with ipilimumab, and in 47% to 48% (grade 3 or 4, 1.3% to 3.9%) of patients treated with nivolumab in combination with cabozantinib or gemcitabine/cisplatin. Additionally, hypercalcemia occurred in 10% to 22% (grade 3 or 4, 6% or less) patients treated with nivolumab monotherapy, hypernatremia in 11% (grade 3 or 4, 0.5%) of patients who received nivolumab in combination with mFOLFOX6 or CapeOx, and hypophosphatemia in 69% (grade 3 or 4, 28%) of patients treated with nivolumab in combination with cabozantinib.
Immune-mediated colitis occurred in 2.9% (grade 3, 1.7%) of patients who received single-agent nivolumab (n = 1,994); 25% (grade 3 or 4, 14.4%) of patients with melanoma or hepatocellular carcinoma (HCC) who received nivolumab 1 mg/kg plus ipilimumab therapy (n = 456); and 9% (grade 3, 4.4%) of patients with renal cell carcinoma or colorectal cancer who received nivolumab 3 mg/kg plus ipilimumab therapy (n = 666) in clinical trials. Additionally, cytomegalovirus (CMV) or CMV reactivation has been reported in patients who had steroid-refractory immune-mediated colitis. Monitor patients for symptoms of colitis. Nivolumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. In patients with steroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In clinical studies, all patients who developed colitis following nivolumab therapy received systemic corticosteroids; 7% to 23% of patients also required the addition of infliximab to high-dose corticosteroids. Resolution of colitis occurred in 86% to 95% of patients; after symptom improvement, colitis recurred in 56% to 75% of patients upon rechallenge. Diarrhea occurred in 17% to 43% (grade 3 or 4, 0.9% to 5%) of patients receiving nivolumab as monotherapy or in combination with cisplatin/gemcitabine, 39% (grade 3 or 4, 5%) of patients receiving nivolumab plus either mFOLFOX6 or CapeOx, 22% to 54% (grade 3 or 4, 1.9% to 11%) of patients receiving nivolumab plus ipilimumab (with or without platinum-doublet chemotherapy), and in 64% (grade 3 or 4, 7%) of patients who received nivolumab plus cabozantinib. The addition of nivolumab to cisplatin and fluorouracil slightly increased the incidence of diarrhea compared to cisplatin and fluorouracil alone in patients with esophageal cancer (29% vs. 20%; grade 3 or 4, 2.9% vs. 2%). The term "diarrhea" included colitis, ulcerative colitis, enteritis, enterocolitis, and gastroenteritis. Diarrhea associated with hypokalemia resulting in death was reported in a patient who received combination therapy with platinum-doublet chemotherapy.
Abdominal pain (34% or less; grade 3 or 4, 6% or less) and constipation (10% to 30%; grade 3 or 4, 0.6% or less) were reported in patients treated with nivolumab as monotherapy or in combination with other therapies. The addition of nivolumab to cisplatin and fluorouracil did not meaningfully increase the incidence of abdominal pain (13% vs. 11%; grade 3 or 4, 1.9% vs. 0.7%) or constipation (44% vs. 43%; grade 3 or 4, 1% vs. 1%) compared with cisplatin and fluorouracil alone in patients with esophageal cancer. GI perforation occurred in less than 10% of patients treated with previously untreated advanced melanoma who were treated with nivolumab in a randomized, double-blind clinical trial.
Immune-mediated gastrointestinal toxicity that was reported in less than 1% of patients who received nivolumab as a single agent or in combination with ipilimumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include gastritis and duodenitis. Nivolumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Gastritis was reported in patients with non-small cell lung cancer who received nivolumab plus ipilimumab (n = 576) in a randomized trial.
Immune-mediated hepatitis occurred in 1.8% (grade 3 or 4, 1.5%) of patients who received single-agent nivolumab (n = 1,994); 15% (grade 3 or 4, 13.4%) of patients with melanoma or hepatocellular carcinoma (HCC) who received nivolumab 1 mg/kg plus ipilimumab therapy (n = 456); and 7% (grade 3 or 4, 6.1%) of patients with renal cell carcinoma or colorectal cancer (n = 666) and 21% (grade 3 or 4, 9%) of patients with metastatic non-small lung cancer (NSCLC) (n = 576) who received nivolumab plus ipilimumab therapy, respectively, in clinical trials. Hepatitis included increased transaminases, autoimmune hepatitis, increased bilirubin levels, hepatic failure, and hepatotoxicity in patients with metastatic NSCLC who received combination therapy. Hepatitis, including cholangitis, occurred in 11% (grade 3 or 4, 4%) of patients receiving adjuvant nivolumab monotherapy for urothelial cancer. Monitor hepatic function at baseline and periodically during treatment. Nivolumab therapy may need to be interrupted or discontinued depending on the severity of hepatitis, if there is tumor involvement of the liver, and if it is used in combination with ipilimumab. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. In clinical studies, all patients who developed hepatitis following nivolumab therapy received systemic corticosteroids; 6% to 19% of patients required the addition of mycophenolic acid to high-dose corticosteroids. Resolution occurred in 88% to 91% of patients; after symptom improvement, 57% to 82% had a recurrence of hepatitis upon rechallenge. Elevated hepatic enzymes including increased ALT (16% to 32%; grade 3 or 4, 1.2% to 5%) and increased AST (24% to 40%; grade 3 or 4, 1.3% to 6%) were reported in patients who received single-agent nivolumab in clinical trials excluding those with HCC. Increased ALT (33% to 55%; grade 3 or 4, 3.4% to 16%) and AST (30% to 52%; grade 3 or 4, 3.5% to 13%) were reported more frequently in patients who received nivolumab plus either ipilimumab or fluoropyrimidine- and platinum-containing chemotherapy in randomized clinical trials, excluding those with HCC. While the overall incidence of transaminitis was similar in patients with HCC treated with nivolumab plus ipilimumab (66%), the incidence of severe (grade 3 or 4) transaminitis was much higher (21% to 40%). The highest incidence of transaminitis was in patients with renal cell cancer treated with nivolumab plus cabozantinib including increased ALT (79%; grade 3 or 4, 9.8%) and increased AST (77%; grade 3 or 4, 7.9%). Grade 3 or 4 increased gamma-glutamyltransferase level occurred in 3.9% of patients with advanced melanoma who received nivolumab in a randomized trial. Increased alkaline phosphatase occurred in 20% to 41% (grade 3 or 4, 0.7% to 6%) of patients treated with nivolumab across clinical trials. Hyperbilirubinemia occurred in 14% or fewer (grade 3 or 4, 4.2% or less) patients who received nivolumab monotherapy, in 21% (grade 3 or 4, 5%) of patients with renal cell cancer treated with nivolumab plus ipilimumab, 24% (grade 3 or 4, 2.8%) of patients with colorectal cancer treated with nivolumab plus either mFOLFOX6 or CapeOx, and in 55% (grade 3 or 4, 11%) of patients with HCC who received nivolumab plus ipilimumab. Hepatotoxicity including increased transaminases, autoimmune hepatitis, hyperbilirubinemia, drug-induced liver injury, and liver failure occurred in 44% (grade 3 or 4, 11%) of patients with advanced renal cell cancer who received nivolumab plus cabozantinib. Cases of fatal hepatotoxicity were also reported in patients with NSCLC who received ipilimumab plus nivolumab in combination with 2 cycles of platinum-doublet chemotherapy (n = 358) in a randomized trial.
Immune-mediated interstitial nephritis and renal dysfunction occurred in 1.2% (grade 3 or 4, 0.5%) of patients who received single-agent nivolumab (n = 1,994) in clinical trials. Monitor renal function at baseline and periodically during treatment. Nivolumab therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. In clinical studies, all patients who developed nephritis following nivolumab therapy received systemic corticosteroids; nephritis resolved in 78% of patients. Of 7 patients who resumed therapy after symptoms improved, 1 patient had a recurrence of nephritis or renal dysfunction. Elevated serum creatinine levels were reported in 12% to 26% (grade 3 or 4, 3.6% or less) of patients in clinical trials who received nivolumab as monotherapy or in combination with ipilimumab (with and without platinum-doublet chemotherapy), mFOLFOX6, or CapeOx, excluding patients with renal cell cancer, urothelial cancer, or esophageal cancer. In patients with urothelial cancer or renal cell cancer who received nivolumab as monotherapy or in combination with other therapies, the incidence of increased creatinine was 36% to 53% (grade 3 or 4, 1.3% to 2.4%). Increased creatinine occurred in 78% (grade 3 or 4, 0.5%) of patients with advanced esophageal cancer treated with nivolumab monotherapy compared with 68% (grade 3 or 4, 0.5%) who received docetaxel or paclitaxel. Renal dysfunction, including acute kidney injury, autoimmune nephritis, immune-mediated nephritis, increased creatinine, renal impairment and renal failure (unspecified), was reported in 14% to 17% (grade 3 or 4, 1.7% to 6%) of urothelial cancer patients receiving adjuvant nivolumab as monotherapy, or in combination with gemcitabine/cisplatin for advanced disease. Renal failure and acute kidney injury were reported in patients with NSCLC who received nivolumab plus ipilimumab with or without platinum-doublet therapy; some cases were fatal.
Nivolumab can cause immune-mediated thyroid disorders. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement or other medical management (e.g., anti-thyroid agents) as clinically indicated. Nivolumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary. Immune-mediated hypothyroidism occurred in 8% (grade 3, 0.2%) of patients who received single-agent nivolumab (n = 1,994); 20% (grade 3, 0.4%) of patients with melanoma or hepatocellular carcinoma (HCC) who received nivolumab 1 mg/kg plus ipilimumab therapy (n = 456); and 18% (grade 3, 0.6%) of patients with renal cell carcinoma (RCC) or colorectal cancer (CRC) who received nivolumab 3 mg/kg plus ipilimumab therapy (n = 666) in clinical trials. Immune-mediated hyperthyroidism occurred in 2.7% (grade 3, less than 0.1%), 9% (grade 3, 0.9%), and 12% (grade 3, 0.6%) of these patients, respectively. Additionally, immune-mediated hypoparathyroidism was reported in less than 1% of patients who received nivolumab as a single agent or in combination with ipilimumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies. Of patients who developed hypothyroidism, 79% to 89% received levothyroxine and 2.2% to 7% received systemic corticosteroids; hypothyroidism resolved in 27% to 41% of patients. Of patients who developed hyperthyroidism, 19% to 47% received an anti-thyroid agent and 9% to 20% received systemic corticosteroids; hypothyroidism resolved in 76% to 91% of patients. Thyroiditis occurred in 0.6% of patients who received single-agent nivolumab; 17% of patients required systemic corticosteroids and thyroiditis resolved in 58% of patients. Thyroiditis may present with or without endocrinopathy. In other clinical studies, hypothyroidism including thyroiditis (5% to 20%; grade 3 or 4, 0.6% or less) and hyperthyroidism (11% or less; grade 3 or 4, 1.3% or less) were reported with nivolumab as monotherapy and as a part of combination therapy with both ipilimumab and gemcitabine/cisplatin; hypothyroidism was more common when nivolumab was administered in combination with cabozantinib (34%; grade 3 or 4, 0.3%). Thyroid disorders including hypothyroidism and hyperthyroidism were reported in 15% of patients with urothelial carcinoma who received nivolumab in a single-arm trial (n = 270).
Immune-mediated pancreatitis and increases in serum amylase levels/hyperamylasemia and lipase levels were reported in less than 1% of patients who received nivolumab as a single agent or in combination with ipilimumab, or may have occurred with the use of other PD-1/PD-L1 blocking antibodies; cases may be severe or fatal. Nivolumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. An increase from baseline in amylase generally occurred in 13% to 18% of patients treated with nivolumab monotherapy (grade 3 or 4, 0.4% to 4.8%), with the exception of one outlier trial where 34% of urothelial cancer patients treated with nivolumab monotherapy experienced increased amylase (grade 3 or 4, 3.9%); the incidence was similar in patients who were treated with nivolumab in combination with FOLFOX6 and CapeOx (12%; grade 3 or 4, 3.1%). The incidence was higher in patients who received nivolumab in combination with ipilimumab or other therapies (23% to 41%; grade 3 or 4, 3.4% to 15%). An increase from baseline in lipase was reported in 14% to 33% of patients treated with nivolumab as monotherapy or in combination with FOLFOX6 or CapeOx (grade 3 or 4, 2.9% to 19%); similar to amylase levels, increases in lipase were more common in patients who received nivolumab in combination with ipilimumab or other therapies (31% to 51%; grade 3 or 4, 12% to 26%). Pancreatitis was reported in patients with non-small cell lung cancer who received nivolumab plus ipilimumab (n = 576) in a randomized trial.
Immune-mediated ocular toxicity that was reported in less than 1% of patients who received nivolumab as a single agent or in combination with ipilimumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include uveitis, iritis, and other ocular inflammation toxicity; some cases may be associated with retinal detachment. Nivolumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Patients may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss. Visual impairment including vision loss/blindness may occur. In postmarketing surveillance, Vogt-Koyanagi-Harada syndrome was reported in patients who received nivolumab or nivolumab in combination with ipilimumab. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a diagnosis of Vogt-Koyanagi-Harada-like syndrome. Iridocyclitis was reported in less than 10% of patients with melanoma who received nivolumab (n = 268) in a randomized trial. Blurred vision and uveitis occurred in patients with metastatic non-small cell lung cancer treated with nivolumab plus ipilimumab in a randomized clinical trial. Uveitis was reported in 0.8% of patients with colorectal cancer who nivolumab plus ipilimumab (n = 119) in a nonrandomized, multicohort trial.
Immune-mediated neurotoxicity that was reported in less than 1% of patients who received nivolumab as a single agent or in combination with ipilimumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, and autoimmune neuropathy; cases may be severe or fatal. Nivolumab therapy may need to be interrupted or discontinued in patients who develop grade 2 or higher neurotoxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. Encephalitis was reported in 0.8% of patients with colorectal cancer who nivolumab plus ipilimumab (n = 119) in a nonrandomized, multicohort trial. Autoimmune encephalitis also occurred in patients with non-small cell lung cancer (NSCLC) who received nivolumab plus ipilimumab (n = 576) in another randomized trial. Death due to limbic encephalitis was reported in 1 patient with NSCLC who received nivolumab monotherapy. Fatal encephalitis also occurred following treatment with nivolumab plus ipilimumab in patients with mesothelioma. Neuritis, peroneal nerve palsy, and sensory or peripheral neuropathy were each reported in less than 10% of patients with melanoma who received nivolumab as a single agent or in combination with ipilimumab in randomized trials. Peripheral neuropathy (e.g., hyperesthesia, hypoesthesia, paresthesias, dysesthesia, motor and sensory peripheral neuropathy, and polyneuropathy) was reported in 12% or fewer (grade 3 or 4, less than 1%) patients treated with nivolumab monotherapy in 2 clinical trials (n = 472) and in 53% (grade 3 or 4, 7%) of patients who received nivolumab in combination with mFOLFOX6 or CapeOx in another clinical trial (n = 782); peripheral neuropathy was also reported in patients with renal cell cancer receiving nivolumab monotherapy and in patients with NSCLC treated with nivolumab in combination with ipilimumab. The addition of nivolumab to gemcitabine and cisplatin increased the incidence of peripheral neuropathy compared with gemcitabine/cisplatin alone (20% vs. 14%; grade 3 or 4, 0.7% vs. 0%).
Immune-mediated type 1 diabetes mellitus occurred in 0.9% (grade 3, 0.4%) of patients who received single-agent nivolumab (n = 1,994) in clinical trials; diabetic ketoacidosis (DKA) occurred in 2 patients. No patients who developed diabetes required systemic corticosteroids; diabetes resolved in 29% of patients. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Withhold nivolumab therapy for cases of severe hyperglycemia until blood sugar control is achieved; administer insulin as clinically indicated. In individual trials, hyperglycemia occurred over a wide range of patients who received nivolumab as monotherapy or in combination with other therapies.
Primary or secondary adrenocortical insufficiency and immune-mediated hypophysitis have been reported with nivolumab therapy. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Nivolumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary. Adrenal insufficiency occurred in 1% (grade 3, 0.4%) of patients who received single-agent nivolumab (n = 1,994); 8% (grade 3 or 4, 2.6%) of patients with melanoma or hepatocellular carcinoma who received nivolumab 1 mg/kg plus ipilimumab therapy (n = 456); 7% (grade 3, 2.8%) of patients with renal cell carcinoma (RCC) or colorectal cancer who received nivolumab 3 mg/kg plus ipilimumab therapy (n = 666), and in 4.7% (grade 3, 2.2%) of patients with RCC who received nivolumab plus cabozantinib (n = 320) in clinical trials. Immune-mediated hypophysitis occurred in 0.6% (grade 3, 0.2%), 9% (grade 3, 2.4%), and 4.4% (grade 3 or 4, 2.7%) of these patients, respectively. Of patients who developed adrenal insufficiency, 71% to 94% received hormone replacement therapy including systemic corticosteroids; adrenal insufficiency resolved in 29% to 37% of patients. Of patients who developed hypophysitis, 67% to 86% received hormone replacement therapy and 67% to 88% received systemic corticosteroids; hypophysitis resolved in 38% to 59% of patients. Hypophysitis can present with acute symptoms associated with mass effect such as photophobia or visual field defects; hypophysitis can cause hypopituitarism. Adrenal insufficiency and hypophysitis were among the most serious adverse reactions in patients with RCC or non-small cell lung cancer treated with nivolumab in combination with ipilimumab, occurring in at least 2% of patients.
Immune-mediated rash occurred in 9% (grade 3, 1.1%) of patients who received single-agent nivolumab (n = 1,994); 28% (grade 3, 4.8%) of patients with melanoma or hepatocellular carcinoma who received nivolumab 1 mg/kg plus ipilimumab therapy (n = 456); and 16% (grade 3, 3.5%) of patients with renal cell carcinoma or colorectal cancer who received nivolumab 3 mg/kg plus ipilimumab therapy (n = 666) in clinical trials. Monitor patients for suspected severe skin reactions including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms; exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Nivolumab therapy may need to be interrupted or discontinued depending on the severity of rash; treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary. In clinical studies, all patients who developed rash following nivolumab therapy received systemic corticosteroids. Overall, resolution of rash occurred in 72% to 84% of patients. Rash was reported in 16% to 40% (grade 3 or 4, 0.4% to 2.3%) of patients treated with nivolumab monotherapy, in combination with ipilimumab 1 mg/kg, or in combination with other therapies; the incidence increased when nivolumab was administered in combination with ipilimumab 3 mg/kg (53%; grade 3 or 4, 6% to 8%). Pruritus occurred in 10% to 33% (grade 3 or 4, 1% or less) of patients treated with nivolumab monotherapy, in combination with ipilimumab 1 mg/kg, or in combination with other therapies, and in up to 53% (grade 3 or 4, 4% or less) of patients who received nivolumab plus ipilimumab 3 mg/kg. Xerosis occurred in 7% of patients with metastatic colorectal cancer treated with nivolumab monotherapy compared with 11% of those who received nivolumab in combination with ipilimumab 1 mg/kg in a multicenter, multicohort, open-label trial. Vitiligo (skin hypopigmentation) occurred in 11% or fewer patients who received nivolumab as monotherapy or in combination with ipilimumab. In 2 trials of patients with metastatic melanoma, erythema (10%), exfoliative dermatitis (less than 10%), erythema multiforme (less than 10%), and psoriasis (less than 10%) were reported. Palmar-plantar erythrodysesthesia (hand and foot syndrome) occurred in 13% (grade 3 or 4, 1.5%) of patients treated with nivolumab plus mFOLFOX6 or CapeOx and in 40% (grade 3 or 4, 8%) of patients who received nivolumab in combination with cabozantinib. Urticaria, erythema multiforme, and vitiligo were reported in non-small cell lung cancer patients receiving combination therapy. In clinical studies, the term rash included acneiform rash, allergic/atopic dermatitis, blister, bullous rash, erythema, erythema multiforme, erythematous rash, palmar-plantar erythrodysesthesia (hand and foot syndrome), exfoliative dermatitis, folliculitis, maculopapular rash, morbilliform rash, papulosquamous rash, pruritic rash, psoriasiform dermatitis, pustular rash, seborrheic dermatitis, eczema, keratoderma blenorrhagica, popular rash, SJS, urticaria, and vesicular rash.
Various forms of edema (e.g., facial edema, generalized edema, gravitational edema, localized edema, lymphedema, periorbital edema, peripheral edema, peripheral swelling, and pulmonary edema) have been reported in grouped terms in 7% to 18% (grade 3 or 4, 2% or less) of patients who received nivolumab, either as monotherapy or in combination with other therapies in clinical trials. Peripheral edema was separately reported in 10% of patients with metastatic melanoma treated with nivolumab monotherapy in 1 clinical trial.
Ventricular tachycardia/arrhythmia occurred in less than 10% of patients with previously treated advanced melanoma who received nivolumab (n = 268) in a randomized trial; adverse reactions occurring in nivolumab-treated patients with head and neck cancer (n = 236) were generally similar to those occurring in patients with melanoma and NSCLC.
Infusion-related reactions occurred in 6.4% of patients receiving nivolumab monotherapy across clinical trials (n = 1,994); the incidence was higher (14%; grade 3 or 4, less than 1%) in a pooled analysis from 2 nonrandomized clinical studies of patients with relapsed or progressive Hodgkin lymphoma who received nivolumab monotherapy (n = 266). Infusion-related reactions were reported in 2.5% to 12% of patients who received nivolumab in combination with ipilimumab in clinical trials; severe infusion-related reactions occurred in less than 1% of patients. Infusion reactions occurred in a similar percentage of patients receiving a 60-minute infusion of nivolumab (n = 368; 2.2%) compared with a 30-minute infusion of nivolumab (n = 369; 2.7%) in a pharmacokinetic and safety study; additionally, 0.5% and 1.4% of patients, respectively, experienced adverse reactions within 48 hours of infusion leading to dose delays, interruption of therapy, or permanent discontinuation of therapy. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions; discontinue nivolumab in patients who develop severe or life-threatening infusion reactions.
Antibody formation was reported in 11% of patients who received single-agent nivolumab (n = 2,085) in clinical trials. When nivolumab was given in combination with ipilimumab, anti-nivolumab antibodies developed in 26% to 56% of patients. Neutralizing antibodies occurred in 2.9% to 41% of patients who developed anti-nivolumab antibodies. There was no evidence of a clinically significant effect on the incidence of infusion-related reactions.
Fever was reported in 10% to 29% (grade 3 or 4, 1% or less) of patients treated with nivolumab monotherapy or in combination with FOLFOX 6, CapeOx, or gemcitabine/cisplatin. Fever occurred with a slightly higher frequency in patients receiving combination therapy with ipilimumab (14% to 40%; grade 3 or 4, 1.6% or less).
Dehydration (2% or more) was among the most frequent serious adverse reactions reported with nivolumab therapy (either alone (n = 319) or in combination with ipilimumab (n = 119)) in two cohorts of patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in separate clinical trials.
Fatigue, asthenia, or malaise occurred in 18% to 62% (grade 3 or 4, 0.4% to 8%) of patients who received nivolumab in clinical trials; in individual studies, the terms were often grouped together for reporting purposes. The combined term of fatigue/asthenia was reported in 12% to 62% (grade 3 or 4, 0.4% to 8%) of patients treated with nivolumab monotherapy or in combination with other therapies in various clinical trials. Fatigue/asthenia/malaise was reported in 46% to 58% (grade 3 or 4, 6% to 8%), fatigue in 27% to 49% (grade 3 or 4, 1.9% to 3.2%), and malaise in 6.5% to 18% (grade 3 or 4, 2% or less) of patients who received nivolumab as monotherapy or in combination with ipilimumab.
In a randomized, clinical trial of patients with advanced renal cell carcinoma (n = 406), nivolumab monotherapy was associated with a lower incidence of hypertriglyceridemia (all grade, 32% vs. 67%; grade 3 or 4, 2% vs. 11%) and hypercholesterolemia (all grade, 21% vs. 55%; grade 3 or 4, 0.3% vs. 1%) than monotherapy with everolimus compared to baseline.
Fatal and serious adverse events occurred in patients who received an allogeneic stem-cell transplant (SCT) prior to and after treatment with a PD-1/PD-L1 blocking antibody, such as nivolumab. Monitor patients closely for evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause); treat adverse events promptly. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Of 17 patients with classical Hodgkin lymphoma who received an allogeneic SCT after treatment with nivolumab in 2 clinical trials, hyperacute GVHD occurred in 2 patients (12%), grade 3 or higher GVHD was reported in 5 patients (29%), and sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) occurred in 1 patient (6%) who received reduced-intensity conditioned allogeneic SCT and died of GVHD and multi-organ failure. Additionally, 6 patients died resulting from complications from an allogeneic SCT; 5 of these deaths were due to severe or refractory GVHD. In postmarketing surveillance, treatment refractory, severe acute and chronic GVHD have been reported in patients who received nivolumab after an allogeneic HSCT.
Immune-mediated cardiovascular toxicity that was reported in less than 1% of patients who received nivolumab as a single agent or in combination with ipilimumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include myocarditis, pericarditis, and vasculitis; cases may be severe or fatal. Nivolumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary.
Insomnia was reported in 9% to 18% of patients treated with nivolumab monotherapy or in combination with ipilimumab in 3 small clinical trials.
Hypertension was reported in patients with unresectable or metastatic melanoma who received nivolumab as a single agent (11%; grade 3 or 4, 5%) and nivolumab in combination with ipilimumab (7%; grade 3 or 4, 2.2%) in a randomized clinical study. Hypertension was also reported in 36% (grade 3 or 4, 13%) of patients with advanced renal cell cancer treated with nivolumab plus cabozantinib. In a small cohort of patients with hepatocellular cancer in another trial, hypotension occurred in 10% of patients receiving combination therapy with ipilimumab.
Decreased appetite/anorexia was reported in 13% to 35% (grade 3 or 4, 0.9% to 4%) of patients treated with nivolumab monotherapy or in combination with other therapies in various clinical trials. Weight loss occurred in 11% to 20% (grade 3 or 4, 1.9% or less) of patients receiving nivolumab as monotherapy or in combination with other therapies in 4 clinical trials. Dysgeusia occurred in 24% of patients who received nivolumab plus cabozantinib. The addition of nivolumab to cisplatin and fluorouracil did not meaningfully increase the incidence of decreased appetite (51% vs. 50%; grade 3 or 4, 7% vs. 6%) or weight loss (12% vs. 11%; grade 3 or 4, 0.6% vs. 1%) compared to cisplatin and fluorouracil alone in patients with esophageal cancer.
Nausea occurred in 11% to 34% (grade 3 or 4, 1.4% or less) and vomiting in 12% to 28% (grade 3 or 4, 4.1% or less) of patients treated with nivolumab monotherapy or in combination with cabozantinib in various clinical trials. The incidence of nausea (20% to 48%; grade 3 or 4, 3.8% or less) and vomiting (11% to 31%; grade 3 or 4, 4.2% or less) was slightly higher in patients treated with nivolumab plus ipilimumab, mFOLFOX6, or CapeOx. The addition of nivolumab to cisplatin and fluorouracil slightly increased the incidence of nausea (65% vs. 56%; grade 3 or 4, 4.2% vs. 2.6%) and vomiting (23% vs. 19%; grade 3 or 4, 2.3% vs. 3%) compared to cisplatin and fluorouracil alone. Dyspepsia including gastroesophageal reflux occurred in 12% to 15% (grade 3 or 4, 2% or less) of patients treated with nivolumab monotherapy or in combination with ipilimumab or cabozantinib in 3 clinical trials. Stomatitis occurred in less than 10% of monotherapy patients, in 10% to 11% (grade 3 or 4, 0.6% or less) of patients treated with nivolumab plus ipilimumab in 2 trials, in 17% (grade 3 or 4, 1.8%) of those who received nivolumab plus mFOLFOX6 or CapeOx (including oral ulceration), and in 37% (grade 3 or 4, 3.4%) of patients who received nivolumab plus cabozantinib in separate trials. The addition of nivolumab to cisplatin and fluorouracil increased the incidence of stomatitis compared to cisplatin and fluorouracil alone in patients with esophageal cancer in a randomized clinical trial (44% vs. 35%; grade 3 or 4, 9% vs. 3%). Xerostomia was also reported in 12% of patients with hepatocellular cancer receiving nivolumab in combination with ipilimumab in a small cohort. Dysphagia was reported in 13% (grade 3 or 4, 0.8%) of patients with esophageal or gastroesophageal junction cancer receiving adjuvant nivolumab monotherapy after neoadjuvant chemoradiotherapy. Additionally, dysphagia occurred in 12% of esophageal cancer patients treated with nivolumab plus ipilimumab (grade 3 or 4, 5%), 12% (grade 3 or 4, 4.9%) in patients treated with cisplatin and fluorouracil, and 14% (grade 3 or 4, 7%) in patients treated with nivolumab, cisplatin, and fluorouracil.
Ascites occurred in 14% (grade 3 or 4, 6%) of a small cohort of patients with hepatocellular cancer treated with nivolumab monotherapy or in combination with ipilimumab in a clinical trial.
Headache occurred in 11% to 23% (grade 3 or 4, 1.7% or less) of patients receiving nivolumab as monotherapy or in combination with other therapies; migraine has also been reported with nivolumab monotherapy. Dizziness/vertigo was reported in 20% of patients or less (grade 3 or 4, 0.6% or less).
Chills were reported in 10% of patients treated with nivolumab in combination with ipilimumab in a small cohort of patients with hepatocellular cancer in 1 clinical trial.
Arthralgia was reported in 10% to 23% (grade 3 or 4, 1.3% or less) of patients who received nivolumab as monotherapy or in combination with ipilimumab or cabozantinib across clinical trials. Sjogren's syndrome and spondylo-arthropathy were each reported in less than 10% of advanced melanoma patients who received single-agent nivolumab or nivolumab in combination with ipilimumab in a separate randomized, double-blind trial. Arthritis was reported in patients with non-small cell lung cancer who received nivolumab in combination with ipilimumab in a randomized trial.
Alopecia occurred in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab in combination with ipilimumab in a randomized clinical trial. Alopecia (11%; grade 3 or 4, 0.8%) occurred in patients who received ipilimumab plus nivolumab in combination with platinum-doublet chemotherapy.
Atrial fibrillation was reported in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab plus ipilimumab in a randomized clinical trial.
Pleural effusion occurred in 1% to 4.5% of patients who received nivolumab monotherapy in clinical trials. Pleural effusion was also reported in at least 2% of patients with mesothelioma treated with nivolumab in combination with ipilimumab in a randomized clinical trial.
Pulmonary embolism occurred in 2% to 3.3% of patients who received nivolumab monotherapy in clinical trials; four NSCLC patients receiving nivolumab monotherapy had a fatal pulmonary embolism. Pulmonary embolism occurred in at least 2% of patients treated with nivolumab plus either ipilimumab or cabozantinib in 3 randomized clinical trials. Additionally, fatal pulmonary embolism (0.5%) and sudden death (0.5%) occurred in patients with esophageal cancer who received nivolumab monotherapy (n = 209) in a randomized trial.
Massive hemoptysis in the setting of thrombocytopenia resulting in death occurred in a patient with NSCLC who received ipilimumab plus nivolumab in combination with 2 cycles of platinum-doublet chemotherapy (n = 358) in a randomized trial.
Hypoglycemia occurred in 12% to 26% (grade 3 or 4, 0.7% to 1.4%) of patients who received nivolumab as monotherapy or in combination with cabozantinib, mFOLFOX6, or CapeOx in 3 randomized trials. In a pooled analysis from 2 nonrandomized clinical studies, fasting hypoglycemia occurred in 16% of evaluable nivolumab-treated patients (n = 69) with relapsed or progressive Hodgkin lymphoma.
Fatal esophageal/tracheoesophageal fistula (0.5%) and GI bleeding (0.5%) occurred in patients with esophageal cancer who received nivolumab monotherapy (n = 209) in a randomized trial.
Anemia occurred in 13% to 52% (grade 3 or 4, 8% or less) of patients who received nivolumab monotherapy across clinical trials, and in 37% to 50% (grade 3 or 4, 2.4% to 9%) of patients treated with nivolumab plus either ipilimumab or cabozantinib. Anemia occurred more often in patients with NSCLC who received nivolumab plus platinum-doublet chemotherapy (70% to 88%; grade 3 or 4, 9% to 21%) or nivolumab in combination with mFOLFOX6 or CapeOx (59%; grade 3 or 4, 14%). Immune-mediated hematologic toxicity that was reported in less than 1% of patients who received nivolumab as a single agent or in combination with ipilimumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include hemolytic anemia and aplastic anemia; cases may be severe or fatal. Nivolumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary.
Leukopenia occurred in 11% to 38% (grade 3 or 4, 10% or less) of patients who received nivolumab monotherapy across clinical trials, in 40% or fewer (grade 3 or 4, 2.1% or less) patients treated with nivolumab plus ipilimumab, in 36% (grade 3 or 4, 10%) of patients who received nivolumab plus ipilimumab and platinum-doublet chemotherapy, in 37% (grade 3 or 4, 0.3%) of patients who received nivolumab plus cabozantinib, and in 69% (grade 3 or 4, 12%) of patients treated with nivolumab in combination with either mFOLFOX6 or CapeOx. Neutropenia occurred in 37% or fewer (grade 3 or 4, 5% or less) patients who received nivolumab monotherapy across clinical trials, in 43% or fewer (grade 3 or 4, 9% or less) patients treated with nivolumab plus ipilimumab, in 40% (grade 3 or 4, 15%) of patients who received nivolumab plus ipilimumab and platinum-doublet chemotherapy, in 35% (grade 3 or 4, 3.2%) of patients who received nivolumab plus cabozantinib, and in 73% (grade 3 or 4, 29%) of patients treated with nivolumab in combination with either mFOLFOX6 or CapeOx. The addition of nivolumab to cisplatin and gemcitabine increased the incidence of neutropenia (82% vs. 76%; grade 3 or 4, 35% vs. 28%) compared with cisplatin/gemcitabine alone. Eosinophilia was also reported in patients with NSCLC treated with nivolumab in combination with ipilimumab.
Lymphopenia occurred in 17% to 59% (grade 3 or 4, 0.4% to 19%) of patients who received nivolumab as monotherapy or in combination with ipilimumab (with and without platinum-doublet chemotherapy), cabozantinib, mFOLFOX6, or CapeOx across clinical trials. The addition of nivolumab to cisplatin and gemcitabine increased the incidence of lymphopenia (71% vs. 56%; grade 3 or 4, 17% vs. 13%) compared with cisplatin/gemcitabine alone.
Thrombocytopenia occurred in 13% to 37% (grade 3 or 4, 1.4% to 7%) of patients who received nivolumab monotherapy across clinical trials, and 34% or fewer patients treated with nivolumab plus ipilimumab (grade 3 or 4, 4.3% or less). Thrombocytopenia occurred with about the same frequency in patients with NSCLC who received ipilimumab plus nivolumab in combination with 2 cycles of platinum-doublet chemotherapy (n = 358) in a randomized trial (23%; grade 3 or 4, 4.3%). The incidence of thrombocytopenia when nivolumab was administered in combination with cabozantinib was similar to nivolumab monotherapy (41%; grade 3 or 4, 0.3%). The addition of nivolumab to cisplatin and gemcitabine increased the incidence of thrombocytopenia (60% vs. 51%; grade 3 or 4, 13% vs. 8%) compared with cisplatin/gemcitabine alone. Thrombocytopenia occurred in 68% (grade 3 or 4, 7%) of those who received nivolumab plus mFOLFOX6 or CapeOx.
Immune-mediated toxicity that was reported in less than 1% of patients who received nivolumab as a single agent or in combination with ipilimumab or that occurred with the use of other PD-1/PD-L1 blocking antibodies include hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, and other transplant rejection including corneal graft rejection; cases may be severe or fatal. Nivolumab therapy may need to be interrupted or discontinued in patients who develop immune-mediated toxicity, depending on the severity of the reaction. Treatment with systemic corticosteroids and other systemic immunosuppressants may be necessary.
Hypoalbuminemia occurred in 14% (grade 3 or 4, 0.3%) of patients treated with nivolumab in combination with mFOLFOX6 or CapeOx in a randomized clinical trial. Increased albumin concentrations occurred in 21% (grade 3 or 4, 0.2%) of patients with esophageal or gastroesophageal junction cancer who received adjuvant nivolumab after neoadjuvant chemoradiotherapy in one clinical trial.
In patients with hepatocellular cancer treated with nivolumab plus ipilimumab, virologic breakthrough defined as at least a 1 log increase in hepatitis B (HBV) or hepatitis C (HCV) DNA occurred in 14% of patients with active HBV (hepatitis B exacerbation; n = 28) and in 50% of patients with active HCV (hepatitis C exacerbation; n = 4) at baseline.
Hematuria occurred in 11% of patients with unresectable or metastatic urothelial cancer treated with nivolumab plus gemcitabine and cisplatin compared with 7% of those receiving gemcitabine/cisplatin alone in a randomized clinical trial (grade 3 or 4, 1% vs. 1.4%).
Immune-mediated reactions, which may be severe or fatal, can occur in patients treated with drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), thus removing inhibition of the immune response, such as nivolumab. These immune-mediated reactions can occur in any organ system or tissue and can also affect more than one body system simultaneously. Although usually occurring during treatment with PD-1/PD-L1 inhibitors, immune-mediated reactions can occur at any time after starting therapy including after discontinuation of therapy. Because early identification and management is critical to safe usage of PD-1/PD-L1 inhibitors, closely monitor patients for signs and symptoms that may be clinical manifestations of underlying immune-mediated reactions. Initiate an appropriate workup to exclude alternative etiologies including infection in cases of suspected immune-mediated reaction. Begin medical management promptly, including specialty consultation as appropriate. An interruption or discontinuation of nivolumab therapy may be necessary, depending on the severity of the reaction. In general, if an interruption or discontinuation of therapy is necessary, administer systemic corticosteroids (1 to 2 mg/kg per day of prednisone or equivalent); upon improvement to grade 1 or less, begin a steroid taper over at least 1 month. Consider additional systemic immunosuppression in patients whose symptoms are not controlled with corticosteroid therapy.
Immune-mediated pneumonitis has been reported with nivolumab therapy. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation therapy. Monitor patients for signs and symptoms of pneumonitis (e.g., new or worsening cough, chest pain, shortness of breath). If confirmed, nivolumab therapy may need to be interrupted or discontinued; treatment with systemic corticosteroids may be necessary.
Immune-mediated colitis has been reported with nivolumab therapy. Additionally, cytomegalovirus (CMV) viral infection/reactivation has been reported in patients with steroid-refractory immune-mediated colitis. Use nivolumab with caution in patients with pre-existing inflammatory bowel disease such as ulcerative colitis or Crohn's disease. Monitor patients for symptoms of colitis (e.g., diarrhea, severe abdominal pain). Nivolumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may be necessary. In patients with steroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.
Immune-mediated hepatitis has been reported with nivolumab therapy. Monitor hepatic function at baseline and periodically during treatment; because hepatotoxicity can occur with a higher frequency when administered in combination with cabozantinib, consider more frequent monitoring in these patients. Nivolumab therapy may need to be interrupted or discontinued depending on the severity of hepatitis, if there is tumor involvement of the liver, and if it is used in combination with ipilimumab or cabozantinib. Treatment with systemic corticosteroids may also be necessary.
Immune-mediated nephritis and renal failure have been reported with nivolumab therapy. Monitor renal function at baseline and periodically during treatment. Nivolumab therapy may need to be interrupted or discontinued depending on the severity of renal impairment; treatment with systemic corticosteroids may also be necessary.
Primary or secondary adrenal insufficiency and immune-mediated hypophysitis can occur in patients treated with nivolumab. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects; hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement therapy for grade 2 or higher adrenal insufficiency and for hypophysitis as clinically indicated. Nivolumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Nivolumab can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy; hypothyroidism can follow hyperthyroidism. Evaluate thyroid function at baseline and monitor periodically during treatment. Begin hormone replacement for hypothyroidism or medical management of hyperthyroidism as clinically indicated. Nivolumab therapy may need to be interrupted or discontinued depending on severity; treatment with systemic corticosteroids may also be necessary.
Severe infusion-related reactions have been reported with nivolumab therapy. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions; discontinue nivolumab in patients who develop severe or life-threatening infusion reactions.
Immune-mediated serious rash, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred in patients treated with PD-1/PD-L1 inhibitors. Monitor patients for suspected severe skin reactions and exclude other causes. Topical emollients and/or topical corticosteroids may be adequate to treat mild-to-moderate non-exfoliative rashes. Nivolumab therapy may need to be interrupted or discontinued depending on the severity of rash; treatment with systemic corticosteroids may also be necessary.
Type 1 diabetes mellitus and diabetic ketoacidosis have been reported with nivolumab therapy. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Withhold nivolumab therapy for cases of severe hyperglycemia until blood sugar control is achieved; administer insulin as clinically indicated.
Fatal and other serious complications including hyperacute, acute, and chronic graft-versus-host-disease, sinusoidal obstruction syndrome (SOS) previously termed veno-occlusive disease (VOD) after reduced intensity conditioning, and a steroid-requiring febrile syndrome (without an identified infectious cause) have been reported in patients who receive an allogeneic stem cell transplant (SCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Therefore, perform a risk/benefit analysis prior to starting treatment with a PD-1/PD-L1 blocking antibody, such as nivolumab, in patients who may receive or who have a history of undergoing an allogeneic SCT. Monitor patients closely for evidence of transplant-related complications and intervene promptly. Complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic SCT.
The use of a PD-1 or PDL1 blocking antibody with a thalidomide analogue plus dexamethasone is not recommended for multiple myeloma treatment outside of a clinical trial. Patients had increased mortality in clinical trials when PD-1 blocking agents, including nivolumab, were added to a thalidomide analog (e.g., lenalidomide, pomalidomide) and dexamethasone for the treatment of multiple myeloma.
Use nivolumab with caution in patients who have previously had an organ transplant or who have autoimmune disease such as systemic lupus erythematosus (SLE). Immune-mediated organ transplant rejection has been reported with PD-1/PD-L1 inhibitor therapy.
Immune-mediated neurotoxicity has been reported with nivolumab or other PD-1/PD-L1 inhibitors. Use nivolumab with caution in patients who have a history of neurological disease such as myasthenia gravis or Guillain-Barre syndrome. Nivolumab may need to be interrupted or discontinued depending on the severity of the neurotoxicity; treatment with systemic corticosteroids may also be necessary.
Geriatric patients treated with nivolumab in combination with ipilimumab may have a higher rate of serious adverse reactions compared to younger patients. Patients aged 75 years or older with malignant pleural mesothelioma treated with nivolumab plus ipilimumab had higher rates of serious adverse reactions compared to all patients who received combination therapy (68% vs. 54%); discontinuation rates due to adverse reactions were also more common in older patients (35% vs. 28%). Patients with NSCLC aged 75 years or older also had a higher discontinuation rate compared to younger patients when treated with nivolumab in combination with ipilimumab (with or without concomitant platinum-doublet chemotherapy) in 2 randomized clinical trials. No overall differences in safety were reported between geriatric patients and younger patients with urothelial cancer, esophageal cancer, renal cell cancer, or in those receiving nivolumab for the adjuvant treatment of melanoma; there were not sufficient numbers of patients with hepatocellular cancer aged 65 and over to determine whether they respond differently from younger patients.
Based on its mechanism of action and data from animal studies, nivolumab may cause fetal harm if used during pregnancy. Nivolumab is an immunoglobulin G4 antibody and may cross the placental barrier. Fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. The risk of fetal harm is likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. There have been reports of healthy infants born following exposure to nivolumab or nivolumab plus ipilimumab in utero. Fetal growth discordance in twins, intrauterine growth restriction, and congenital hypothyroidism were also reported following maternal use of nivolumab or nivolumab plus ipilimumab during pregnancy. A premature infant (gestational age, 24 weeks) with no signs of intrauterine growth inhibition was delivered via cesarean section after maternal use of nivolumab plus ipilimumab during pregnancy. During the first year, the infant had some typical preterm issues. At 6 months of corrected age, the infant had modestly elevated tonus of the lower extremities combined with a slight delay in motor development but showed age-appropriate speech and social emotional development and no evidence of melanoma. HELLP syndrome occurring after the 27th week of pregnancy developed in a patient who received single-agent nivolumab; however, therapy had been discontinued in the sixth week of pregnancy. The PD-1 pathway is associated with decidual CD8-positive T-cell function and the PD1/PD-L1 interaction may be important in maintaining fetal tolerance during pregnancy. PD1/PDL1 Inhibitors, such as nivolumab, may impair maternal immune tolerance resulting in spontaneous abortion, intrauterine growth restriction, or early-onset preeclampsia. In animal reproduction studies in pregnant cynomolgus monkeys, increased rates of abortion and premature infant death were observed with twice weekly nivolumab administration at doses resulting in AUC values of 9 to 42 times higher than the clinical human dose of 3 mg/kg.
Counsel patients about the reproductive risk and contraception requirements during nivolumab treatment. Nivolumab can cause fetal harm if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 5 months after treatment with nivolumab. Females of reproductive potential should undergo pregnancy testing prior to initiation of nivolumab. Women who become pregnant while receiving nivolumab should be apprised of the potential hazard to the fetus.
Due to the potential for serious adverse reactions in breastfed children, the manufacturer recommends that patients avoid breast-feeding during nivolumab therapy and for 5 months after the final dose. It is not known if nivolumab is present in human milk or if it has effects on the breastfed child or on milk production. Use nivolumab with caution during breastfeeding, especially while nursing a newborn or preterm infant. Because nivolumab is a large protein molecule (molecular weight of 146,000 Daltons), the amount of drug in milk is likely to be very low. It may also be partially destroyed in the gastrointestinal tract resulting in minimal absorption.
For the treatment of malignant melanoma:
NOTE: The FDA has designated nivolumab as an orphan drug for the treatment of stage IIB to IV melanoma.
-for the treatment of unresectable or metastatic melanoma, as single-agent therapy:
Intravenous dosage:
Adults: 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks until disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. At a follow-up of approximately 2 years, the median overall survival (OS) (15.7 months vs. 14.4 months; hazard ratio (HR) = 0.95; 95% CI, 0.73 to 1.24) and progression-free survival (PFS) (3.1 months vs. 3.7 months; HR = 1; 95% CI, 0.78 to 1.436) times were not significantly improved with nivolumab compared with investigator's choice chemotherapy (ICC) in patients with previously treated, unresectable, stage IIIc or IV melanoma in a multicenter, randomized (2:1), open-label, phase 3 trial (the CheckMate 037 trial; n = 405). ICC chemotherapy consisted of dacarbazine 1,000 mg/m2 IV every 3 weeks or carboplatin (AUC 6) plus paclitaxel 175 mg/m2 every 3 weeks. At a minimum follow-up of approximately 38.5 months, the median OS (37.5 months vs. 11.2 months; HR = 0.46; 95% CI, 0.36 to 0.59; p-value less than 0.001) and PFS (5.1 months vs. 2.2 months; HR = 0.42; 95% CI, 0.33 to 0.53; p-value less than 0.001) times were significantly improved with nivolumab plus placebo compared with dacarbazine plus placebo in previously untreated patients with unresectable stage III or IV melanoma without a BRAF mutation in a multinational, randomized, double-blind, phase 3 trial (the CheckMate 066 trial; n = 418). Prior adjuvant therapy was permitted in this study. At a minimum follow-up of approximately 60 months, the median OS (36.9 months vs. 19.9 months; HR = 0.63; 95% CI 0.52 to 0.76) and PFS (6.9 months vs. 2.9 months; HR = 0.53; 95% CI 0.44 to 0.64) times were significantly improved in patients with previously untreated, unresectable, stage III or stage IV melanoma who received single-agent nivolumab compared with ipilimumab in a 3-arm, randomized, double-blind, phase 3 trial (CheckMate 067 trial; n = 945).
Children and Adolescents 12 to 17 years weighing 40 kg or more: 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks until disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The efficacy of nivolumab in pediatric patients aged 12 years and older is extrapolated from evidence in adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients.
Children and Adolescents 12 to 17 years weighing less than 40 kg: 3 mg/kg IV every 2 weeks OR 6 mg/kg IV every 4 weeks until disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The efficacy of nivolumab in pediatric patients aged 12 years and older is extrapolated from evidence in adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients.
-for the treatment of unresectable or metastatic melanoma, in combination with ipilimumab:
Intravenous dosage:
Adults: 1 mg/kg IV followed by ipilimumab 3 mg/kg IV repeated every 3 weeks for 4 doses. After completion of 4 doses of combination therapy, continue nivolumab monotherapy at a dosage of 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks until disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the nivolumab infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. At a minimum follow-up of approximately 60 months, the median overall survival (60 months vs. 19.9 months; hazard ratio (HR) = 0.52; 95% CI 0.42 to 0.64) and progression-free survival (11.5 months vs. 2.9 months; HR = 0.42; 95% CI 0.35 to 0.51) times were significantly improved in patients with previously untreated, unresectable, stage III or stage IV melanoma who received nivolumab plus ipilimumab compared with ipilimumab in a 3-arm, randomized, double-blind, phase 3 trial (CheckMate 067 trial; n = 945).
Children and Adolescents 12 to 17 years weighing 40 kg or more: 1 mg/kg IV followed by ipilimumab 3 mg/kg IV on day 1 every 3 weeks for 4 doses. After completion of 4 doses of combination therapy, continue nivolumab monotherapy at a dosage of 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks until disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The efficacy of nivolumab in pediatric patients aged 12 years and older is extrapolated from evidence in adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients
Children and Adolescents 12 to 17 years weighing less than 40 kg: 1 mg/kg IV followed by ipilimumab 3 mg/kg IV on day 1 every 3 weeks for 4 doses. After completion of 4 cycles of combination therapy, continue nivolumab monotherapy at a dosage of 3 mg/kg IV every 2 weeks OR 6 mg/kg IV every 4 weeks until disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The efficacy of nivolumab in pediatric patients aged 12 years and older is extrapolated from evidence in adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients.
-for the adjuvant treatment of completely resected stage IIB, IIC, III, or IV melanoma:
Intravenous dosage:
Adults: 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks until disease progression or for up to 1 year. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions.
Children and Adolescents 12 to 17 years weighing 40 kg or more: 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks until disease progression or for up to 1 year. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The efficacy of nivolumab in pediatric patients aged 12 years and older is extrapolated from evidence in adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients.
Children and Adolescents 12 to 17 years weighing less than 40 kg: 3 mg/kg IV every 2 weeks OR 6 mg/kg IV every 4 weeks until disease progression or for up to 1 year. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The efficacy of nivolumab in pediatric patients aged 12 years and older is extrapolated from evidence in adequate and well-controlled studies in adults with melanoma and additional pharmacokinetic data in pediatric patients.
For the treatment of non-small cell lung cancer (NSCLC):
-for the neoadjuvant treatment of resectable (tumors 4 cm or larger, or node-positive) non-small cell lung cancer (NSCLC), in combination with platinum doublet chemotherapy:
Intravenous dosage:
Adults: 360 mg IV over 30 minutes in combination with platinum doublet chemotherapy given on the same day, every 3 weeks for 3 cycles. In the randomized clinical trial, platinum doublet chemotherapy consisted of paclitaxel (175 mg/m2 or 200 mg/m2) and carboplatin (AUC 5 or 6) for patients with any histology; pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) for patients with non-squamous histology; or gemcitabine (1,000 mg/m2 or 1,250 mg/m2) and cisplatin (75 mg/m2) for patients with squamous histology. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a randomized, open-label clinical trial (CHECKMATE-816), patients with resectable stage IB, II, or IIIA NSCLC were randomized to neoadjuvant treatment with up to 3 cycles of nivolumab plus platinum-doublet chemotherapy or platinum doublet chemotherapy alone; 83% of patients in the nivolumab arm had definitive surgery after treatment compared to 75% of patients in the control arm. Neoadjuvant treatment with nivolumab plus platinum doublet chemotherapy significantly improved event-free survival (31.6 months vs. 20.8 months) and the rate of pathologic complete response (pCR) (24% vs. 2.2%) compared with patients receiving neoadjuvant chemotherapy alone. Overall survival was not significantly improved in the nivolumab arm at a prespecified interim analysis.
-for the treatment of metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy, and after progression on EGFR- or ALK-targeted therapy if applicable, as monotherapy:
Intravenous dosage:
Adults: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In an open-label, randomized, clinical trial of patients with metastatic squamous non-small cell lung cancer (NSCLC), treatment with nivolumab (n = 135) after progression during or after platinum-based chemotherapy was associated with a statistically significant improvement in overall survival (OS) and progression-free survival (PFS) compared with docetaxel (n = 137) at a prespecified interim analysis; PD-L1 expression did not correlate with significantly improved OS. OS was also significantly improved in patients with platinum-resistant metastatic non-squamous NSCLC who received nivolumab (n = 292) compared with docetaxel (n = 290) in a separate randomized, open-label study; the objective response rate was 19% vs. 12%, with a median duration of response of 17 months vs. 6 months, respectively. PFS was not improved in the nivolumab arm. In this study, PD-L1 expression correlated with improved outcomes in both OS and PFS. In a pooled analysis providing a minimum of 2 years follow-up for these studies, OS with nivolumab versus docetaxel was 23% vs. 8% in patients with squamous NSCLC, and 29% vs. 16% in non-squamous NSCLC. Ongoing responses after 2 years of follow-up were evident in 37% of nivolumab-treated patients with squamous NSCLC and 34% of patients with non-squamous NSCLC; no patients who received docetaxel had an ongoing response.
-for the first-line treatment of EGFR- and ALK-negative metastatic non-small cell lung cancer (NSCLC) in patients whose tumors express PD-L1 (1% or more), in combination with ipilimumab:
NOTE: Patients should be selected based on PD-L1 expression. Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults: 360 mg IV over 30 minutes every 3 weeks in combination with ipilimumab (1 mg/kg IV over 30 minutes every 6 weeks) until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a randomized, open-label, multi-part trial (CHECKMATE-227), first-line treatment with nivolumab in combination with ipilimumab significantly improved overall survival compared with treatment with a platinum-based doublet for patients with metastatic or recurrent NSCLC and PD-L1 expression of 1% or more (17.1 months vs. 14.9 months); patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy were excluded from the study. The median progression-free survival as assessed by a blinded independent central review (BICR) was 5.1 months versus 5.6 months, respectively; the confirmed objective response rate by BICR was 36% versus 30%, respectively, for a median duration of 23.2 months in the nivolumab/ipilimumab arm and 6.2 months in the platinum doublet arm.
-for the first-line treatment of EGFR- and ALK-negative metastatic or recurrent NSCLC, in combination with ipilimumab and platinum-doublet chemotherapy:
Intraveous dosage:
Adults: 360 mg IV over 30 minutes every 3 weeks and ipilimumab (1 mg/kg IV over 30 minutes every 6 weeks) until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression in combination with platinum-doublet chemotherapy given every 3 weeks for 2 cycles of therapy. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The overall survival time was significantly improved (14.1 months vs. 10.7 months; hazard ratio (HR) = 0.69; 95% CI, 0.55 to 0.87; p = 0.0006) in patient with metastatic or recurrent NSCLC who received first-line treatment with nivolumab and ipilimumab in combination with 2 cycles of platinum-based doublet chemotherapy (n = 361) compared with 4 cycles of platinum-doublet chemotherapy (n = 358) in a randomized, open-label, phase 3 trial (CHECKMATE-9LA). In this trial, platinum-doublet chemotherapy was administered every 3 weeks and consisted of either carboplatin (AUC 5 or 6) and pemetrexed 500 mg/mg2 OR cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC (plus optional pemetrexed maintenance therapy); or carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC. The progression-free survival time was also significantly improved in the nivolumab and ipilimumab plus platinum-based doublet chemotherapy arm compared with platinum-doublet chemotherapy alone arm (6.8 months vs. 5 months; HR = 0.7; 95% CI, 0.57 to 0.86; p = 0.0001).
For the treatment of advanced renal cell cancer:
-for the first-line treatment of intermediate or poor risk advanced renal cell cancer, in combination with ipilimumab:
Intravenous dosage:
Adults: 3 mg/kg IV over 30 minutes on day 1, followed by ipilimumab (1 mg/kg IV over 30 minutes) on day 1, every 3 weeks for 4 doses. After completion of 4 doses of nivolumab plus ipilimumab, continue nivolumab as monotherapy (240 mg IV over 30 minutes every 2 weeks or 480 mg IV over 30 minutes every 4 weeks) until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a randomized, open-label study, treatment with nivolumab plus ipilimumab significantly improved median overall survival (not estimated vs. 25.9 months) and objective response rate (41.6% vs. 26.5%) compared with sunitinib in patients with intermediate/poor risk patients with previously untreated renal cell cancer; a complete response was achieved in 9.4% of patients in the nivolumab plus ipilimumab arm compared with 1.2% of those who received sunitinib. Median progression-free survival was 11.6 months compared with 8.4 months, respectively. In a separate analysis, the combination of nivolumab plus ipilimumab in patients with favorable risk disease did not significantly improve overall survival; efficacy in this population has not been established.
-for the first-line treatment of advanced renal cell cancer, in combination with cabozantinib:
Intravenous dosage:
Adults: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. Administer in combination with cabozantinib 40 mg PO once daily without food; continue cabozantinib until disease progression or unacceptable toxicity. Nivolumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. First-line treatment with nivolumab plus cabozantinib significantly improved median progression-free survival (16.6 months vs. 8.3 months) compared with sunitinib in a randomized, open-label study. The median overall survival was also significantly improved in the nivolumab plus cabozantinib arm (37.7 months vs. 34.3 months); in an exploratory analysis, these findings were not significant in patients with IMDC favorable or intermediate risk. The objective response rate was 55.7% (complete response, [8%]) versus 27.1% (CR, 4.6%), respectively.
-for the treatment of advanced renal cell cancer in patients who have received prior anti-angiogenic therapy, as monotherapy:
Intravenous dosage:
Adults: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The primary outcome of overall survival was significantly improved in patients with advanced renal cell cancer who received nivolumab after prior anti-angiogenic therapy compared with everolimus (25 vs. 19.6 months), regardless of PD-L1 expression level, in a randomized, open-label clinical trial. The confirmed objective response rate (ORR) was 21.5% in nivolumab-treated patients with a median time to onset of 3 months, compared to 3.9% ORR in those who received everolimus and a time to onset of 3.7 months. Responses lasted for a median duration of 23 months and 13.7 months, respectively.
For the treatment of Hodgkin lymphoma:
NOTE: The FDA has designated nivolumab as an orphan drug for the treatment of Hodgkin lymphoma.
-for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin:
Intravenous dosage:
Adults: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. The investigator-assessed objective response rate (ORR) was 87% in a cohort of patients with relapsed or refractory classical Hodgkin lymphoma (HL) who received nivolumab (median therapy duration of 36 weeks; range, 13 to 77 weeks) in a phase I trial (n = 23; median age, 35 years; range, 20 to 54 years); the complete response (CR) rate was 17% in these patients. In 15 patients that had previously received an autologous HSCT and post-transplant brentuximab vedotin, the ORR was 87% and the CR rate was 7%. At a median follow-up time of 40 weeks (range, 0 to 75 weeks), the median overall survival (OS) time had not been reached and the 24-week progression-free survival (PFS) rate was 86%. In this study, 78% of patients had previously received brentuximab vedotin therapy, 78% of patients had undergone a prior autologous HSCT, and 65% of patients had received 4 or more prior therapies. In a multinational, multicohort, phase II trial, the ORR (primary endpoint assessed by an independent radiological review committee) was 66.3% in 80 patients with classical HL who had failed to respond to autologous SCT and had either relapsed after or failed to respond to brentuximab vedotin; the CR rate was 9% in these patients. The median response duration was 7.8 months. All patients (median age, 37 years) had previously received brentuximab vedotin; patients had received a median of 4 prior therapies. At a median follow-up of 8.9 months, the 6-month PFS and OS rates were 76.9% and 98.7%, respectively. At 12 months, the median PFS time was 10 months.
-for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after 3 or more lines of systemic therapy that includes an autologous hematopoietic stem cell transplantation (HSCT) :
Intravenous dosage:
Adults: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a pooled analysis from 2 clinical studies (n = 258), the objective response rate was 69% in patients who had relapsed or progressive classical Hodgkin lymphoma following an autologous HSCT; the complete remission rate was 14%. In this analysis, patients had received a median of 4 prior systemic regimens (range, 2 to 15 regimens) and 76% of patients had received prior brentuximab vedotin.
For the treatment of recurrent or metastatic head and neck cancer (squamous cell) with disease progression on or after platinum-containing chemotherapy:
Intravenous dosage:
Adults: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. In clinical trials, nivolumab could be continued beyond disease progression, as long as clinical benefit was evident. In a multicenter, randomized, open-label clinical trial, nivolumab significantly improved overall survival compared with investigator's choice of weekly monotherapy with cetuximab, methotrexate, or docetaxel (7.5 months vs. 5.1 months; HR 0.7; p = 0.01) in patients with recurrent, platinum-resistant, squamous-cell cancer of the head and neck.
For the treatment of urothelial carcinoma:
-for the adjuvant treatment of urothelial carcinoma in patients who are at high risk of recurrence after undergoing a radical resection:
Intravenous dosage:
Adults: 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks. Continue until disease progression or unacceptable toxicity for up to 1 year. Patients with urinary carcinoma of the bladder or upper urinary tract (renal pelvis or ureter) at high risk of recurrence were randomized within 120 days of radical resection (R0) to treatment with nivolumab or placebo in a multicenter, randomized, double-blind clinical trial (CHECKMATE-274). At a prespecified interim analysis, treatment with nivolumab significantly improved the median disease-free survival (DFS) compared with placebo in the intent-to-treat group (20.8 months vs. 10.8 months) as well as in patients with PD-L1 expression of 1% or higher (not reached vs. 8.4 months); the effect on DFS was not statistically significant in an exploratory subgroup analysis in patients with PD-L1 of less than 1%. In an exploratory subgroup analysis, no improvement in DFS occurred in patients with upper tract urothelial cancer with nivolumab compared with placebo.
-for the first-line treatment of unresectable or metastatic urothelial carcinoma, in combination with gemcitabine and cisplatin:
Intravenous dosage:
Adults: 360 mg IV on day 1 in combination with cisplatin (70 mg/m2 IV on day 1) and gemcitabine (1,000 mg/m2 IV on days 1 and 8), every 3 weeks for up to 6 cycles. Administer nivolumab prior to chemotherapy when given on the same day. After completion of 6 cycles of combination therapy, continue nivolumab 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks as monotherapy for up to 2 years from the first dose, or until disease progression or unacceptable toxicity. Treatment with nivolumab plus cisplatin and gemcitabine significantly improved median overall survival (21.7 months vs. 18.9 months) and median progression-free survival (7.9 months vs. 7.6 months) compared with cisplatin and gemcitabine alone in patients with previously untreated unresectable or metastatic urothelial cancer in a multicenter, randomized, open-label phase 3 clinical trial (CHECKMATE-901); prior neoadjuvant or adjuvant chemotherapy was permitted as long as the disease recurrence was at least 12 months from completion. The objective response rate was 57.6% in the nivolumab arm (complete response [CR], 22%) compared with 43.1% in the chemotherapy alone arm (CR, 12%) for a median duration of 9.5 months versus 7.3 months, respectively.
-for the treatment of locally advanced or metastatic urothelial carcinoma, in patients with disease progression on or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy:
Intravenous dosage:
Adults: 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks. Continue until disease progression or unacceptable toxicity. Patients with platinum-resistant, locally advanced or metastatic urothelial cancer treated with nivolumab had an objective response rate of 19.6% (complete response (CR), 2.6%) in an open-label, single-arm clinical trial (CHECKMATE-275). The median duration of response was 10.3 months (range, 1.9 months to 12+ months). Patients with PD-L1 expression of 1% or higher had an objective response rate of 25% (CR, 4.8%) and those with PD-L1 expression less than 1% had an objective response rate of 15.1% (CR, 0.7%).
For the treatment of colorectal cancer:
-For the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, as monotherapy:
Intravenous dosage:
Adults: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, nonrandomized, multiple parallel-cohort, open-label study, treatment with nivolumab monotherapy resulted in an overall response rate by independent radiographic review of 28% in patients with locally determined dMMR or MSI-H metastatic colorectal cancer who had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (n = 53), with 26% partial responses. The duration of response was 6 months or longer in 67% of these patients, and was 12 months or longer in 40% of patients.
Children and Adolescents 12 to 17 years weighing 40 kg or more: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult MSI-H or dMMR metastatic colorectal cancer patients with additional population pharmacokinetic data. In a multicenter, nonrandomized, multiple parallel-cohort, open-label study, treatment with nivolumab monotherapy resulted in an overall response rate by independent radiographic review of 28% in patients with locally determined dMMR or MSI-H metastatic colorectal cancer who had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (n = 53), with 26% partial responses. The duration of response was 6 months or longer in 67% of these patients, and was 12 months or longer in 40% of patients.
Children and Adolescents 12 to 17 years weighing less than 40 kg: 3 mg/kg IV over 30 minutes every 2 weeks until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult MSI-H or dMMR metastatic colorectal cancer patients with additional population pharmacokinetic data. In a multicenter, nonrandomized, multiple parallel-cohort, open-label study, treatment with nivolumab monotherapy resulted in an overall response rate by independent radiographic review of 28% in patients with locally determined dMMR or MSI-H metastatic colorectal cancer who had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (n = 53), with 26% partial responses. The duration of response was 6 months or longer in 67% of these patients, and was 12 months or longer in 40% of patients.
-For the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, in combination with ipilimumab:
Intravenous dosage:
Adults: 3 mg/kg IV over 30 minutes, followed by ipilimumab 1 mg/kg IV over 30 minutes, on day 1 every 3 weeks for 4 cycles. After completion of 4 cycles of combination therapy, continue nivolumab monotherapy at a dose of 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, non-randomized, multiple parallel-cohort, open-label study (the CHECKMATE-142 study), treatment with nivolumab plus ipilimumab resulted in an overall response rate by blinded independent central review (BICR) of 56% in patients with locally determined dMMR or MSI-H metastatic colorectal cancer who had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (n = 82), with 13% complete responses. The duration of response was 6 months or longer in 87% of these patients and was 12 months or longer in 74% of patients.
Children and Adolescents 12 to 17 years weighing 40 kg or more: 3 mg/kg IV over 30 minutes, followed by ipilimumab 1 mg/kg IV over 30 minutes, on day 1 every 3 weeks for 4 cycles. After completion of 4 cycles of combination therapy, continue nivolumab monotherapy at a dose of 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks, until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult MSI-H or dMMR metastatic colorectal cancer patients with additional population pharmacokinetic data. In a multicenter, non-randomized, multiple parallel-cohort, open-label study (the CHECKMATE-142 study), treatment with nivolumab plus ipilimumab resulted in an overall response rate by blinded independent central review (BICR) of 56% in patients with locally determined dMMR or MSI-H metastatic colorectal cancer who had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (n = 82), with 13% complete responses. The duration of response was 6 months or longer in 87% of these patients and was 12 months or longer in 74% of patients.
Children and Adolescents 12 to 17 years weighing less than 40 kg: 3 mg/kg IV over 30 minutes, followed by ipilimumab 1 mg/kg IV over 30 minutes, on day 1 every 3 weeks for 4 cycles. After completion of 4 cycles of combination therapy, continue nivolumab monotherapy at a dose of 3 mg/kg IV over 30 minutes every 2 weeks until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Efficacy for pediatric patients has been extrapolated from results from clinical trials in adult MSI-H or dMMR metastatic colorectal cancer patients with additional population pharmacokinetic data. In a multicenter, non-randomized, multiple parallel-cohort, open-label study (the CHECKMATE-142 study), treatment with nivolumab plus ipilimumab resulted in an overall response rate by blinded independent central review (BICR) of 56% in patients with locally determined dMMR or MSI-H metastatic colorectal cancer who had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (n = 82), with 13% complete responses. The duration of response was 6 months or longer in 87% of these patients and was 12 months or longer in 74% of patients.
For the treatment of hepatocellular cancer (HCC):
-for the treatment of hepatocellular cancer (HCC) after disease progression on or intolerance to sorafenib therapy, as monotherapy*:
NOTE: FDA approval was removed for this indication in July 2021 after initial accelerated approval due to failure to meet the primary endpoint of overall survival in the CheckMate-459 trial.
Intravenous dosage:
Adults: Dosage not established.
-for the treatment of hepatocellular cancer in patients who have been previously treated with sorafenib, in combination with ipilimumab:
Intravenous dosage:
Adults: 1 mg/kg IV over 30 minutes followed by ipilimumab (3 mg/kg IV over 30 minutes) on day 1 every 3 weeks for up to 4 cycles. After completion of 4 cycles of combination therapy, continue nivolumab (240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks) as a single agent until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a multicohort, open-label clinical trial, treatment with ipilimumab plus nivolumab followed by nivolumab monotherapy resulted in an overall response rate (ORR) of 33% (complete response [CR], 8%; partial response [PR], 24%) by RECIST v1.1 and 35% (CR, 12%; PR, 22%) by mRECIST for a median duration of 4.6 months; 88% of patients had a response of at least 6 months, 56% had a response of at least 12 months, and 31% had a response of at least 24 months.
For the treatment of esophageal cancer:
NOTE: The FDA has designated nivolumab as an orphan drug for the treatment of esophageal cancer and gastroesophageal (GEJ) cancer.
-for the adjuvant treatment of completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease after neoadjuvant chemoradiotherapy:
Intravenous dosage:
Adults: 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks, until disease progression or unacceptable toxicity for a total treatment duration of 1 year. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. In a multicenter, randomized, double-blind trial (CHECKMATE-577), adjuvant treatment with nivolumab (n = 532) significantly improved median disease-free survival compared with placebo (n = 262) in patients with completely resected esophageal or gastroesophageal junction (GEJ) cancer who had residual pathologic disease after neoadjuvant concurrent chemoradiotherapy (22.4 months vs. 11 months); the effect remained significant in the subgroup of patients with adenocarcinoma (19.4 months vs. 11.4 months) and in patients with squamous cell carcinoma (29.7 months vs. 11 months).
-for the first-line treatment of unresectable advanced or metastatic esophageal squamous cell cancer, in combination with ipilimumab:
Intravenous dosage:
Adults: 3 mg/kg IV over 30 minutes every 2 weeks OR 360 mg IV over 30 minutes every 3 weeks, in combination with ipilimumab (1 mg/kg IV every 6 weeks) until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Treatment with ipilimumab plus nivolumab significantly improved the median overall survival time compared with fluorouracil plus cisplatin (13.7 months vs. 9.1 months) in patients with previously untreated, unresectable advanced, recurrent or metastatic esophageal squamous cell cancer and at least 1% of tumor cells expressing PD-L1 in a multicenter, randomized, open-label, phase 3 clinical trial (CHECKMATE-648); median overall survival was also significantly improved with ipilimumab and nivolumab in the overall population (12.8 months vs. 10.7 months). Median progression-free survival (PFS) was shorter with immunotherapy compared with chemotherapy in patients with at least 1% PD-L1 expression (4 months vs. 4.4 months) and in those in the overall population (2.9 months vs. 5.6 months). The overall response rate was also higher in patients treated with nivolumab plus ipilimumab in both the PD-L1 positive population (35.4% vs. 20%) and the overall population (27.7% vs. 27%). Complete responses (CR) occurred in 17.7% of PD-L1 positive immunotherapy patients and in 11.1% of those in the overall population; CR occurred in 5.1% of PD-L1 positive patients who received chemotherapy and in 6.2% of those in the overall population. The median duration of response for PD-L1 positive patients was 11.8 months versus 5.7 months, respectively; the median duration of response in the overall population was 11.1 versus 7.1 months, respectively.
-for the first-line treatment of patients with unresectable advanced or metastatic esophageal squamous cell cancer, in combination with fluoropyrimidine- and platinum-containing chemotherapy:
Intravenous dosage:
Adults: 240 mg IV over 30 minutes every 2 weeks (days 1 and 15), in combination with fluorouracil (800 mg/m2 per day as a continuous IV infusion on days 1 through 5) and cisplatin (80 mg/m2 IV on day 1), every 4 weeks until disease progression or unacceptable toxicity; discontinue nivolumab after 2 years in patients without disease progression. Alternatively, nivolumab may be dosed at 480 mg IV over 30 minutes every 4 weeks (day 1) with chemotherapy. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Treatment with nivolumab plus fluorouracil and cisplatin Treatment with nivolumab plus fluorouracil and cisplatin significantly improved the median overall survival time compared with fluorouracil plus cisplatin alone (15.4 months vs. 9.1 months) in patients with previously untreated, unresectable advanced, recurrent or metastatic esophageal squamous cell cancer and at least 1% of tumor cells expressing PD-L1 in a multicenter, randomized, open-label, phase 3 clinical trial (CHECKMATE-648); median overall survival was also significantly improved with nivolumab and chemotherapy in the overall population (13.2 months vs. 10.7 months). Median progression-free survival (PFS) was significantly longer with nivolumab/fluorouracil/cisplatin compared with fluorouracil/cisplatin alone in patients with at least 1% PD-L1 expression (6.9 months vs. 4.4 months) but was not significantly different in the overall population (5.8 months vs. 5.6 months). The overall response rate was also higher in patients treated with nivolumab plus chemotherapy in both the PD-L1 positive population (53% vs. 20%) and the overall population (47% vs. 27%). Complete responses (CR) occurred in 16% of PD-L1 positive patients treated with nivolumab and chemotherapy, and in 13% of those in the overall population; CR occurred in 5% of PD-L1 positive patients who received chemotherapy and in 6% of those in the overall population. The median duration of response for PD-L1 positive patients was 8.4 months versus 5.7 months, respectively; the median duration of response in the overall population was 8.2 versus 7.1 months, respectively.
-for the treatment of advanced or metastatic esophageal adenocarcinoma or gastroesophageal junction (GEJ) cancer, in combination with fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6):
Intravenous dosage:
Adults: 240 mg IV every 2 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. Administer in combination with oxaliplatin (85 mg/m2 IV on day 1) infused concurrently but in separate bags via Y-site with leucovorin (400 mg/m2 IV on day 1), followed by fluorouracil (400 mg/m2 IV bolus on day 1, followed by 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion, every 2 weeks until disease progression or unacceptable toxicity. Administer nivolumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8 months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively (complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.
-for the treatment of advanced or metastatic esophageal adenocarcinoma or gastroesophageal junction (GEJ) cancer, in combination with capecitabine and oxaliplatin (XELOX/CapeOx):
Intravenous dosage:
Adults: 360 mg IV every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. Administer in combination with oxaliplatin (130 mg/m2 IV on day 1 every 3 weeks) and capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14 of each 21 day cycle) until disease progression or unacceptable toxicity. Administer nivolumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8 months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively (complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.
-for the treatment of unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based chemotherapy:
Intravenous dosage:
Adults: 240 mg IV over 30 minutes every 2 weeks OR 480 mg IV over 30 minutes every 4 weeks until disease progression or unacceptable toxicity. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. At a minimum follow-up time of 17.6 months, the overall survival (OS) time was significantly improved (10.9 months vs. 8.4 months; hazard ratio (HR) = 0.77; 95% CI, 0.62 to 0.96; p = 0.019) in patients with advanced esophageal squamous-cell carcinoma who received nivolumab (n = 210) compared with chemotherapy (n = 209) in a multinational, randomized, open-label, phase 3 trial (ATTRACTION-3 trial). In a subgroup analysis, OS was significantly improved with nivolumab in patients with PD-L1 expression of 1% or greater (HR = 0.69; 95% CI, 0.51 to 0.94). The median progression-free survival (PFS) time was not significantly different in the nivolumab arm compared with the chemotherapy arm (1.7 months vs. 3.4 months; HR = 1.08; 95% CI, 0.87 to 1.34); however the 6-month (24% vs. 17%) and 12-month (12% vs. 7%) PFS rates were higher in the nivolumab arm. Patients who were refractory or intolerant to at least 1 prior fluoropyrimidine-and platinum-based regimen were eligible for study enrollment; 48% of patients had PD-L1 expression of 1% or greater. In this trial, chemotherapy consisted of either paclitaxel 100 mg/m2 IV once weekly for 6 weeks (cycles repeated every 7 weeks) OR docetaxel 75 mg/m2 IV every 3 weeks until disease progression.
For the treatment of mesothelioma:
NOTE: The FDA has designated nivolumab as an orphan drug for the treatment of mesothelioma.
-for the first-line treatment of unresectable malignant pleural mesothelioma, in combination with ipilimumab:
Intravenous dosage:
Adults: 360 mg IV over 30 minutes every 3 weeks, in combination with ipilimumab (1 mg/kg IV over 30 minutes every 6 weeks), until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Treatment with nivolumab in combination with ipilimumab significantly improved median overall survival (OS) compared with pemetrexed plus either cisplatin or carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma in a randomized, open-label trial (CHECKMATE-743) (18.1 months vs. 14.1 months). Median progression-free survival was 6.8 months in the nivolumab plus ipilimumab arm compared with 7.2 months in patients receiving chemotherapy. The overall response rate was 40% versus 43%, for a median duration of 11 months and 6.7 months, respectively. In a prespecified exploratory analysis, patients with non-epitheliod histology had a median OS of 16.7 months in the nivolumab and ipilimumab arm and 8.9 months in the chemotherapy arm. The median OS was 18.7 months in patients with epitheliod histology who received nivolumab and ipilimumab and 16.2 months in the chemotherapy arm.
For the treatment of gastric cancer:
NOTE: The FDA has designated nivolumab as an orphan drug for the treatment of gastric cancer and gastroesophageal junction (GEJ) cancer.
-for the treatment of advanced or metastatic gastric cancer or gastroesophageal junction cancer (GEJ), in combination with fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6):
Intravenous dosage:
Adults: 240 mg IV every 2 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. Administer in combination with oxaliplatin (85 mg/m2 IV on day 1) infused concurrently but in separate bags via Y-site with leucovorin (400 mg/m2 IV on day 1), followed by fluorouracil (400 mg/m2 IV bolus on day 1, followed by 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion, every 2 weeks until disease progression or unacceptable toxicity. Administer nivolumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8 months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively (complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.
-for the treatment of advanced or metastatic gastric cancer or gastroesophageal junction (GEJ) cancer, in combination with capecitabine and oxaliplatin (XELOX/CapeOx):
Intravenous dosage:
Adults: 360 mg IV every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. Administer in combination with oxaliplatin (130 mg/m2 IV on day 1 every 3 weeks) and capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14 of each 21 day cycle) until disease progression or unacceptable toxicity. Administer nivolumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. Interrupt or slow the rate of the infusion in patients who develop mild or moderate infusion reactions; discontinue therapy for severe or life-threatening infusion-related reactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8 months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively (complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Immune-Mediated Reactions
NOTE: Corticosteroid therapy consists of prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less. Consider starting other systemic immunosuppressants if toxicity is not controlled by corticosteroids. Permanently discontinue nivolumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids. When nivolumab is administered in combination with ipilimumab, withhold or permanently discontinue both ipilimumab and nivolumab for toxicity.
Colitis
Nivolumab Monotherapy
Grade 2 or 3 toxicity: Hold nivolumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 4 toxicity: Permanently discontinue nivolumab and administer corticosteroids.
Combination Therapy with Ipilimumab
Grade 2 toxicity: Hold nivolumab and ipilimumab; administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 3 or 4 toxicity: Permanently discontinue nivolumab and ipilimumab; administer corticosteroids.
Endocrinopathies (including Type 1 diabetes, Hypophysitis, Hypothyroidism, Hyperthyroidism, and Adrenal Insufficiency)
Grade 2 toxicity: Consider holding nivolumab until symptoms improve with hormone replacement therapy. Resume therapy when acute symptoms resolve.
Grade 3 or 4 toxicity: Hold nivolumab until the patient is clinically stable; administer appropriate treatment (e.g., hormone replacement therapy, corticosteroids, insulin). Permanently discontinue ipilimumab for severe toxicity.
Exfoliative Skin Reactions
Suspected Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS): Hold nivolumab and administer corticosteroids as applicable.
Confirmed SJS, TEN, or DRESS: Permanently discontinue nivolumab and administer corticosteroids.
Infusion-Related Reactions
Grade 1 or 2 toxicity: Hold nivolumab or slow the infusion rate.
Grade 3 or 4 toxicity: Permanently discontinue nivolumab.
Myocarditis
Grade 2, 3, or 4 toxicity: Permanently discontinue nivolumab and administer corticosteroids.
Neurologic Toxicity
Grade 2 toxicity: Hold nivolumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 3 or 4 toxicity: Permanently discontinue nivolumab and administer corticosteroids.
Pneumonitis
Grade 2 toxicity: Hold nivolumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Grade 3 or 4 toxicity: Permanently discontinue nivolumab and administer corticosteroids.
Other Immune-Mediated Adverse Reactions
Grade 3 toxicity: Hold nivolumab and administer corticosteroids. Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper.
Recurrent grade 3 toxicity that requires treatment with systemic immunosuppressants: Permanently discontinue nivolumab.
Grade 4 toxicity: Permanently discontinue nivolumab and administer corticosteroids.
Maximum Dosage Limits:
-Adults
Monotherapy: 480 mg IV every 4 weeks or 240 mg IV every 2 weeks.
Combination therapy with ipilimumab: 3 mg/kg IV every 3 weeks.
Combination therapy with ipilimumab and platinum-doublet chemotherapy: 360 mg IV every 3 weeks.
Combination therapy with cabozantinib: 480 mg IV every 4 weeks or 240 mg IV every 2 weeks.
Combination therapy with mFOLFOX6 or XELOX/CapeOx: 360 mg IV every 3 weeks or 240 mg IV every 2 weeks.
-Geriatric
Monotherapy: 480 mg IV every 4 weeks or 240 mg IV every 2 weeks.
Combination therapy with ipilimumab: 3 mg/kg IV every 3 weeks.
Combination therapy with ipilimumab and platinum-doublet chemotherapy: 360 mg IV every 3 weeks.
Combination therapy with cabozantinib: 480 mg IV every 4 weeks or 240 mg IV every 2 weeks.
Combination therapy with mFOLFOX6 or XELOX/CapeOx: 360 mg IV every 3 weeks or 240 mg IV every 2 weeks.
-Adolescents
40 kg or more:
-Monotherapy: 480 mg IV every 4 weeks or 240 mg IV every 2 weeks.
-Combination therapy with ipilimumab: 1 mg/kg IV every 3 weeks (melanoma only) or 3 mg/kg IV every 3 weeks (colon cancer only).
Less than 40 kg:
-Monotherapy: 3 mg IV every 2 weeks (colon cancer and melanoma) or 6 mg/kg IV every 4 weeks (melanoma only).
-Combination therapy with ipilimumab: 1 mg/kg IV every 3 weeks (melanoma only) or 3 mg/kg IV every 3 weeks (colon cancer only).
-Children
12 years and 40 kg or more:
-Monotherapy: 480 mg IV every 4 weeks or 240 mg IV every 2 weeks.
-Combination therapy with ipilimumab: 1 mg/kg IV every 3 weeks (melanoma only) or 3 mg/kg IV every 3 weeks (colon cancer only).
12 years and less than 40 kg:
-Monotherapy: 3 mg IV every 2 weeks (colon cancer and melanoma) or 6 mg/kg IV every 4 weeks (melanoma only).
-Combination therapy with ipilimumab: 1 mg/kg IV every 3 weeks (melanoma only) or 3 mg/kg IV every 3 weeks (colon cancer only).
1 to 11 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Treatment-Related Immune-Mediated Hepatitis
-Monotherapy
No Tumor Involvement of the Liver
AST or ALT level of more than 3 to 8 times the ULN or a total bilirubin level of more than 1.5 to 3 times the ULN: Hold nivolumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue nivolumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
AST or ALT level more than 8 times the ULN or a total bilirubin level more than 3-times the ULN: Permanently discontinue nivolumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
Tumor Involvement of the Liver
Baseline AST or ALT level at the ULN or less: Hold or permanently discontinue nivolumab based on recommendations for hepatitis with no tumor involvement of the liver.
Baseline AST or ALT level of more than 1 to 3 times the ULN
AST or ALT level of more than 5 to 10 times the ULN: Hold nivolumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue nivolumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Baseline AST or ALT level of more than 3 to 5 times the ULN
AST or ALT level of more than 8 to 10 times the ULN: Hold nivolumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue nivolumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Any Baseline AST or ALT level
AST or ALT level more than 10 times the ULN or a total bilirubin level to more than 3 times the ULN: Permanently discontinue nivolumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
-Combination Therapy with Ipilimumab
No Tumor Involvement of the Liver OR Tumor Involvement of the Liver and non-Hepatocellular Carcinoma (HCC)
AST or ALT level of more than 3 to 5 times the ULN or a total bilirubin level of more than 1.5 to 3 times the ULN: Hold nivolumab and ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue nivolumab and ipilimumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
AST or ALT level more than 5 times the ULN or a total bilirubin level more than 3-times the ULN: Permanently discontinue nivolumab and ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
Tumor Involvement of the Liver and HCC
Baseline AST or ALT level at the ULN or less: Hold or permanently discontinue nivolumab and ipilimumab based on recommendations for hepatitis with no tumor involvement of the liver.
Baseline AST or ALT level of more than 1 to 3 times the ULN
AST or ALT level of more than 5 to 10 times the ULN: Hold nivolumab and ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue nivolumab and ipilimumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Baseline AST or ALT level of more than 3 to 5 times the ULN
AST or ALT level of more than 8 to 10 times the ULN: Hold nivolumab and ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue nivolumab and ipilimumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Any Baseline AST or ALT level
AST or ALT level more than 10 times the ULN or a total bilirubin level more than 3 times the ULN: Permanently discontinue nivolumab and ipilimumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
-Combination Therapy with Cabozantinib
AST or ALT level of more than 3 to 10 times the ULN with concurrent total bilirubin level less than 2 times the ULN: Hold nivolumab and cabozantinib and consider the use of corticosteroid therapy. Upon recovery to grade 1 or less, consider rechallenge with one or both of nivolumab and cabozantinib.
AST or ALT level more than 10 times the ULN or more than 3 times the ULN with concurrent total bilirubin level 2 times the ULN or more: Permanently discontinue nivolumab and cabozantinib; consider the use of corticosteroid therapy.
Patients with Renal Impairment Dosing
Treatment-Related Immune-Mediated Nephritis with Renal Dysfunction
Grade 2 or 3 increased serum creatinine (SCr) level: Hold nivolumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper). Resume therapy when the adverse event recovers to grade 1 or less after the corticosteroid taper. Permanently discontinue nivolumab in patients who do not have a complete or partial resolution of toxicity or who cannot reduce their daily prednisone dose to less than 10 mg (or equivalent) within 12 weeks of initiating steroids.
Grade 4 increased SCr level: Permanently discontinue nivolumab and administer corticosteroids (i.e., prednisone 1 to 2 mg/kg per day or equivalent, followed by a 1-month taper starting when the toxicity resolves to grade 1 or less).
*non-FDA-approved indication
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Nivolumab is a fully human IgG4 monoclonal antibody that inhibits the programmed death receptor-1 (PD-1) immune checkpoint protein, one of the key checkpoint molecules that mediates tumor-induced immune suppression. PD-1 receptors are expressed on T cells, B cells, monocytes, and natural killer T cells, following their activation in response to inflammatory signals. PD-1 has two known ligands, programmed death-ligand-1 (PD-L1) and programmed death-ligand-2 (PD-L2), which are expressed on antigen-presenting cells, including dendritic cells. PD-L1, which is also expressed on some nonhematopoietic cells, is believed to be the primary mediator of PD-1-dependent immunosuppression. The PD-1 pathway regulates the balance between T-cell activation and the protection of healthy tissues from immune-mediated damage. In tumor cells, the PD-1 pathway is thought to play an important role in the interaction of tumor cells with the host immune response, and PD-L1 expression in a tumor cell may provide adaptive immune resistance and lead to a poor outcome. Nivolumab selectively binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, which causes a release of the PD-1 pathway-mediated inhibition of the immune response. This prevents the negative regulatory signal mediated by the receptor (PD-1)-ligand interaction and thus promotes the host immune response in which the tumor cells are recognized as foreign and eliminated. Syngeneic mouse tumor models have shown that blocking the PD-1 pathway results in decreased growth of tumors. The combination of nivolumab and the anti-cytotoxic T-lymphocyte-associated protein-4 antibody, ipilimumab, appear to have additive inhibitory effects on T-cell function and result in improved tumor response in melanoma.
Nivolumab is administered intravenously. In patients who received nivolumab 0.1 to 20 mg/kg IV once or as multiple IV doses every 2 or 3 weeks, the geometric mean volume of distribution at steady state was 6.8 L (coefficient of variation (CV%), 27.3%), and the geometric mean half-life was 25 days (CV%, 77.5%). Nivolumab clearance decreases over time, with mean maximal reduction from baseline of approximately 24.5% (CV%, 47.6%); this reduction is not clinically relevant. The geometric mean clearance at steady state of 8.2 mL/hour (CV%, 53.9%). In patients with completely resected melanoma, nivolumab clearance does not decrease over time; the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady-state. When administered at 3 mg/kg every 2 weeks, steady-state was reached by 12 weeks and systemic accumulation was approximately 3.7-fold. Nivolumab exposure increased in a dose-proportional manner over 0.1 to 10 mg/kg every 2 weeks. There are no clinically significant differences in safety and efficacy between a nivolumab dose of 240 mg or 3 mg/kg when administered every 2 weeks in patients with melanoma, non-small cell lung cancer (NSCLC), renal cell cancer (RCC), and urothelial carcinoma.
The clearance of nivolumab was unchanged when administered as 3 mg/kg in combination with ipilimumab 1 mg/kg every 3 weeks, 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg every 6 weeks, and 360 mg every 3 weeks in combination with ipilimumab 1 mg/kg every 6 weeks compared to nivolumab monotherapy; clearance of nivolumab was increased by 29% when administered as 1 mg/kg in combination with ipilimumab 3 mg/kg every 3 weeks compared to nivolumab monotherapy. Nivolumab clearance was increased by 20% in the presence of anti-nivolumab antibodies.
-Route-Specific Pharmacokinetics
Intravenous Route
The predicted exposure of nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion.
-Special Populations
Hepatic Impairment
Mild or moderate hepatic impairment (total bilirubin less than or equal to the upper limit of normal [ULN] and AST greater than the ULN or total bilirubin less than or equal to 3 times the ULN and any AST) did not have a clinically important effect on the clearance of nivolumab. Nivolumab has not been studied in patients with severe hepatic impairment (total bilirubin greater than 3 times the ULN and any AST).
Renal Impairment
Renal impairment (eGFR 15 mL/min/1.72 m2 or more) did not have a clinically important effect on nivolumab clearance compared to that of patients with normal renal function.
Pediatrics
When administered at the recommended dosage, nivolumab exposures in pediatric patients 12 years and older are comparable with the exposures in adult patients.
Geriatric
Age (29 to 87 years) did not significantly affect the clearance of nivolumab based on a population pharmacokinetic analysis.
Gender Differences
Gender did not significantly affect the clearance of nivolumab based on a population pharmacokinetic analysis.
Ethnic Differences
Race did not significantly affect the clearance of nivolumab based on a population pharmacokinetic analysis.
Obesity
Weight (35 kg to 160 kg) did not significantly affect the clearance of nivolumab based on a population pharmacokinetic analysis.
Other
Baseline LDH, PD-L1 expression, tumor type, or tumor size did not significantly affect the clearance of nivolumab based on a population pharmacokinetic analysis.
The clearance of nivolumab was increased by 42% in patients who had anti-nivolumab antibodies and received combination therapy with nivolumab and ipilimumab; ipilimumab clearance was not affected in patients who developed anti-ipilimumab antibodies.