Opdivo

Antineoplastic Monoclonal Antibodies Targeting Programmed Death-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) Pathways

Emetic Risk
Minimal

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.

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.[58668]

graft-versus-host disease (GVHD) / Delayed / 0-29.0
lymphopenia / Delayed / 0.4-19.0
neutropenia / Delayed / 0-15.0
hepatitis B exacerbation / Delayed / 0-14.0
hyperamylasemia / Delayed / 0-12.0
hyponatremia / Delayed / 1.1-11.0
hepatotoxicity / Delayed / 0-11.0
ventricular tachycardia / Early / 0-10.0
leukopenia / Delayed / 0-10.0
anemia / Delayed / 0-9.0
hyperglycemia / Delayed / 0-7.0
thrombocytopenia / Delayed / 0-7.0
veno-occlusive disease (VOD) / Delayed / 0-6.0
sinusoidal obstruction syndrome (SOS) / Delayed / 0-6.0
ascites / Delayed / 0-6.0
hyperkalemia / Delayed / 0-5.0
hypertension / Early / 0-5.0
dysphagia / Delayed / 0-5.0
pneumonitis / Delayed / 0.9-4.7
musculoskeletal pain / Early / 0-4.5
pleural effusion / Delayed / 1.0-4.5
anorexia / Delayed / 0.9-4.0
back pain / Delayed / 0-3.4
dyspnea / Early / 0.4-3.3
pulmonary embolism / Delayed / 2.0-3.3
hypercalcemia / Delayed / 0-3.2
hypokalemia / Delayed / 0-3.2
influenza / Delayed / 0-2.0
hypertriglyceridemia / Delayed / 0-2.0
weight loss / Delayed / 0-1.9
hypocalcemia / Delayed / 0-1.7
headache / Early / 0-1.7
fever / Early / 0-1.6
hypoglycemia / Early / 0-1.4
hyperthyroidism / Delayed / 0-1.3
arthralgia / Delayed / 0-1.3
hypomagnesemia / Delayed / 0-1.2
interstitial nephritis / Delayed / 0-1.2
rhabdomyolysis / Delayed / 0-1.0
pancreatitis / Delayed / 0-1.0
uveitis / Delayed / 0-1.0
peripheral neuropathy / Delayed / 0-1.0
myelitis / Delayed / 0-1.0
hypoesthesia / Delayed / 0-1.0
hyperesthesia / Delayed / 0-1.0
myasthenia gravis / Delayed / 0-1.0
Guillain-Barre syndrome / Delayed / 0-1.0
dysesthesia / Delayed / 0-1.0
infusion-related reactions / Rapid / 0-1.0
vasculitis / Delayed / 0-1.0
pericarditis / Delayed / 0-1.0
myocarditis / Delayed / 0-1.0
hemolytic anemia / Delayed / 0-1.0
aplastic anemia / Delayed / 0-1.0
organ transplant rejection / Delayed / 0-1.0
hemophagocytic lymphohistiocytosis / Delayed / 0-1.0
alopecia / Delayed / 0-0.8
cough / Delayed / 0-0.7
hypothyroidism / Delayed / 0-0.6
stomatitis / Delayed / 0-0.6
dizziness / Early / 0-0.6
GI bleeding / Delayed / 0-0.5
tracheoesophageal fistula / Delayed / 0-0.5
diabetes mellitus / Delayed / 0-0.4
hypercholesterolemia / Delayed / 0-0.3
diabetic ketoacidosis / Delayed / 0-0.1
pharyngitis / Delayed / 1.1
sinusitis / Delayed / 1.1
infection / Delayed / 0.8
rhinitis / Early / 1.1
interstitial lung disease / Delayed / 2.0
renal failure (unspecified) / Delayed / Incidence not known
Vogt-Koyanagi-Harada syndrome / Delayed / Incidence not known
visual impairment / Early / Incidence not known
retinal detachment / Delayed / Incidence not known
atrial fibrillation / Early / Incidence not known

antibody formation / Delayed / 0.7-38.0
myopathy / Delayed / 0-10.0
neuritis / Delayed / 0-10.0
peripheral edema / Delayed / 0-10.0
hypotension / Rapid / 0-10.0
hepatitis / Delayed / 1.5-9.0
gastritis / Delayed / 0-1.0
hypoparathyroidism / Delayed / 0-1.0
ocular inflammation / Early / 0-1.0
iritis / Delayed / 0-1.0
meningitis / Delayed / 0-1.0
paresis / Delayed / 0-1.0
dehydration / Delayed / 2.0
cystitis / Delayed / Incidence not known
dysphonia / Delayed / Incidence not known
synovitis / Delayed / Incidence not known
hypernatremia / Delayed / Incidence not known
hypophosphatemia / Delayed / Incidence not known
cholangitis / Delayed / Incidence not known
blurred vision / Early / Incidence not known
oral ulceration / Delayed / Incidence not known
migraine / Early / Incidence not known
hemoptysis / Delayed / Incidence not known
eosinophilia / Delayed / Incidence not known
hypoalbuminemia / Delayed / Incidence not known

insomnia / Early / 0-18.0
nasal congestion / Early / 0-11.0
chills / Rapid / 0-10.0
arthropathy / Delayed / 0-10.0
xerosis / Delayed / 0-7.0
paresthesias / Delayed / 0-1.0
purpura / Delayed / 0-1.0
muscle cramps / Delayed / Incidence not known
dysgeusia / Early / Incidence not known
gastroesophageal reflux / Delayed / Incidence not known
vertigo / Early / Incidence not known

Opdivo

Rx

Programmed death receptor-1 (PD-1) blocking monoclonal antibody
Used for esophageal cancer, gastric cancer, gastroesophageal junction cancer, head and neck cancer, hepatocellular cancer, Hodgkin lymphoma, melanoma (adult and pediatric patients 12 years and older), mesothelioma, microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer (adult and pediatric patients 12 years and older), non-small cell lung cancer, renal cell cancer, and urothelial cancer
Immune-mediated reactions have been reported; treatment may need to be withheld or permanently discontinued

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.[58668] 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.[62159] 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.[64008] 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).

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.

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.

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.[58668] 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).

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

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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. 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 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.

240 mg IV every 2 weeks OR 480 mg IV every 4 weeks. Continue 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. 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. 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%).

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.[58668]

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.

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.

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.[58668]

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.

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.[58668]

Dosage not established.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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 o

Treatment-Related Immune-Mediated Hepatitis
Monotherapy
No Tumor Involvement of the LiverAST 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 LiverBaseline 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 ULNAST 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 ULNAST 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 levelAST 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 HCCBaseline 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 ULNAST 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 ULNAST 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 levelAST 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.

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).

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/Opdivo Intravenous Inj Sol: 1mL, 10mg

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.

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.

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).

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.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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.[58668]

The predicted exposure of nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion.

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.

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.