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

    DEA CLASS

    Rx

    DESCRIPTION

    Programmed death receptor-1 (PD-1) blocking monoclonal antibody
    Used for certain types of colorectal cancer, esophageal cancer, gastric cancer, gastroesophageal junction (GEJ) cancer, head and neck cancer, hepatocellular cancer, Hodgkin lymphoma, melanoma, mesothelioma, 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

    COMMON BRAND NAMES

    Opdivo

    HOW SUPPLIED

    Nivolumab/Opdivo Intravenous Inj Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    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 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.[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).

    For the treatment of unresectable or metastatic melanoma, in combination with ipilimumab.
    Intravenous dosage
    Adults

    1 mg/kg IV over 30 minutes followed by ipilimumab 3 mg/kg IV over 30 minutes repeated every 3 weeks for 4 doses followed by nivolumab 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. Nivolumab and ipilimumab 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).

    For the adjuvant treatment of melanoma in patients with lymph node involvement or metastatic disease who have undergone complete resection.
    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 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.

    For the treatment of non-small cell lung cancer (NSCLC).
    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

    3 mg/kg IV over 30 minutes every 2 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 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 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 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 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, with the lower end of the confidence interval not reached in the nivolumab plus cabozantinib arm compared with 22.6 months in the sunitinib arm. The objective response rate was 55.7% (complete response, [8%]) versus 27.1% (CR, 4.6%), 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. 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.

    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. 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%).

    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.[58668]

    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.[58668]

    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.[58668]

    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 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 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 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 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.

    MAXIMUM DOSAGE

    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

    Single agent (colorectal cancer only): 480 mg IV every 4 weeks or 240 mg IV every 2 weeks.

    Children

    12 years: Single agent (colorectal cancer only): 480 mg IV every 4 weeks or 240 mg IV every 2 weeks.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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    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).

    ADMINISTRATION

    Emetic Risk
    Minimal

    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.[58668]

    STORAGE

    Opdivo:
    - Diluted product must be used within 8 hours
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store diluted product in accordance with package insert instructions
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Immune-mediated reactions

    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.

    Pneumonitis, radiation 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.[58668]

    Colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, viral infection

    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.[58668]

    Hepatitis, hepatotoxicity

    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.[58668]

    Renal failure, renal impairment

    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.

    Adrenal insufficiency, hypophysitis, hypopituitarism

    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.[58668]

    Hyperthyroidism, hypothyroidism

    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.

    Infusion-related reactions

    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.

    Serious rash

    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.[58668]

    Diabetic ketoacidosis, hyperglycemia, type 1 diabetes mellitus

    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.

    Allogeneic stem cell transplant

    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.[58668]

    Multiple myeloma, treatment outside of a clinical trial

    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.[58668]

    Autoimmune disease, organ transplant, systemic lupus erythematosus (SLE)

    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.

    Guillain-Barre syndrome, myasthenia gravis, neurological disease

    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

    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.

    Pregnancy

    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.

    Contraception requirements, pregnancy testing, reproductive risk

    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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    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
    pneumonitis / Delayed / 0.9-4.7
    musculoskeletal pain / Early / 0-4.5
    pleural effusion / Delayed / 1.0-4.5
    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
    anorexia / Delayed / 0.9-2.2
    influenza / Delayed / 0-2.0
    hypertriglyceridemia / Delayed / 0-2.0
    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
    weight loss / 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
    dysphagia / Delayed / 0-0.8
    alopecia / Delayed / 0-0.8
    cough / Delayed / 0-0.7
    hypothyroidism / 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

    Moderate

    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

    Mild

    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

    DRUG INTERACTIONS

    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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]

    Intravenous Route

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