Nivolumab

Previously treated patients. Accelerated approval was based on a planned noncomparative interim analysis of the first 120 patients who received nivolumab with at least 6 months of follow-up from a multicenter, open-label trial (CheckMate 037 [NCT01721746]). In this trial, patients were randomly assigned (2:1) to receive either nivolumab (3 mg/kg every 2 weeks) or the investigator’s choice of chemotherapy (either dacarbazine 1,000 mg/m2 IV every 3 weeks or the combination of carboplatin [area under the curve 6] every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks).[FDA label][Level of evidence C3] Patients were required to have unresectable or metastatic melanoma that had progressed after treatment with ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe irAEs from treatment with ipilimumab.The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

Previously treated patients. Accelerated approval was based on a planned noncomparative interim analysis of the first 120 patients who received nivolumab with at least 6 months of follow-up from a multicenter, open-label trial (CheckMate 037 [NCT01721746]). In this trial, patients were randomly assigned (2:1) to receive either nivolumab (3 mg/kg every 2 weeks) or the investigator’s choice of chemotherapy (either dacarbazine 1,000 mg/m2 IV every 3 weeks or the combination of carboplatin [area under the curve 6] every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks).[FDA label][Level of evidence C3] Patients were required to have unresectable or metastatic melanoma that had progressed after treatment with ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe irAEs from treatment with ipilimumab.The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

The median age of patients was 58 years; 65% of patients were male; and ECOG PS was 0 in 58% of patients. BRAF V600 pathogenic variants were present in 22% of patients; 76% had M1c disease; 56% had elevated LDH levels; 18% had a history of brain metastases; and, 68% had previously received two or more systemic therapies for metastatic disease.

Previously treated patients. Accelerated approval was based on a planned noncomparative interim analysis of the first 120 patients who received nivolumab with at least 6 months of follow-up from a multicenter, open-label trial (CheckMate 037 [NCT01721746]). In this trial, patients were randomly assigned (2:1) to receive either nivolumab (3 mg/kg every 2 weeks) or the investigator’s choice of chemotherapy (either dacarbazine 1,000 mg/m2 IV every 3 weeks or the combination of carboplatin [area under the curve 6] every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks).[FDA label][Level of evidence C3] Patients were required to have unresectable or metastatic melanoma that had progressed after treatment with ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe irAEs from treatment with ipilimumab.The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

Objective response rate and OS were coprimary end points. The objective response rate was 32% (95% CI, 23%–41%), with four complete responses and 34 partial responses as assessed by RECIST 1.1 criteria and an independent central review. Among the 38 patients with responses, 33 (87%) had ongoing responses, with durations from 2.6+ to 10.0+ months.

Previously treated patients. Accelerated approval was based on a planned noncomparative interim analysis of the first 120 patients who received nivolumab with at least 6 months of follow-up from a multicenter, open-label trial (CheckMate 037 [NCT01721746]). In this trial, patients were randomly assigned (2:1) to receive either nivolumab (3 mg/kg every 2 weeks) or the investigator’s choice of chemotherapy (either dacarbazine 1,000 mg/m2 IV every 3 weeks or the combination of carboplatin [area under the curve 6] every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks).[FDA label][Level of evidence C3] Patients were required to have unresectable or metastatic melanoma that had progressed after treatment with ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe irAEs from treatment with ipilimumab.The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

Responses were seen in patients with and without BRAF V600 pathogenic variants.

Previously treated patients. Accelerated approval was based on a planned noncomparative interim analysis of the first 120 patients who received nivolumab with at least 6 months of follow-up from a multicenter, open-label trial (CheckMate 037 [NCT01721746]). In this trial, patients were randomly assigned (2:1) to receive either nivolumab (3 mg/kg every 2 weeks) or the investigator’s choice of chemotherapy (either dacarbazine 1,000 mg/m2 IV every 3 weeks or the combination of carboplatin [area under the curve 6] every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks).[FDA label][Level of evidence C3] Patients were required to have unresectable or metastatic melanoma that had progressed after treatment with ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe irAEs from treatment with ipilimumab.The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

Safety analysis is based on 268 patients. Nivolumab was discontinued because of adverse events in 9% of patients. Serious adverse events occurred in 41% of patients, and grade 3 and grade 4 adverse events occurred in 42% of patients. The most common adverse events were rash, cough, upper respiratory tract infection, and peripheral edema. Other important adverse events included ventricular arrhythmia, iridocyclitis, increased amylase and lipase, dizziness, and neuropathy.

Previously untreated patients. A double-blind multicenter trial (CheckMate 066 [NCT01721772]) included 418 patients with unresectable stage III or stage IV melanoma without BRAF pathogenic variants. Patients were randomly assigned (1:1) to receive either nivolumab (3 mg/kg every 2 weeks) and a dacarbazine-matched placebo (every 3 weeks) or dacarbazine (1,000 mg/m2 every 3 weeks with a nivolumab-matched placebo every 2 weeks). The primary end point was OS.[4][Level of evidence A1] The trial was conducted in 80 centers in Europe, Israel, Australia, Canada, and South America, which are countries where dacarbazine had been a standard first-line treatment in patients without BRAF pathogenic variants.

Previously untreated patients. A double-blind multicenter trial (CheckMate 066 [NCT01721772]) included 418 patients with unresectable stage III or stage IV melanoma without BRAF pathogenic variants. Patients were randomly assigned (1:1) to receive either nivolumab (3 mg/kg every 2 weeks) and a dacarbazine-matched placebo (every 3 weeks) or dacarbazine (1,000 mg/m2 every 3 weeks with a nivolumab-matched placebo every 2 weeks). The primary end point was OS.[4][Level of evidence A1] The trial was conducted in 80 centers in Europe, Israel, Australia, Canada, and South America, which are countries where dacarbazine had been a standard first-line treatment in patients without BRAF pathogenic variants.

The Data and Monitoring Safety Board (DMSB) noted a potential difference in OS during safety review. In 2014, an abbreviated report from an unplanned interim–database lock was reviewed showing a significant difference in OS, in favor of nivolumab. The DMSB recommended that the study be unblinded and allow patients on dacarbazine to receive nivolumab. The intended sample size was approximately 410 patients; a total of 418 patients had been entered.

Previously untreated patients. A double-blind multicenter trial (CheckMate 066 [NCT01721772]) included 418 patients with unresectable stage III or stage IV melanoma without BRAF pathogenic variants. Patients were randomly assigned (1:1) to receive either nivolumab (3 mg/kg every 2 weeks) and a dacarbazine-matched placebo (every 3 weeks) or dacarbazine (1,000 mg/m2 every 3 weeks with a nivolumab-matched placebo every 2 weeks). The primary end point was OS.[4][Level of evidence A1] The trial was conducted in 80 centers in Europe, Israel, Australia, Canada, and South America, which are countries where dacarbazine had been a standard first-line treatment in patients without BRAF pathogenic variants.

Results from the double-blind portion of the study before the crossover amendment showed that median OS was not reached in the nivolumab group and was 10.8 months (95% CI, 9.3–12.1) in the dacarbazine group. The 1-year OS rate was 72.9% (95% CI, 65.%–78.9%) in the nivolumab group and 42.1% (95% CI, 33.0%–50.9%) in the dacarbazine group. The HRdeath was 0.42 (99.79% CI, 0.25–0.73; P < .001).

Previously untreated patients. A double-blind multicenter trial (CheckMate 066 [NCT01721772]) included 418 patients with unresectable stage III or stage IV melanoma without BRAF pathogenic variants. Patients were randomly assigned (1:1) to receive either nivolumab (3 mg/kg every 2 weeks) and a dacarbazine-matched placebo (every 3 weeks) or dacarbazine (1,000 mg/m2 every 3 weeks with a nivolumab-matched placebo every 2 weeks). The primary end point was OS.[4][Level of evidence A1] The trial was conducted in 80 centers in Europe, Israel, Australia, Canada, and South America, which are countries where dacarbazine had been a standard first-line treatment in patients without BRAF pathogenic variants.

The most common adverse events in the nivolumab group were fatigue (19.9%), pruritus (17%), nausea (16.5%), and diarrhea (16%). Adverse events led to treatment discontinuation in 6.8% of patients in the nivolumab group and 11.7% of patients in the dacarbazine group. Adverse events with potential immunological etiology that occurred included gastrointestinal, hepatic, pulmonary, renal, endocrine, and skin. However, most resolved with a delay in study treatment, glucocorticoid administration, or both per management guidelines for nivolumab. No deaths were attributed to drug-related adverse events in either group.

Change in dosing regimen for nivolumab in metastatic melanoma.

Change in dosing regimen for nivolumab in metastatic melanoma.

In a population pharmacokinetic response analysis and a dose/exposure-response analysis, the flat dose of 240 mg of nivolumab every 2 weeks was considered pharmacokinetically equivalent to the dosing regimen of 3 mg/kg. Clinical safety and efficacy at the two doses appeared similar across body weight and tumor types in melanoma, non-small cell lung cancer, and renal cell carcinoma.[5]

Change in dosing regimen for nivolumab in metastatic melanoma.

The dosing regimen approved by the FDA for monotherapy has changed from 3 mg/kg to 240 mg IV every 2 weeks until disease progression or intolerable toxicity. The dosing regimen of 1 mg/kg of IV nivolumab when combined with ipilimumab will remain unchanged until after therapy with ipilimumab is complete, when the regimen will change to a 240 mg dose every 2 weeks until disease progression or intolerable toxicity.