In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On December 22, 2014, the anti–PD-1 (programmed cell death protein 1) monoclonal antibody nivolumab (Opdivo) was granted accelerated approval for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy) treatment and, if BRAF V600 mutation–positive, a BRAF inhibitor.1,2 As a condition of accelerated approval, Bristol-Myers Squibb is required to conduct a multicenter randomized trial establishing the superiority of nivolumab over standard therapy in this setting to verify and describe the clinical benefit of nivolumab.
Supporting Study
Approval was based on objective response rate and durability of response in the first 120 patients treated with nivolumab who had at least 6 months of follow-up from an ongoing open-label trial in which 370 patients with unresectable or metastatic melanoma were randomized to receive intravenous nivolumab 3 mg/kg every 2 weeks (n = 268) or investigator choice of chemotherapy (n = 102). Chemotherapy consisted of either dacarbazine or the combination of carboplatin/paclitaxel. Patients were treated until disease progression or unacceptable toxicity.
Patients had to have disease progression after ipilimumab treatment and after BRAF inhibitor treatment if BRAF V600 mutation–positive. Patients were excluded from the study if they had an autoimmune disease, a medical condition that required corticosteroids or immunosuppression, or a history of severe ipilimumab-related adverse reactions.
Among the first 120 patients, the median age was 58 years (68% younger than age 65), 65% were male, 98% were white, 58% and 42% had a baseline Eastern Cooperative Oncology Group performance status of 0 and 1, 22% had BRAF V600–mutant disease, 56% had an elevated LDH level, 76% had M1c disease, 18% had a history of brain metastases, and 68% had received at least two prior therapies for advanced or metastatic disease.
On blinded independent review, the objective response rate was 32% (95% confidence interval = 23%–41%), including four complete responses. At the time of reporting, 33 of the 38 responders had an ongoing response of 2.6+ to 10+ months, with 13 having a response of at least 6 months. Responses occurred in patients with and without BRAF V600–mutant disease.
How It Works
Nivolumab binds the PD-1 receptor on T cells and prevents its interaction with the ligands PD-L1 and PD-L2, thereby blocking the PD-1 pathway–mediated inhibition of the immune response, including the antitumor immune response. Binding of PD-L1 and PD-L2 to the PD-1 receptor inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse tumor models, blocking PD-1 activity results in decreased tumor growth.
How It Is Given
The recommended dose of nivolumab is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
Nivolumab treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, an alanine transaminase or aspartate transaminase level more than 3 to 5 times the upper limit of normal or total bilirubin more than 1.5 to 3 times the upper limit of normal, serum creatinine more than 1.5 to 6 times the upper limit of normal or more than 1.5 times baseline level, and any other severe or grade 3 treatment-related adverse reaction. There are no recommended dose modifications for hypothyroidism or hyperthyroidism.
Nivolumab can be resumed when adverse reactions resolve to grade 0 or 1. No dose modifications are required in patients with renal impairment or mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment.
Nivolumab should be discontinued for any life-threatening or grade 4 adverse reaction, grade 3 or 4 pneumonitis, grade 4 colitis, an alanine transaminase or aspartate transaminase level more than 5 times the upper limit of normal or total bilirubin more than 3 times the upper limit of normal, serum creatinine more than 6 times the upper limit of normal, any recurring severe or grade 3 treatment-related adverse reaction, inability to reduce the corticosteroid dose to ≤ 10 mg/day of prednisone or equivalent within 12 weeks, and persistent grade 2 or 3 treatment-related adverse reactions that do not recover to grade 0 or 1 within 12 weeks after the last dose.
Safety Profile
Adverse event data are from 268 nivolumab and 102 chemotherapy patients in the randomized trial. Adverse events of any grade that occurred in at least 10% of the nivolumab group and at an incidence at least 5% higher vs the chemotherapy group were rash (21% vs 7%), pruritus (19% vs 4%), cough (17% vs 6%), upper respiratory tract infection (11% vs 2%), and peripheral edema (19% vs 5%). Grade 3 or 4 adverse events occurred in 42% of nivolumab patients, with the most frequent (all 2% to 5%) being abdominal pain, hyponatremia, increased aspartate transaminase level, and increased lipase level. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, nephritis/renal dysfunction, hypothyroidism, and hyperthyroidism.
The most common laboratory abnormalities of any grade occurring at an incidence of more than 5% higher vs the chemotherapy group were an increased aspartate transaminase level (28% vs 12%, 2.4% vs 1.0% grade 3/4), hyponatremia (25% vs 18%, 5% vs 1.1% grade 3/4), increased alkaline phosphatase level (22% vs 13%, 2.4% vs 1.1% grade 3/4), increased alanine transaminase level (16% vs 5%, 1.6% vs 0% grade 3/4), and hyperkalemia (15% vs 6%, 2.0 vs 0% grade 3/4).
Serious adverse events occurred in 41% of nivolumab patients, and adverse events led to treatment delay in 26% and treatment discontinuation in 9%.
Nivolumab carries warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, nephritis/renal dysfunction, hypothyroidism and hyperthyroidism, as well as embryo-fetal toxicity. Patients should receive corticosteroid treatment for immune-mediated adverse reactions based on reaction severity. Patients should be monitored for liver and kidney function. Thyroid hormone replacement should be used as needed. ■
References
1. US FDA Press Release: Approved drugs. Nivolumab. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm427807.htm. Accessed January 7, 2015.
2. Opdivo (nivolumab) injection prescribing information, Bristol-Myers Squibb Company, December 2014. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf.
Accessed January 7, 2015.
