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 November 24, 2015, nivolumab (Opdivo) was approved for use as a single agent in the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.1 Nivolumab has prior approvals in unresectable or metastatic melanoma for use as a single agent in patients with BRAF V600 mutation–positive disease and disease progression following treatment with ipilimumab (Yervoy) and a BRAF inhibitor and in combination with ipilimumab in patients with BRAF V600 wild-type disease.
Supporting Efficacy Data
Approval was based on improvement in overall survival in a double-blind phase III trial (CheckMate 066) in which 418 treatment-naive patients were randomized to receive nivolumab at 3 mg/kg every 2 weeks and dacarbazine every 3 weeks (n = 210) or dacarbazine at 1,000 mg/m2 every 3 weeks and placebo every 2 weeks (n = 208).1,2
Patients had a median age of 65 years, 59% were male, 99.5% were white, 61% had stage M1c disease, 74% had cutaneous melanoma, 11% had mucosal melanoma, 37% had elevated lactate dehydrogenase, 35% had programmed cell death ligand 1 (PD-L1) ≥ 5% tumor cell membrane expression, and 4% had a history of brain metastasis. More patients in the nivolumab group had a performance status of 0 (71% vs 58%).
In an interim analysis based on 47% of the total planned events, median overall survival (the primary endpoint) was not reached in the nivolumab group vs 10.8 months (95% confidence interval [CI] = 9.3–12.1 months) in the dacarbazine group (hazard ratio [HR] = 0.42, P < .0001). Median progression-free survival was 5.1 months (95% CI = 3.5–10.8 months) vs 2.2 months (95% CI = 2.1–2.4 months; HR = 0.43, P < .0001).
Objective response rates were 34% (complete response in 4%) vs 9% (complete response in 1%). At the time of analysis, 88% of responders in the nivolumab group had ongoing responses, with an ongoing response of ≥ 6 months in 60%.
How It Works
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds the PD-1 receptor on T cells and prevents its interaction with the ligands PD-L1 and PD-L2, thereby blocking PD-1 pathway–mediated inhibition of immune response, including 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.
How It Is Used
The recommended dose of single-agent nivolumab in this setting is 3 mg/kg via intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Infusion should be interrupted or slowed in patients with mild or moderate infusion reactions. Nivolumab should be discontinued for severe or life-threatening infusion reactions.
Single-agent nivolumab should be withheld for grade 2 pneumonitis, grade 2 or 3 diarrhea or colitis, alanine transaminase (ALT) or aspartate transaminase (AST) levels > 3 to 5 times the upper limit of normal or total bilirubin > 1.5 to 3 times the upper limit of normal, serum creatinine > 1.5 to 6 times the upper limit of normal, grade 2 or 3 hypophysitis, grade 2 adrenal insufficiency, grade 3 hyperglycemia, grade 3 rash, encephalitis indicated by new-onset moderate or severe neurologic signs/symptoms, and first occurrence of other grade 3 adverse reactions. There are no recommended dose modifications for hypothyroidism or hyperthyroidism. No dose adjustment is 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 grade 4 diarrhea or colitis, grade 3 or 4 pneumonitis, grade 4 hypophysitis, grade 3 or 4 adrenal insufficiency, grade 4 hyperglycemia, grade 4 rash, any life-threatening or grade 4 adverse reaction, AST or ALT levels > 5 times the upper limit of normal or total bilirubin > 3 times the upper limit of normal, serum creatinine > 6 times the upper limit of normal, immune-mediated encephalitis, recurrence of grade 3 adverse reactions, any life-threatening or grade 4 adverse reaction, persistent grade 2 or 3 adverse reactions lasting ≥ 12 weeks, and requirement of prednisone or equivalent dose of ≥ 10 mg for > 12 weeks.
In the phase III trial, the most common adverse events of any grade occurring at a frequency ≥ 5% higher in the nivolumab vs dacarbazine group were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). Grade 3 or 4 adverse events occurred in 41% of the nivolumab group, with the most common being increased gamma-glutamyltransferase (3.9%) and diarrhea (3.4%). Grade 3 or 4 increases in AST, ALT, bilirubin, or alkaline phosphatase levels occurred in 2.6% to 3.6% of nivolumab patients. Serious adverse events occurred in 36%. Adverse events led to dose interruption in 26% and permanent treatment discontinuation in 7%, with no single type accounting for a majority of treatment discontinuations.
Adverse events in patients who received nivolumab that are among immune-related reactions known to be caused by nivolumab included the following: pneumonitis (1.4% vs 0%); diarrhea or colitis (28% vs 25%); liver test abnormalities including increased ALT (25% vs 19%), AST (24% vs 19%), alkaline phosphatase (21% vs 14%), and total bilirubin levels (13% vs 6%) and immune-mediated hepatitis (0.9%); hypothyroidism (7% vs 0.9%) and hyperthyroidism (4.4% vs 0.9%); diabetes or diabetic ketoacidosis (1.0% vs 0%); and elevated creatinine (11% vs 10%).
Nivolumab carries warnings/precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, encephalitis, and embryofetal toxicity. Patients should be monitored for changes in liver, kidney, thyroid, and neurologic function and for hyperglycemia. Breastfeeding women should discontinue breastfeeding while receiving nivolumab. ■
1. Opdivo (nivolumab) injection for intravenous use prescribing information, Bristol-Myers Squibb Company, November 2015. Available at www.opdivo.com. Accessed December 14, 2015.
2. Robert C, Long GV, Brady B, et al: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320-330, 2015.