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 23, 2015, nivolumab (Opdivo) was approved for use in the treatment of patients with advanced renal cell carcinoma who have received prior antiangiogenic therapy.1,2
Supporting Efficacy Data
Approval was based on improved overall survival in a phase III trial (CheckMate 025) in which 821 patients with advanced renal cell carcinoma who had received prior antiangiogenic therapy were randomly assigned to nivolumab at 3 mg/kg intravenously every 2 weeks (n = 410) or oral everolimus (Afinitor) at 10 mg once daily (n = 411).2,3 Patients had a median age of 62 years (40% ≥ 65 and 9% ≥ 75 years), 75% were male, 88% were white, Karnofsky performance score was 70 to 80 in 34% and 90 to 100 in 66%, 77% had received prior antiangiogenic therapy, and Memorial Sloan Kettering risk was favorable in 34%, intermediate in 47%, and poor in 19%.
At a prespecified interim analysis based on 70% of planned events, median overall survival, the primary endpoint, was 25.0 months (95% confidence interval [CI] = 21.7 months to not estimable) in the nivolumab group vs 19.6 months (95% CI = 17.6–23.1 months) in the everolimus group (hazard ratio = 0.73, P = .0018). A survival benefit was observed regardless of programmed cell death ligand 1 (PD-L1) expression level. The confirmed response rate was 21.5% vs 3.9%, median response duration was 23.0 vs 13.7 months, and median time to response was 3.0 to 3.7 months.
How It Works
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds the programmed cell death protein 1 (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) > 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 > 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 in the nivolumab group were asthenic conditions (56% vs 57% in everolimus group), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), and dyspnea (27% vs 31%). Grade 3 or 4 adverse events occurred in 56% vs 62% of patients, including asthenic conditions in 6% vs 7%, dyspnea in 3% vs 2%, and back pain in 3% vs 3%.
Serious adverse events occurred in 47% of nivolumab patients, with those occurring in ≥ 2% consisting of acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common grade 3 or 4 laboratory abnormalities were anemia (8% vs 16%), hyponatremia (7% vs 6%), and lymphopenia (6% vs 11%). Among patients with thyroid-stimulating hormone less than the upper limit of normal, increase to greater than upper limit of normal was more common in the nivolumab group (26% vs 14%).
Adverse events led to treatment delay in 44% of nivolumab patients and to discontinuation in 16% (vs 19% of the everolimus group). Death during or within 30 days of treatment occurred in 4.7% vs 8.6% of patients.
Potential immune-mediated adverse events were pneumonitis (including interstitial lung disease) in 5.2% (immune-mediated pneumonitis in 4.4%) vs 18.4%; diarrhea or colitis in 25% (immune-mediated in 3.2%) vs 32%; liver test abnormalities including increases in AST in 33% vs 39%, alkaline phosphatase in 32% vs 32%, ALT in 22% vs 31%, and total bilirubin in 9% vs 3%, with immune-mediated hepatitis requiring systemic immunosuppression in 1.5% of nivolumab patients; hypophysitis in 0.5%; adrenal insufficiency in 2%; thyroid disease in 10.6% vs 3.0%, with hypothyroidism/thyroiditis in 8.1% and hyperthyroidism in 2.5% of the nivolumab group; hyperglycemia in 9%, with diabetes or diabetic ketoacidosis in 1%; renal injury in 6.6% vs 3.0%, with immune-mediated nephritis and renal dysfunction in 3.2% of the nivolumab group; and rash in 28% (immune-mediated in 7.4%) vs 36%.
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 during nivolumab therapy. ■
1. U.S. Food and Drug Administration: Nivolumab (Opdivo injection). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm474092.htm. Accessed December 7, 2015.
2. Opdivo (nivolumab) injection for intravenous use prescribing information, Bristol-Myers Squibb Company, November 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/125554s012lbl.pdf. Accessed December 7, 2015.
3. Motzer RJ, Escudier B, McDermott DF, et al: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803-1813, 2015.