On December 20, 2017, nivolumab (Opdivo) was granted regular approval for adjuvant treatment of patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection.1,2 Nivolumab was previously approved for the treatment of patients with unresectable or metastatic melanoma.
Supporting Efficacy Data
Approval was based on improvement in recurrence-free survival in a double-blind phase III trial (CHECKMATE-238) in which 906 patients with completely resected stage IIIB/C or stage IV melanoma were randomized to receive nivolumab at 3 mg/ kg every 2 weeks (n = 453) or ipilimumab (Yervoy) at 10 mg/kg every 3 weeks for 4 doses and then every 12 weeks beginning at week 24 (n = 453) for up to 1 year.2,3 Enrollment required complete resection of melanoma with margins negative for disease within 12 weeks prior to randomization. Randomization was stratified by programmed cell death ligand 1 (PD-L1) status and disease stage.
Nivolumab carries warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis.
The median age of patients was 55 years; 58% were male; 95% were white; the disease stage was IIIB in 34%, IIIC in 47%, IV in 19%, and M1a–b in 14%; 42% had BRAF V600–positive disease; and 34% had PD-L1 tumor cell membrane expression ≥ 5%.
Patients in the nivolumab group had fewer recurrences/deaths (34.0% vs 45.5%), yielding a hazard ratio of 0.65 (P < .0001). Median recurrence-free survival was not reached in either group.
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 PD-L1 and PD-L2, thereby releasing 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. In syngeneic mouse tumor models, blocking PD-1 activity results in decreased tumor growth.
Combined anti–PD-1 and anti–CTLA-4 (cytotoxic T-lymphocyte–associated protein 4)–mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone and results in improved antitumor responses in metastatic melanoma. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased antitumor activity.
How It Is Used
The recommended dose/schedule of nivolumab in the current indication is 240 mg (changed from the study dose) given by intravenous infusion over 60 minutes every 2 weeks until disease recurrence or unacceptable toxicity for a maximum of 1 year. 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. There are no recommended dose modifications for hypothyroidism or hyperthyroidism.
In patients receiving single-agent nivolumab, treatment should be withheld for the following conditions: grade 2 or 3 diarrhea or colitis; grade 2 pneumonitis; hepatitis/nonhepatocellular carcinoma (HCC)—for alanine transaminase (ALT) or aspartate transaminase (AST) > 3 up to 5 times the upper limit of normal (ULN) or total bilirubin level > 1.5 up to 3 times ULN; hepatitis/HCC—if AST/ALT is within normal limits at baseline and increases to more than 3 and up to 5 times ULN, if AST/ALT is > 1 and up to 3 times ULN at baseline and increases to > 5 and up to 10 times ULN, or if AST/ALT is > 3 and up to 5 times ULN at baseline and increases to > 8 and up to 10 times ULN; grade 2 or 3 hypophysitis; serum creatinine > 1.5 to 6 times ULN; grade 2 adrenal insufficiency; grade 3 hyperglycemia; grade 3 rash or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis; new-onset moderate or severe neurologic signs or symptoms; and first occurrence of other grade 3 adverse reactions.
Nivolumab should be permanently discontinued for the following conditions: grade 4 diarrhea or colitis; grade 3 or 4 pneumonitis; hepatitis/non-HCC—for AST or ALT > 5 times ULN or total bilirubin > 3 times ULN; hepatitis/HCC—if AST/ALT increases to > 10 times ULN or total bilirubin level increases to > 3 times ULN; grade 4 hypophysitis; grade 3 or 4 adrenal insufficiency; grade 4 hyperglycemia; serum creatinine levels > 6 times ULN; grade 4 rash or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis; immune-mediated encephalitis; recurrence of grade 3 adverse reactions; life-threatening or grade 4 adverse reactions; grade 3 myocarditis; requirement of ≥ 10 mg/d of prednisone or equivalent for > 12 weeks; and persistent grade 2 or 3 adverse reactions lasting ≥ 12 weeks.
In clinical trials, the most common adverse events (> 20%) with nivolumab as a single agent have been fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, and abdominal pain.
In CHECKMATE-238, the median duration of exposure was 11.5 months in nivolumab patients and 2.7 months in ipilimumab patients. In this ongoing trial, 74% of nivolumab patients received the drug for more than 6 months. The most common adverse events of any grade in the nivolumab group were fatigue (57% vs 55% in the ipilimumab group), diarrhea (37% vs 55%), rash (35% vs 47%), and musculoskeletal pain (32% vs 27%). Grade 3 or 4 adverse events occurred in 25% of the nivolumab group, with the most common being increased lipase (7.0%), increased amylase (3.3%), and diarrhea (2.4%). The most common immune-mediated adverse events in the nivolumab group were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). Serious adverse events were noted in 18% of nivolumab patients. Adverse events led to drug discontinuation in 9% of nivolumab patients vs 42% of ipilimumab patients.
Nivolumab carries warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. It also carries warnings/precautions for infusion reactions, complications of allogeneic hematopoietic stem cell transplantation after nivolumab treatment, and embryofetal toxicity. Patients should be monitored for changes in liver, thyroid, kidney, and neurologic function and for hyperglycemia. Breastfeeding women should discontinue breastfeeding when receiving nivolumab. ■
1. U.S. Food and Drug Administration: FDA grants regular approval to nivolumab for adjuvant treatment of melanoma. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590004.htm. Accessed April 11, 2018.
2. Opdivo (nivolumab) injection prescribing information, Bristol-Myers Squibb Company, December 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s055lbl.pdf. Accessed April 11, 2018.
3. Weber J, Mandala M, Del Vecchio M, et al: Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 377:1824-1835, 2017.