In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On April 16, 2018, nivolumab (Opdivo) and ipilimumab (Yervoy) were approved for use in combination for the treatment of previously untreated intermediate- or poor-risk advanced renal cell carcinoma.^1–3

Supporting Efficacy Data

The approvals were based on findings in the open-label phase III CheckMate 214 trial, in which 1,096 patients were randomly assigned to receive nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab at 3 mg/kg every 2 weeks (n = 550) or sunitinib (Sutent) at 50 mg daily for 4 weeks followed by 2 weeks off every cycle (n = 546).^2-4 

Efficacy was evaluated in intermediate/poor-risk patients with ≥ 1 of 6 prognostic risk factors on International Metastatic Renal Cell Carcinoma Database Consortium criteria: < 1 year from the time of initial renal cell carcinoma diagnosis to randomization, Karnofsky performance status < 80%, hemoglobin < lower limit of normal, corrected calcium > 10 mg/dL, platelet count > upper limit of normal (ULN), and absolute neutrophil count > ULN. 

The trial included 425 patients with intermediate risk (n = 334) or poor risk (n = 91) in the nivolumab/ipilimumab group and 422 with an intermediate (n = 333) or poor risk (n = 89) in the sunitinib group. Among these patients, the median age was 61 years (range = 21–85 years, 38% ≥ 65 years and 8% ≥ 75 years), 73% were male, and 87% were white. In addition, 26% of patients had a Karnofsky performance status of 70% to 80%, and 74% had a score of 90% to 100%. 

Among patients with intermediate- or poor-risk disease, median overall survival was not estimable in the nivolumab/ipilimumab group vs 25.9 months in the sunitinib arm (hazard ratio [HR] = 0.63, P < .0001). Median progression-free survival was 11.6 vs 8.4 months (HR = 0.82, P = not significant). The objective response rate was 41.6% vs 26.5% (P < .0001). The efficacy of the combination was not established in patients with favorable-risk disease. 

How These Drugs Work

Nivolumab is a human immunoglobulin G4 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 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 inhibition mediated by nivolumab (anti–PD-1) and ipilimumab (anti–cytotoxic T-lymphocyte–associated protein 4 [CTLA-4]) results in enhanced T-cell function that is greater than the effects of either antibody alone and 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 regimen for the combination in this indication is nivolumab at 3 mg/kg followed by ipilimumab at 1 mg/kg on the same day every 3 weeks for 4 doses followed by nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks. When either drug is withheld, the other drug should also be withheld.

Nivolumab product labeling provides instructions for dose modification for adverse reactions and management of immune-mediated reactions, including dose modification for diarrhea or colitis, pneumonitis, hepatitis/non–hepatocellular carcinoma (HCC), hepatitis/HCC, hypophysitis, adrenal insufficiency, hyperglycemia, serum creatinine increase, rash or suspected -Stevens-Johnson syndrome or toxic epidermal necrolysis, new-onset moderate or severe neurologic signs or symptoms (suspected immune-related encephalitis), and first occurrence of other grade 3 adverse reactions. Nivolumab infusion should be interrupted or slowed in patients with mild or moderate infusion reactions, and treatment should be discontinued in those with severe or life-threatening infusion reactions.

Nivolumab should be permanently discontinued for the following conditions: grade 3 diarrhea or colitis when administered in combination with ipilimumab and grade 4 diarrhea or colitis; grade 3 or 4 pneumonitis; hepatitis/non-HCC—if aspartate transaminase (AST) or alanine transaminase (ALT) is > 5 times ULN or total bilirubin is > 3 times ULN; hepatitis/HCC—if AST/ALT increases to > 10 times ULN or total bilirubin increases to > 3 times ULN; grade 4 hypophysitis; grade 3 or 4 adrenal insufficiency; grade 4 hyperglycemia; serum creatinine > 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. 

Ipilimumab product labeling provides instructions for dose modification for and management of immune-mediated reactions, including immune-mediated toxicities consisting of endocrinopathies, ophthalmologic toxicity, and all other immune-related adverse reactions. Treatment should be permanently discontinued for the following conditions: symptomatic endocrine reactions lasting 6 weeks or longer or an inability to reduce the corticosteroid dose to 7.5 mg of prednisone or equivalent per day; grade 2 through 4 ophthalmologic reactions not improving to grade 1 within 2 weeks while receiving topical therapy or requiring systemic treatment; and for all other immune-mediated adverse reactions—grade 2 reactions lasting 6 weeks or longer, inability to reduce corticosteroid dose to 7.5 mg of prednisone or equivalent per day, and any grade 3 or 4 reactions. Ipilimumab infusion should be interrupted or slowed in patients with mild or moderate infusion reactions, and treatment should be discontinued in those with severe or life-threatening infusion reactions.

Safety Profile

Among all patients in CheckMate 214, the median duration of treatment was 7.9 months in the nivolumab/ipilimumab group and 7.8 months in the sunitinib group. Among all patients in the trial, the most common adverse events of any grade (≥ 20% of patients) among those receiving nivolumab plus ipilimumab were fatigue (58% vs 69% with sunitinib), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough, pyrexia, arthralgia, and decreased appetite. Grade 3 or 4 adverse events occurred in 65% vs 76% of patients, with the most common in the nivolumab/ipilimumab group including fatigue (8% vs 13% with sunitinib), diarrhea (4.6% vs 6%), and musculoskeletal pain (4% vs 2.6%). The most common grade 3 or 4 laboratory abnormalities in the nivolumab/ipilimumab group were increased lipase (20% vs 20% with sunitinib), increased amylase (12% vs 7%), and hyponatremia (10% vs 7%).

Adverse events led to dose delay in 54% vs 43% of patients and to treatment discontinuation in 31% vs 21%; dose reduction was not permitted for nivolumab/ipilimumab treatment. Serious adverse events occurred in 59% vs 43% of patients, with the most common occurring in ≥ 2% of the nivolumab/ipilimumab group being diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. 

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. Women should discontinue breastfeeding before treatment with nivolumab.

Ipilimumab carries a boxed warning for immune-mediated adverse reactions, including severe fatal cases. These reactions may involve any organ system; the most common severe reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of reactions have onset during treatment; a minority occurred weeks to months after discontinuation of ipilimumab. Patients should be routinely assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and should undergo evaluation with clinical chemistries, including liver function tests, adrenocorticotropic hormone level, and thyroid function tests, before starting treatment and before each dose.

Ipilimumab also carries warnings/precautions for immune-mediated adverse reactions, including hepatitis, endocrinopathies, pneumonitis, nephritis and renal dysfunction, and encephalitis, as well as for infusion-related reactions and embryofetal toxicity. Women should discontinue breastfeeding before treatment with ipilimumab. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves nivolu-mab plus ipilimumab combination for intermediate- or poor-risk advanced renal cell carcinoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm604685.htm. Accessed April 23, 2018.

2. Opdivo (nivolumab) injection prescribing information, Bristol-Myers Squibb Company, April 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf. Accessed August 20, 2018.

3. Yervoy (ipilimumab) injection prescribing information, Bristol-Myers Squibb Company, April 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/125377s094lbl.pdf. Accessed August 20, 2018.

4. Motzer RJ, Tannir NM, McDermott DF, et al: Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277-1290, 2018.