In April 2018, the US Food and Drug Administration expanded the approval of the combination of nivolumab and ipilimumab into a new indication, following a previous approval in patients with metastatic melanoma. The double immune checkpoint inhibitor combination was approved on the basis of the phase 3 CheckMate-214 study for the treatment of patients with intermediate- or poor-risk, previously untreated advanced renal cell carcinoma (RCC).1
Nivolumab monotherapy is already approved in the second-line setting for the treatment of advanced RCC, and the demonstration of significantly improved overall survival (OS) in this study suggests that the combination should supplant sunitinib in the front-line setting in the treatment of this type of cancer.
A total of 1,096 patients at 175 sites in 28 countries were randomized 1:1 to receive nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) intravenously every 3 weeks for 4 doses in an induction phase, followed by nivolumab monotherapy (3 mg/kg) every 2 weeks in a maintenance phase or sunitinib (50 mg) orally daily for 4 weeks of each 6-week cycle.
Eligible patients were 18 years or older, had previously untreated advanced RCC with a clear-cell component, had measurable disease according to Response Evaluation Criteria in Solid Tumors (version 1.1), and had a Karnofsky performance status of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability). Patients with central nervous system metastases or autoimmune disease who were being treated with glucocorticoids and immunosuppressants were excluded from the study.
Around three-quarters of patients with advanced RCC have intermediate- or poor-risk disease and experience worse outcomes than patients with favorable-risk disease. Patients in CheckMate-214 were stratified according to International Metastatic Renal Cell Carcinoma Database Consortium risk score as favorable (score of 0), intermediate (score of 1 or 2) or poor risk (score of 3-6), according to the number of risk factors present.
Risk factors included a Karnofsky performance score of 70, time from initial diagnosis to randomization of <1 year, a hemoglobin level below the lower limit of normal, a corrected serum calcium concentration of >10 mg/dL, or an absolute neutrophil count or platelet count above the upper limit of normal. Patients were also stratified according to geographic region (United States versus Canada and Europe versus the rest of the world).
The coprimary endpoints were objective response rate (ORR), progression-free survival (PFS), and OS in a subset of 847 intermediate- and poor-risk patients. Over a median follow-up of 25.2 months, there was a statistically significant improvement in OS and ORR in patients treated with nivolumab and ipilimumab (mPFS not reached; ORR, 41.6%), compared with sunitinib (OS, 25.9 months; ORR, 26.5%), with P <.001 for both. The immunotherapy combination was favored across subgroups.
The most common adverse events (AEs) in patients treated with nivolumab and ipilimumab included fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The combination was associated with fewer grade 3/4 AEs (63% vs 46% for sunitinib), but a higher rate of treatment discontinuations because of AEs (31% vs 21%, respectively). There were 8 deaths in the combination arm, and 4 in the sunitinib arm that were reported to be treatment related.2
The warnings and precautions related to nivolumab–ipilimumab combination therapy outlined in the prescribing information include mostly immune-mediated AEs, such as immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. There are also warnings relating to the risk of infusion reactions and the potential for embryofetal toxicity.
Patients should be monitored for hyperglycemia and for changes in liver, thyroid, renal, and neurologic function. Treatment with nivolumab and ipilimumab should be withheld for moderate and permanently discontinued for severe or life-threatening immune-mediated pneumonitis, colitis, and hepatitis, as well as transaminase or total bilirubin elevation. It should also be withheld for moderate or severe hypophysitis and serum creatinine elevation, moderate adrenal insufficiency and severe hyperglycemia, and permanently discontinued for life-threatening hypophysitis and serum creatinine elevation, severe or life-threatening adrenal insufficiency, and life-threatening hyperglycemia.
New-onset moderate to severe neurologic signs or symptoms warrant treatment being withheld, and immune-mediated encephalitis should lead to treatment discontinuation. For mild or moderate infusion reactions, the infusion rate can be slowed or interrupted, and infusions should be discontinued in the event of severe or life-threatening infusion reactions. Patients should be advised of the potential for fetal harm and the need for effective contraception during and after treatment. Ipilimumab and nivolumab are marketed as Yervoy and Opdivo, respectively, by Bristol-Myers Squibb.3,4