An immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) extended overall survival compared with sunitinib (SUTENT) as first-line treatment of patients with advanced or metastatic renal cell carcinoma.
An immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) extended overall survival (OS) compared with sunitinib (SUTENT) as first-line treatment of patients with advanced or metastatic renal cell carcinoma (RCC).
On an intent-to-treat (ITT) basis, median OS was significantly longer in the combination immunotherapy arm than in the sunitinib arm (not reached vs. 32.9 months, HR=0.68, p=.0003) in the randomized CheckMate 214 study, reported Bernard Escudier, MD, at the 2017 European Society for Medical Oncology annual congress in Madrid, Spain. In intermediate- and poor-risk patients, who constituted about 75% of the ITT population, median OS was not reached in the nivolumab/ipilimumab arm and was 26.0 months in the sunitinib arm.
“These results support the use of nivolumab and ipilimumab as a new first-line standard of care option for patients with advanced RCC,” said Dr. Escudier, from Institut Gustave Roussy, Villejuif, France.
In CheckMate 214, patients with advanced or metastatic clear cell RCC who were treatment-naïve were randomized 1:1 to nivolumab plus ipilimumab administered intravenously or to oral sunitinib in 6-week cycles. Patients were stratified by risk group and region, and treatment was continued until progression or unacceptable toxicity.
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Among the 847 patients in the intermediate- or-poor risk groups, 79% were classified as intermediate risk by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and 21% as IMDC poor risk. In the 1,096 patients in the ITT population, 23% were considered favorable risk, 61% intermediate risk, and 17% poor risk in each arm.
The most common sites of metastasis were the lung (approximately 70%), lymph nodes (approximately 50%), liver, and bone (approximately 20% each).
In IMDC intermediate/poor-risk patients, nivolumab/ipilimumab was significantly superior to sunitinib on the endpoint of OS (HR 0.63, p<.0001). Progression-free survival was also extended significantly in the nivolumab/ipilimumab arm versus the sunitinib arm (11.6 vs. 8.4 months, HR=0.82, p=.0331). In this subset, the confirmed objective response rate (ORR) was 42% and 27% in the two arms, respectively, with 9% of patients assigned to nivolumab/ipilumumab achieving a complete response, compared with 1% in the sunitinib arm.
In contrast, favorable-risk patients fared better with sunitinib, with a confirmed ORR of 52% compared with 29% for combination immunotherapy (p=.0002), and a significantly longer PFS (25.1 vs. 15.3 months, p<.0001).
In an exploratory analysis, PD-L1 expression at baseline correlated with response to nivolumab/ipilimumab. Median PFS was significantly longer with the immunotherapy combination than with sunitinib (22.9 vs. 5.9 months, HR=0.48, p=.0003) in patients with PD-L1 expression ≥1% but not in those with PD-L1 expression <1% (HR=1.00, p=.9670).
With a median follow-up of 25.2 months, 77% of patients assigned to nivolumab/ipilimumab and 82% assigned to sunitinib discontinued treatment. The main reason for discontinuation in each group was disease progression (42% in the combination immunotherapy group and 55% in the sunitinib group). The median duration of therapy was 7.9 and 7.8 months, respectively.
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The safety profile of nivolumab/ipilimumab was consistent with previous studies. The most common grade 3/4 adverse events in the combination group were fatigue (4%) and diarrhea (4%), and in the sunitinib group, hypertension (16%), fatigue (9%), and Palmar-plantar erythrodysaesthesia syndrome (9%).
Manuela Schmidinger, MD, from the University of Vienna, Austria, who was not involved in the study, observed that sunitinib had never been defeated before in a head-to-head comparison in the setting of advanced or metastatic clear cell RCC. While nivolumab/ipilimumab as a first-line treatment should be a new standard of care in this patient population, with massive impact, “it’s not the final picture yet,” Dr. Schmidinger said.
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She endorsed addressing the biology of an individual patient’s tumor to select among many first-line treatment options. Selections may eventually be made based on PD-L1 expression or the presence of bone metastases, for which cabozantinib (CABOMETYX) may offer preferential benefit.
Bristol-Myers Squibb and Ono Pharmaceutical Co. Ltd. provided funding for the trial. Dr. Escudier has received honoraria from Bayer, Novartis, Pfizer, Bristol-Myers Squibb, Exelixis, and Roche. Several of his co-authors have a financial or other relationship with Bristol-Myers Squibb and/or other pharmaceutical companies.
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