A CHANGE IN PARADIGM may be on the horizon for the treatment of metastatic renal cell carcinoma. According to the results of CheckMate 214, the combination of ipilimumab (Yervoy) plus nivolumab (Opdivo) outperformed the standard of care—sunitinib (Sutent)—for first-line treatment, with improved overall response rates, progression-free survival, as well as the gold standard—overall survival in intermediate- and poor-risk patients.1 These findings were selected for inclusion in the Presidential Symposium at the European Society for Medical Oncology (ESMO) 2017 Congress.
Although the benefits of the immunotherapy combination were pronounced in intermediate- and poor-risk patients with metastatic renal cell carcinoma, an exploratory analysis showed that favorable-risk patients did better with sunitinib.
“In intermediate- and poor-risk patients, the combination of nivolumab and ipilimumab achieved a statistically significant overall survival benefit vs sunitinib, with a 37% reduction in the risk of death. The combination had a significantly improved overall response rate and a median progression-free survival improvement of more than 3 months compared with sunitinib. The safety of the combination seemed to be manageable, and some toxicities were more frequent with sunitinib. This study supports the use of nivolumab plus ipilimumab as a new first-line option,” stated lead investigator Bernard Escudier, MD, of the Institut Gustave Roussy, Villejuif, France.
Nivolumab is approved by the U.S. Food and Drug Administration for previously treated metastatic renal cell carcinoma; it is not yet approved as a first-line treatment for this indication. In a phase Ib trial, the combination of nivolumab and ipilimumab had manageable safety and high antitumor activity in previously treated and treatment-naive patients, leading to the phase III CheckMate 214 trial, designed to compare this combination with sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma.
THE STUDY INCLUDED 1,096 treatment-naive patients with advanced or metastatic renal cell carcinoma. Tumor tissue was obtained for biomarker testing. Patients were randomized 1:1 to receive nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 2 weeks vs sunitinib at 50 mg/d for 4 weeks, with 2 weeks off treatment (1 cycle = 6 weeks). Treatment was continued until disease progression or unacceptable toxicity.
The co-primary endpoint included overall response rates, progression-free survival, and overall survival for intermediate- and poor-risk patients. Secondary endpoints included overall response rates, progression-free survival, and overall survival in the intent-to-treat population. Tumors were tested for programmed cell death ligand 1 (PD-L1) expression, and quality of life was evaluated.
For the intermediate- and poor-risk patients, 425 were randomized to receive combination immunotherapy and 422, sunitinib. Median age was about 62 years; 79% were at intermediate risk and 21% were at poor risk, evenly distributed between the two treatment arms. Seventy-four percent of patients in the combination immunotherapy arm and 71% treated with sunitinib had negative PD-L1 expression (ie, < 1% of cells expressing PD-L1); 26% and 29%, respectively, were PD-L1–positive (ie, ≥ 1% expression).
In the intent-to-treat analysis of all 1,096 patients, 23% were at good risk. Eighty percent had more than two metastases. Among all treated patients, 77% discontinued nivolumab plus ipilimumab and 82% discontinued sunitinib, mainly due to disease progression. Treatment-related adverse events led to treatment discontinuation in 24% of the combination immunotherapy arm vs 12% of the sunitinib arm.
AT A MEDIAN FOLLOW-UP of 25.2 months in the intermediate-and poor-risk group, the overall response rate was 42% with immunotherapy vs 27% with sunitinib (P < .0001). The complete response rate was 9% for the combination vs 1% for sunitinib.
The duration of response was not yet reached for the combination immunotherapy arm vs 18.2 months for sunitinib. Seventy-two percent of patients had an ongoing response to the combination, Dr. Escudier said.
Median progression-free survival was 11.6 months for the combination vs 8.4 months for sunitinib (P = .0331), which did not meet the prespecified P value for statistical significance. “This difference in progression-free survival is clinically meaningful in my view,” Dr. Escudier told the audience.
Overall survival was also significantly improved by combination immunotherapy. Median overall survival was not reached in the combination arm vs 26 months in the sunitinib arm, for a 37% reduction in the risk of death (P < .0001).
In the secondary intent-to-treat analysis, the overall response rate was still better with combination immunotherapy than sunitinib: 39% vs 32% (P < .0191). Median progression-free survival did not significantly differ between the two arms, but overall survival did. Median overall survival was not reached in the combination immunotherapy arm vs 32 months for the sunitinib arm, representing a 32% reduction in the risk of death favoring combination immunotherapy compared with sunitinib (P = .0003).
Favorable-risk patients did better with sunitinib, with an overall response rate of 52% for sunitinib vs 29% for the combination (P < .0001, favoring sunitinib). Progression-free survival also favored sunitinib over the combination therapy: 25.1 months vs 15.3 (P < .0001).
IN INTERMEDIATE- AND POOR-RISK patients, PD-L1 expression was associated with a better response to immunotherapy. In patients who were PD-L1–positive, the overall response rate was 58% vs 22% for sunitinib. The complete response rate was 16% for PD-L1–positive patients treated with combination immunotherapy vs 1% for sunitinib. “It seems that response rates drop when you go from PD-L1–positive to PD-L1–negative,” Dr. Escudier explained.
Median progression-free survival was similar in both arms in PD-L1–negative patients but was 22.8 months with immunotherapy vs 5.9 months with sunitinib in PD-L1–positive patients (P = .0003). “This is very interesting,” Dr. Escudier added.
“TOXICITY [OF NIVOLUMAB PLUS IPILIMUMAB] was manageable and consistent with previous studies,” Dr. Escudier noted. The combination of nivolumab plus ipilimumab led to fewer serious side effects: in all treated patients, grades 3 to 5 treatment-related adverse events were reported in 46%, vs 63% in the sunitinib arm. The most common adverse events in the immunotherapy arm were fatigue and pruritus. Sixty percent of patients treated with immunotherapy required steroids to manage immune-related adverse events.
There was more treatment discontinuation in the immunotherapy arm (15% vs 7% with sunitinib) and more treatment-related deaths (seven vs four patients, respectively). No significant differences between treatment arms were observed in health-related quality of life. ■
DISCLOSURE: Dr. Escudier reported no conflicts of interest.
1. Escudier B. Tannir N, McDermott DF, et al: CheckMate 214: Efficacy and safety of nivolumab + ipilimumab v sunitinib for treatment-naive advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. ESMO 2017 Congress. Abstract LBA5. Presented September 10, 2017.
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FORMAL DISCUSSANT, Manuela Schmidinger, MD, of the Medical University of Austria, Vienna, commented on the CheckMate 214 findings. “We have just seen a change in the paradigm in the treatment of...