Results of the phase III Checkmate-025 trial demonstrate that the PD-1 inhibitor nivolumab significantly prolongs the survival of patients with advanced renal cell carcinoma (RCC) with disease progression after standard first-line therapy. Moreover, the treatment with nivolumab was also shown to be less toxic than the standard therapy with everolimus, with a lower incidence of high-grade adverse events.
The treatment options for patients with advanced RCC who failed first-line therapy are limited. In the Checkmate-025 study, a total of 821 advanced RCC patients, who progressed after one or two previous anti-angiogenic therapies, were randomised between a treatment with nivolumab (3 mg/kg IV, every 2 weeks), or everolimus (10 mg oral, once daily). The primary endpoint of the study was overall survival (OS), while the secondary objectives included objective response rate (ORR) and safety.
At the time of data cut-off, patients were followed up for at least 15 months and 17% of the patients in the nivolumab arm was still on therapy (as compared to 7% in the everolimus arm). This study demonstrated a median OS of 25 months with nivolumab as compared to 19.6 months with everolimus. This translates into a significant 27% reduction in the risk of death with nivolumab (HR[95%CI]: 0.73[0.57-0.93]; p= 0.002). In addition to this, the analysis showed that nivolumab was associated with a larger ORR as compared to everolimus: 25% versus 5.4% (OR[95%CI]: 5.98[3.68-9.72]; p< 0.0001). In general, the observed responses were partial (24.1% with nivolumab and 4.9% with everolimus), with a minority of patients having a complete response (1% with nivolumab and 0.5% with everolimus). In a significant proportion of patients disease stabilisation was reported. This was the case in 34.4% with nivolumab and in 55.2% of patients treated with everolimus. The median progression-free survival was similar in both treatment arms: 4.6 months with nivolumab and 4.4 months with everolimus (HR[95%CI]: 0.88[0.75-1.03]; p= 0.11). Interestingly, the significant survival advantage with nivolumab did not come at the cost of added toxicity. On the contrary, the rate of grade 3/4 adverse events with nivolumab was only 19% as compared to 37% with everolimus. The most common grade 3/4 adverse events with nivolumab were fatigue (33%), nausea (14%) and serious itching (14%). For everolimus, the most frequent high grade toxicities were fatigue (34%), infections of the oral mucosa (30%) and anaemia (24%). No treatment-related deaths were reported in the nivolumab arm as compared to 2 such events with everolimus.
In summary, the presented phase III study demonstrates that second-line therapy with nivolumab results in a significantly longer survival in patients with advanced RCC as compared to everolimus. Moreover, the safety profile of nivolumab was superior to that of everolimus. In reaction to the clear survival advantage seen with nivolumab, the Checkmate-025 study was stopped prematurely after a planned interim analysis in July 2015.
Sharma P, et al. CheckMate 025: a randomized, open-label, phase III study of nivolumab (NIVO) versus everolimus (EVE) in advanced renal cell carcinoma (RCC). Presented at ECC 2015; Abstract 3LBA.