Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial

Abstract

Background: CheckMate 025 has shown superior efficacy for nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis assesses the long-term clinical benefits of nivolumab versus everolimus.

Methods: The randomized, open-label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression-free survival (PFS), safety, and health-related quality of life (HRQOL).

Results: Eight hundred twenty-one patients were randomized to nivolumab (n = 410) or everolimus (n = 411); 803 patients were treated (406 with nivolumab and 397 with everolimus). With a minimum follow-up of 64 months (median, 72 months), nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months [95% CI, 22.2-29.8 months] vs 19.7 months [95% CI, 17.6-22.1 months]; hazard ratio [HR], 0.73; 95% CI, 0.62-0.85) with 5-year OS probabilities of 26% and 18%, respectively. ORR was higher with nivolumab (94 of 410 [23%] vs 17 of 411 [4%]; P < .001). PFS also favored nivolumab (HR, 0.84; 95% CI, 0.72-0.99; P = .0331). The most common treatment-related adverse events of any grade were fatigue (34.7%) and pruritus (15.5%) with nivolumab and fatigue (34.5%) and stomatitis (29.5%) with everolimus. HRQOL improved from baseline with nivolumab but remained the same or deteriorated with everolimus.

Conclusions: The superior efficacy of nivolumab over everolimus is maintained after extended follow-up with no new safety signals, and this supports the long-term benefits of nivolumab monotherapy in patients with previously treated aRCC.

Lay summary: CheckMate 025 compared the effects of nivolumab (a novel immunotherapy) with those of everolimus (an older standard-of-care therapy) for the treatment of advanced kidney cancer in patients who had progressed on antiangiogenic therapy. After 5 years of study, nivolumab continues to be better than everolimus in extending the lives of patients, providing a long-lasting response to treatment, and improving quality of life with a manageable safety profile. The results demonstrate that the clinical benefits of nivolumab versus everolimus in previously treated patients with advanced kidney cancer continue in the long term.

Keywords: CheckMate 025; advanced renal cell carcinoma (aRCC); everolimus; immune checkpoint inhibitor; nivolumab; previously treated.

Figure 1.

OS (A) and PFS (B) for patients treated with nivolumab and everolimus. CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

Figure 2.

Duration of response in all randomized patients. CI, confidence interval.

Figure 3.

Treatment-free interval (TFI), duration of therapy, duration of response, and subsequent therapy in all patients with confirmed response to nivolumab (A) or everolimus (B).

Figure 3.

Treatment-free interval (TFI), duration of therapy, duration of response, and subsequent therapy in all patients with confirmed response to nivolumab (A) or everolimus (B).

Figure 4.

Treatment-related adverse events (AEs) reported in ≥10% of treated patients in either arm (A) and median time to onset and resolution of nivolumab-related select (immune-related) AEs of any grade (B). ^aNo patient reported a grade 3–4 treatment-related AE. ^b<1% of patients experienced a grade 3 or 4 treatment-related AE.

Figure 5.

Mean changes from baseline Functional Assessment of Cancer Therapy Kidney Symptom Index–Disease-Related Symptoms (FKSI-DRS) scores. ^aMean change from baseline was also clinically meaningful at weeks 144, 164, and 176 in the nivolumab arm. ^bN=8 for week 232 and n<10 after week 236 in the nivolumab arm; N=9 for weeks 124, 128, and 136 in the everolimus arm, and n<10 otherwise after week 132. *Denotes clinically meaningful improvement with nivolumab (+2) or deterioration with EVE (–2) from baseline (dashed lines). Only time points for which data were available for ≥10 randomized patients with baseline plus ≥1 postbaseline HRQoL assessment with non-missing patient-reported outcome data per arm were included. Time 0 indicates baseline. Bars show 95% confidence intervals.