Nivolumab Approved in Europe for Renal Cell Carcinoma

Bernard Escudier, MD

The European Commission has approved nivolumab (Opdivo) for use in previously treated patients with advanced renal cell carcinoma (RCC), according to Bristol-Myers Squibb (BMS), the developer of the PD-1 inhibitor.

The approval was based on data from the pivotal CheckMate-025 trial, in which nivolumab reduced the risk of death by 27% versus everolimus (Afinitor), representing a 5.4-month improvement in median overall survival (OS). Grade 3/4 adverse events (AEs) were also lower with the PD-1 inhibitor compared with everolimus.

“For the first time, previously treated advanced renal cell carcinoma patients in Europe will now have access to an immuno-oncology agent that has demonstrated a significant overall survival benefit along with a favorable safety profile compared to everolimus,” Bernard Escudier, MD, chair of the Genitourinary Oncology Committee, Institut Gustave Roussy in Villejuif, France, said in a statement.

“In addition to the clinical efficacy results, patients treated with Opdivo experienced an improvement in their health-related quality of life and had significantly lower symptom burden throughout treatment compared to patients receiving everolimus. Combined, these data support the use of Opdivo in clinical practice and represent important progress toward establishing a new standard of care in Europe.”

In the open-label CheckMate-025 trial, 821 pretreated patients with advanced or metastatic clear-cell RCC were randomized in a 1:1 ratio to nivolumab or everolimus. Of randomized patients, 803 received treatment. Nivolumab was administered intravenously at 3 mg/kg every 2 weeks (n = 406), and everolimus was given orally at 10 mg daily (n = 397).

The median patient age was 62 years. Seventy-two percent of patients had received one angiogenesis inhibitor and 28% had received two. OS was the primary endpoint, with secondary outcome measures focused on objective response rate (ORR), progression-free survival (PFS), and safety.

According to data published in The New England Journal of Medicine after a minimum follow-up of 14 months, the median OS was 25.0 months with nivolumab versus 19.6 months with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93; P = .0018). The OS benefit was observed across patient subgroups, with the greatest improvement with nivolumab seen for those with a poor MSKCC prognostic score (HR, 0.47; 95% CI, 0.30-0.73).

Median PFS was 4.6 and 4.4 months in the nivolumab and everolimus arms, respectively (HR, 0.88; 95% CI, 0.75-1.03; P = .11). In an ad hoc sensitivity analysis of patients who had not progressed at 6 months, the median PFS was 15.6 months with nivolumab versus 11.7 months with everolimus (HR, 0.64; 95% CI, 0.47-0.88). This analysis was meant to take pseudoprogression into consideration.

The ORR with nivolumab was 25.1% compared with 5.4% for those receiving everolimus. Among the patients who responded to nivolumab, 47.6% (n = 49) had ongoing responses of up to 27.6 months.

PD-L1 expression was not found to significantly impact the efficacy of nivolumab. Among patients with PD-L1 expression ≥1%, median OS was 21.8 versus 18.8 months for nivolumab and everolimus, respectively. In patients with PD-L1 expression ≤1%, median OS was 27.4 and 21.2 months in the two arms, respectively. Similar outcomes were observed when using a 5% threshold for PD-L1 expression status, although only a small number of patients were evaluable by this criterion.

The safety profile of nivolumab in CheckMate-025 was consistent with previous trials, according to BMS. The most common all-grade AEs with nivolumab versus everolimus included asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%).

Forty-seven percent of patients receiving nivolumab had serious AEs. The most frequently reported serious AEs with nivolumab were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.

Commenting on the approval, Emmanuel Blin, senior vice president, head of Commercialization, Policy and Operations at BMS, said, “Today’s approval is reflective of our commitment to bring Opdivo and the potential for long-term survival to broad patient populations, including previously treated advanced renal cell carcinoma. Opdivo is the only PD-1 inhibitor approved in Europe to demonstrate a significant survival advantage in this patient population. At Bristol-Myers Squibb, we are driven to work with speed to deliver new treatment options to help more patients, and in less than a year, we have expanded the approval of Opdivo in Europe to include three distinct types of advanced cancer.”

Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-1813.