Nivolumab's Survival Benefit Sustained Across RCC Subgroups

Nivolumab’s second-line survival benefit in renal cell carcinoma was consistent across subgroups categorized by patient risk status, prior treatment, and degree of metastases, according to an update of the phase III CheckMate-025 trial.

Robert J. Motzer, MD

Nivolumab’s second-line survival benefit in renal cell carcinoma (RCC) was consistent across subgroups categorized by patient risk status, prior treatment, and degree of metastases.

The findings, which came from an analysis of the phase III CheckMate-025 trial, were presented at the 2016 Genitourinary Cancers Symposium.1 Based on results from CheckMate-025, the FDA approved nivolumab (Opdivo) in November 2015 for the treatment of metastatic RCC after the failure of an angiogenesis inhibitor.

“Nivolumab is a new standard of care for patients with advanced RCC who have received prior antiangiogenic therapy and we think it’s a good choice as a second-line agent,” lead author Robert J. Motzer, an attending physician at Memorial Sloan Kettering Cancer Center (MSKCC), said when presenting the data at the meeting.

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 1 angiogenesis inhibitor and 28% had received 2. Overall survival (OS) was the primary endpoint, with secondary outcome measures focused on objective response rate (ORR), progression-free survival (PFS), and safety. The study was halted by an independent panel in July 2015 at a preplanned interim OS analysis.

According to data published in The New England Journal of Medicine, after a minimum follow-up of 14 months, the median OS in the overall study population was 25.0 months with nivolumab versus 19.6 months with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93; P = .002).2 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).

The ORR with nivolumab was 25% compared with 5% for those receiving everolimus (P <.001). The median duration of response was 12 months, and at the time of the analysis, many of the responses were ongoing, according to Motzer.

The primary analysis also reported that 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 2 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.

When assessing patients based on risk status, there was an improvement in survival across the various risk groups, according to Motzer. Median OS for patients with a favorable risk score by MSKCC criteria was not evaluable with nivolumab and 29.0 months with everolimus (HR, 0.80; 95% CI, 0.52-1.21). For patients with a poor MSKCC risk status, median OS was 15.3 months versus 7.9 months, respectively (HR, 0.48; 95% CI, 0.32-0.70).

“The relatively high benefit for nivolumab in the poor-risk patients is particularly noteworthy,” said Motzer.

He also reported that in subgroups defined by metastases criteria, nivolumab bested everolimus regardless of the number (1 or ≥2) or site of metastases.

In patients with bone metastases, median OS was 18.5 months with nivolumab versus 13.8 months with everolimus (HR, 0.72; 95% CI, 0.47-1.09). Median OS was 18.3 and 16.0 months, respectively, in patients with liver metastases (HR, 0.81; 95% CI, 0.55-1.18).

The benefit in the bone metastases population was particularly important, Motzer said, because “bone [metastases] has been problematic with the VEGF TKIs.”

Outcomes were also examined by prior systemic therapy, with the 2 most common being sunitinib and pazopanib, respectively.

Among patients who previously received sunitinib, the median OS was 23.6 months with nivolumab versus 19.8 months with everolimus (HR, 0.81; 95% CI, 0.64-1.04). For patients with prior pazopanib, median OS was not evaluable versus 17.6 months, respectively (HR, 0.60; 95% CI, 0.42-0.84).

Survival was improved with nivolumab versus everolimus regardless of the length of first-line therapy (<6 vs ≥6 months) or the number of prior antiangiogenic therapies received (1 vs 2).

ORR comparisons were also conducted across the various subgroups, Motzer said.

“In all the cases we examined, the overall response rate was higher for nivolumab compared to everolimus,” said Motzer, adding that “the responses were consistent across all the groups we examined.”

Safety data for the trial were previously reported. All-grade adverse events (AEs) occurred in 79% of patients treated with nivolumab versus 88% in the everolimus group. Fatigue (33%), nausea (14%), and pruritus (14%) were the most frequently reported AEs with nivolumab. The most common AEs in the everolimus arm were fatigue (34%), stomatitis (29%), and anemia (24%).

The rate of grade 3/4 toxicities was lower with nivolumab (19%) versus everolimus (37%). The most common grade 3/4 adverse events were fatigue (2%) in the nivolumab arm and anemia (8%) in the everolimus arm. Two treatment-related deaths were reported for the everolimus group and none for the nivolumab cohort.

“Nivolumab should be considered as a second-line drug, following VEGF TKI therapy. This is based on the survival benefit we’ve established in this trial, it’s favorable safety profile, and the improvement in quality of life compared with everolimus, which has always been regarded as a very well-tolerated and safe drug,” Motzer concluded.


  1. Motzer RJ, Sharma P, McDermott DF, et al. CheckMate 025 phase III trial: Outcomes by key baseline factors and prior therapy for nivolumab (NIVO) versus everolimus (EVE) in advanced renal cell carcinoma (RCC). J Clin Oncol 34, 2016 (suppl 2S; abstr 498).
  2. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803-1813.


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