Padmanee Sharma, MD, PhD

Nivolumab (Opdivo) reduced the risk of death by 27% versus everolimus (Afinitor) in patients with advanced renal cell carcinoma (RCC), improving overall survival (OS) by 5.4 months. Grade 3/4 adverse events (AEs) were also lower with the PD-1 inhibitor, according to results from the phase III CheckMate-025 trial presented at the 2015 European Cancer Congress (ECC) and simultaneously published in The New England Journal of Medicine.1,2

The FDA recently granted nivolumab a breakthrough therapy designation for the treatment of patients with advanced RCC, which will expedite the development and regulatory review of the anti­­—­PD-1 agent in this setting.

“It is exciting to see the outcome of this study, as the results are significant and clinically meaningful to patients and healthcare professionals alike. They are likely to change the treatment of patients with advanced kidney cancer, whose disease has progressed on prior treatment,” study author Padmanee Sharma, MD, PhD, said during a press briefing at the ECC.

“Although we cannot speculate at this time on when nivolumab might enter the clinic, we hope that this study will quickly lead to approval of nivolumab as a standard of care therapy for these patients,” added Sharma, who is scientific director of the Immunotherapy Platform and professor in the Departments of Genitourinary Medical Oncology and Immunology at the MD Anderson Cancer Center.

The open-label, parallel assignment CheckMate-025 trial randomized 821 previously treated patients with advanced or metastatic clear-cell RCC in a 1:1 ratio to 3 mg/kg of IV nivolumab every 2 weeks or 10 mg of oral everolimus daily until progression or unacceptable toxicity. Prior treatment with one or two antiangiogenic treatment regimens for advanced or metastatic disease was required, along with evidence of disease progression within 6 months of enrollment.

Patient characteristics were well balanced between the two arms. The median patient age across the trial was 62 years. Seventy-two percent of patients in the overall study population had previously been treated with 1 angiogenesis inhibitor for advanced RCC. OS was the primary endpoint, with secondary outcome measures including objective response rate (ORR) and progression-free survival (PFS).

At 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 = .002). The difference was statistically significant, meeting the criteria established in the trial design of P ≤.0148. The OS benefit was observed across patient subgroups, including cohorts defined by geography, MSKCC prognostic score, and number of prior antiangiogenic regimens.

The trial was stopped early after meeting the primary OS endpoint, and eligible patients in the everolimus cohort were allowed to cross over and receive nivolumab in an open-label extension of the study.

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 researchers noted in their article that there was a delayed separation of the PFS Kaplan Meier curves and to further examine the results, they conducted an ad hoc sensitivity analysis of PFS in patients who had not progressed at 6 months. The median PFS in this cohort was 15.6 months with nivolumab versus 11.7 months with everolimus (HR, 0.64; 95% CI, 0.47-0.88).

ORR was 25% in the nivolumab arm versus 5% in the everolimus group (odds ratio, 5.98; 95% CI, 3.68-9.72; P <.001). There were 99 (24%) partial responses with nivolumab compared with 20 (5%) in the everolimus group. The number of complete responses was 4 (1%) and 2 (<1%), respectively. The median duration of response was 12.0 months for both arms, and the median time to response was 3.5 and 3.7 months in the nivolumab and everolimus arms, respectively.

The all-grade AE rates were comparable between the two arms at 79% in the nivolumab arm and 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 at 19% versus 37% with everolimus. 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.

PD-L1 status was not an efficacy biomarker for nivolumab. Among patients with PD-L1 expression ≥1%, median OS was 21.8 months with nivolumab versus 18.8 months with everolimus. 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 finding that overall survival was higher among patients treated with nivolumab, irrespective of PD-L1 expression, suggests that PD-L1 expression should not be used to determine which patients might respond to the therapy and whether or not offer it to them,” said Sharma.

“PD-L1 is a dynamic biomarker that changes over time as a result of evolving immune responses. So it is not surprising that PD-L1 measured in tumor samples before treatment does not capture the true expression of PD-L1 and how it may correlate to responses to treatment. I would expect that tumour samples taken while patients were on-treatment, as opposed to pretreatment, might indicate that PD-L1 expression, as well as other markers of immune response, has a correlation with response to treatment,” Sharma added.

Nivolumab was initially approved in December 2014 for patients with unresectable or metastatic melanoma following treatment with ipilimumab (Yervoy) or a BRAF inhibitor. In March 2015, the PD-1 inhibitor was approved for the treatment of patients with advanced squamous non—small cell lung cancer (NSCLC) who have progressed on or after platinum-based chemotherapy.

The FDA is currently reviewing applications for frontline nivolumab as a monotherapy and in combination with ipilimumab for patients with advanced melanoma, as well as for an indication for patients with previously treated nonsquamous NSCLC.

References:

1. Sharma P, Escudier B, McDermott DF, et al. CheckMate 025: a randomised, open-label, phase III study of nivolumab (NIVO) versus everolimus (EVE) in advanced renal cell carcinoma (RCC). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract LBA 3.

2. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma [published online September 25, 2015]. N Engl J Med. doi:10.1056/NEJMoa1510665.

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