Nivolumab CheckMate-025 Halted With Positive Data in RCC

Michael Giordano, MD

Michael Giordano, MD

An independent panel has halted the phase III CheckMate-025 trial after determining that nivolumab (Opdivo) improved overall survival (OS) versus everolimus (Afinitor) in patients with advanced renal cell carcinoma (RCC), according to Bristol-Myers Squibb (BMS), the manufacturer of the PD-1 inhibitor. BMS reported that eligible patients in the everolimus cohort will now be allowed to cross over and receive nivolumab in an open-label extension of the study.

“The results of CheckMate-025 mark the first time an immuno-oncology agent has demonstrated a survival advantage in advanced renal cell carcinoma, a patient group that currently has limited treatment options,” Michael Giordano, MD, senior vice president, head of development, oncology, BMS, said in a statement.

BMS reported that eligible patients in the everolimus cohort will now be allowed to cross over and receive nivolumab in an open-label extension of the study. The CheckMate-025 data will be presented at an upcoming scientific meeting, the company noted.

The open-label, parallel assignment CheckMate-025 trial randomized 821 previously treated patients with advanced or metastatic clear-cell RCC who were previously treated 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. OS was the primary endpoint, with secondary outcome measures including objective response rate (ORR) and progression-free survival (PFS).

Previously published phase II data¹demonstrated clinical activity for nivolumab with acceptable toxicity in 168 patients with metastatic RCC (mRCC) who had previously received anti-VEGF therapy. Seventy percent of patients in the study (n = 118) had received more than one prior systemic regimen.

In a blinded 1:1:1 randomization, patients received either 0.3 (n = 60), 2.0 (n = 54), or 10 mg/kg (n = 54) of IV nivolumab once every 3 weeks. PFS was the primary outcome measure, with secondary endpoints including ORR and OS.

In order of increasing dosage, median PFS was 2.7, 4.0, and 4.2 months, respectively (P= .9), with ORRs of 20%, 22%, and 20%. In the three treatment arms, median OS was 18.2 months (80% CI, 16.2-24.0 months), 25.5 months (80% CI, 19.8-28.8 months), and 24.7 months (80% CI, 15.3-26.0 months), respectively.

Fatigue was the most frequently reported adverse event (AE), with rates of 24%, 22%, and 35%, in the 0.3-, 2.0-, and 10-mg/kg cohorts, respectively. Grade 3/4 treatment-related AEs were reported for 11% of patients (n =19) in the overall study population.

The 5-year global survival rate for patients with metastatic or advanced kidney cancer is 12.1%, BMS noted in its press release. More than 100,000 individuals worldwide die of RCC each year.

“Through ourOpdivoclinical development program, we aim to redefine treatment expectations for patients with advanced RCC by providing improved survival,” Giordano said.

In other encouraging news for patients with RCC, results from a second positive trial were also released today. In the phase III METEOR trial, the multikinase inhibitor cabozantinib (Cometriq) improved PFS and OS in the second-line setting for the treatment of patients with mRCC. Exelixis, the company developing cabozantinib, plans to file for regulatory approval of the drug in this setting in early 2016.

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 who have progressed on or after platinum-based chemotherapy. The FDA is currently reviewing an application for nivolumab in combination with ipilimumab in the frontline setting for patients with advanced melanoma, with a decision scheduled by September 30, 2015.

1. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial.J Clin Oncol.2015;33(13):1430-1437.