Axitinib Study Does Not Meet Primary Endpoint as Front-Line Therapy for Renal Cell Carcinoma

Mace Rothenberg, MD

A phase III study of axitinib (Inlyta) as a front-line therapy for metastatic renal cell carcinoma (mRCC) did not meet its primary endpoint of demonstrating a longer period of median progression-free survival (PFS) than sorafenib (Nexavar), according to a statement released by axitinib’s manufacturer, Pfizer.

Pfizer reported that a preliminary analysis of data from the phase III AGILE 1051 trial did not show an improvement in median PFS when the two drugs were compared head-to-head. The trial enrolled more than 280 patients with mRCC who were either treatment-naïve or had progressive disease per RECIST criteria after one prior systemic first-line regimen for metastatic disease containing sunitinib, cytokines, or both. Overall, the median PFS for patients with mRCC who received axitinib was slightly higher than for those who received sorafenib, but the results were not statistically significant.

Among patients in a pre-specified subgroup with an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, which is considered a good performance status, the median PFS for patients who received axitinib was higher than the median PFS observed in patients who received sorafenib, according to Pfizer. Among another pre-specified subgroup of patients with an ECOG Performance Status score of 1, considered an intermediate status, there was no difference in survival between patients who received axitinib and those who received sorafenib.

“We narrowly missed the primary endpoint in this trial,” said Mace Rothenberg, MD, senior vice president of clinical development and medical affairs for Pfizer's Oncology Business Unit, in a statement. “We are analyzing the study findings to determine whether further evaluation of Inlyta in specific subpopulations of treatment-naïve patients with advanced RCC would be warranted.”

An oral kinase inhibitor, axitinib is designed to selectively inhibit vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, which have been known to promote tumor progression and angiogenesis.

Axitinib was granted FDA approval in January to treat advanced RCC in patients who failed to respond to prior therapy. The approval was based on the results of a randomized, open-label, multicenter study involving 723 patients from 22 countries who had RCC and progressed despite receiving sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or a cytokine as first-line therapy. Like those in AGILE 1051, patients were randomly assigned to receive either axitinib or sorafenib.

In that study, the median PFS observed in patients who received axitinib was 6.7 months (95% CI, 6.3-8.6) compared with 4.7 months (95% CI, 4.6-5.6) for those receiving sorafenib, demonstrating a 33.5% improvement in PFS (hazard ratio [HR] = 0.665; 95% CI, 0.544-0.812; P < .0001).

“We set a high bar in our Inlyta trials to understand how it compares to another VEGF-targeted therapy,” Rothenberg said. “Since approval, Inlyta has established its utility in the second-line setting where it is an important treatment option for many patients with advanced kidney cancer.”

A separate cohort of more than 200 Asian patients who were treated with axitinib or sorafenib in a second-line setting was also part of the AGILE 1051 study. The results of that portion of the cohort were originally expected to be presented at the American Society of Clinical Oncology (ASCO) meeting earlier this year, but were withdrawn and will be presented at a future medical meeting, according to Pfizer.

Several other clinical trials are underway to determine whether axitinib has treatment uses beyond those currently approved. One trial, the AGILE 1046 study, is a randomized phase II study in treatment-naïve patients with advanced RCC in which axitinib is given with or without dose titration, with overall response rate serving as the primary outcome. Data from the trial presented at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) demonstrated a median PFS of more than 1 year and an overall response rate of 40.2% in the treatment arm of the study.¹

1. Rini BI, Grünwald V, Fishman MN, et al. Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall efficacy and pharmacokinetic analyses from a randomized phase II study. J Clin Oncol. 2012;30(suppl; abstr 4503).