AZD2014 Inferior to Everolimus for VEGFR-refractory RCC

AZD2014, a dual TORC1 and TORC2 inhibitor, was less active than everolimus for the treatment of patients with metastatic renal cell carcinoma (mRCC) who were refractory to vascular endothelial growth factor (VEGF) inhibitors, a study published in the journal European Urology has shown.¹

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor indicated for VEGF-refractory mRCC. It only acts on part of the mTOR complex (TORC1), while AZD2014 has broader activity. Therefore, researchers sought to evaluate whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in this setting.

For the phase 2 trial, researchers enrolled 49 patients with VEGF-refractory clear cell mRCC. Participants were randomly assigned 1:1 to receive AZD2014 50 mg twice daily or everolimus 10 mg once daily until disease progression.

Results showed that median progression-free survival was 1.8 months with AZD2014 and 4.6 months with everolimus (HR, 2.8; 95% CI, 1.2 – 6.5; P = .01). Furthermore, researchers found that disease progression was the best response to therapy in 69% and 13% of patients treated with AZD2014 and everolimus, respectively (P < .001).

AZD2014 was also inferior to everolimus with regard to overall survival (HR, 3.1; 95% CI, 1.1 – 8.4; P < .02).

Due to lack of efficacy, the investigators decided to end recruitment into the trial early.

In terms of safety, treatment-related grade 3 to 4 adverse events were reported in 35% of patients who received AZD2014 vs 48% of patients in the everolimus group (P = .3). Of note, only 4% of patients in the AZD2014 arm discontinued treatment due to adverse events.

“This study is the first randomised trial to show that AZD2014 (a TORC1 and TORC2 inhibitor) was less active than everolimus (TORC1 inhibitor) in mRCC,” the authors concluded. “This study contradicts preclinical data that support the use of broader spectrum mammalian target of rapamycin inhibitors.”

Reference

1. Powles T, Wheater M, Din O, et al. A randomised phase 2 study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer. Eur Urol. 2015; 69(3):450-456.