A randomized phase II study of AZ2014 versus everolimus in patients with VEGF refractory metastatic clear cell renal cancer (mRCC).

Abstract

409 Background: Dual TORC1 and 2 inhibitors such as AZD2014 have theoretical advantages over isolated TORC1 inhibitors such as everolimus in the treatment of mRCC. In this study we compare the activity of these drugs in patients with vascular endothelial growth factor (VEFG) refractory mRCC. Methods: Patients with measurable VEGF refractory mRCC were randomised (1:1) to AZD2014 or everolimus stratified by MSKCC prognostic score and 1st line targeted therapy. Progression free survival (PFS) measured by RECIST v1.1 was the primary endpoint. Adverse events (AE) (CTCAE v4.03), response rates (RR) and overall survival (OS) were reported. This was an investigator led study and had appropriate ethical approval. Results: The study was stopped early (May 2014) with the recommendation of the IDMC. At this point 48 patients were recruited and 40 (AZD2014 23 :everolimus 17) patients were assessable for efficacy. Patient’s demographics were similar in the 2 groups. The median PFS was shorter for AZD2014 than everolimus (2.0 [95% CI 1.6-3.2] months vs. 5.8 [95% CI 2.8-11.2] months: stratified HR [2.4 95% CI:1.0-5.7; p<0.05]). Progression of disease as a best response was higher for AZD2014 than everolimus (65% vs. 18%: p=0.03). Response rates for AZD2014 and everolimus were 0% and 12% respectively. There were 9 deaths in this patient group, 7 in AZD2014 and 2 in everolimus group, all were due to disease progression. Grade III-IV adverse events (AEs) occurred with AZD2014 and everolimus in 30% and 59% of patients respectively. Discontinuation for AEs did not occur with AZD. PK analysis revealed AZD2014 doses within therapeutic window. Results for the 48 patient will be presented along with the survival data. Conclusions: The PFS for AZD2014 is inferior to everolimus in this setting despite excellent tolerability. These results are consistent with previous results with broader spectrum mTOR inhibitors in VEGF refractory mRCC (GDC0890: HR2.04 [Powles et al ASCO 2014]). This approach appears to be flawed. Clinical trial information: NCT01793636.

mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia

“…A phase II clinical trial in refractory renal cancer demonstrated that AZD2014 treated patients exhibited a shorter progression-free survival and increased disease progression compared to patients treated with everolimus [ 31 ], akin to our findings. In an APC-deficient mouse model of colorectal cancer (CRC), rapamycin treatment reduced tumor growth and increased survival of mice [ 32 ].…”

mTORC1 activity is essential for disease progression in chronic lymphocytic leukemia

“…Similar findings have been noted in an APC-deficient mouse model of colorectal cancer (CRC), in which mTORC1 targeted inhibition via rapamycin treatment reduced tumor growth and increase survival of mice ( 28 ). Of note, a phase II clinical trial showed similar results in patients with refractory renal cancer, with AZD2014 treated patients exhibiting a shorter progression-free survival and increased disease progression compared to patients treated with everolimus, a compound related to rapamycin ( 29 ). Therefore, delineating the distinct mechanism of action of the two drugs may enable better treatment options for cancer patients.…”

What’s New in Renal Cell Cancer Research? Highlights of GU-ASCO 2015

“…3 These subjects were randomized to receive the dual TORC1/2 inhibitor AZD2014 or the isolated TORC1 inhibitor everolimus. Median progression-free survival (PFS) with everolimus was 4.6 months, compared to 1.8 months for patients receiving AZD2014.…”