ASCO 2014 - Abstract 4505

ASCO 2014. Abstract 4505. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (The ESPN Trial): A multicenter randomized phase 2 trial.

Nizar M. Tannir, Eric Jonasch, Emre Altinmakas, Chaan S. Ng, Wei Qiao, Pheroze Tamboli, Priya Rao, David F. McDermott, Christopher G. Wood, Toni K. Choueiri; The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX; Beth Israel Deaconess Medical Center, Boston, MA; Dana-Farber Cancer Institute, Boston, MA

Background: In a single-arm phase II trial of sunitinib in non-clear cell RCC (nccRCC) we previously reported (Tannir et al. Eur Urol 2012), objective response rate [ORR] was 5% and median progression-free survival [PFS] was 2.7 months. Temsirolimus was previously shown to produce overall survival (OS) benefit in poor-risk RCC including nccRCC (Hudes et al. NEJM 2007).

Methods: This is a randomized phase II trial of everolimus (E) vs. sunitinib (S) with crossover design in metastatic nccRCC. Primary endpoint was PFS in first-line (1L). Secondary endpoints were PFS in second-line (2L), safety, and OS. A sample size calculation of 108 pts (54/arm) was based on an assumption of improved median PFS from 12 weeks with S to 20 weeks with E. Pts were stratified by histology (papillary vs. others), and MSKCC risk groups. Kaplan-Meier curves were used to estimate unadjusted time-to-event distributions. Stratified log rank tests were used to compare each time-to-event variable between groups.

Results: Seventy-three pts were enrolled. Sixty-eight pts were eligible and evaluable (median age 59, 43 males [63%], 52 pts [77%] had prior nephrectomy). Twenty-seven pts had papillary, 11 pts had chromophobe, 9 pts had unclassified, 7 pts had translocation, 13 pts had sarcomatoid, and 1 pt had oncocytic RCC. Thirty-five pts received E (good-risk 4, intermediate-risk 29, poor-risk 2). Thirty-three pts received S (good-risk 4, intermediate-risk 29). ORR with S in 1L was 12% (2 pts had chromophobe, 1 pt had papillary type 1 and 1 pt had 99% sarcomatoid); ORR with E in 1L was 0%. Median PFS in 1L with S was 6.1 mos (95% CI: 4.7, 10.8) and 4.1 mos with E (95% CI: 2.7, 7.4); p = 0.25. Thirty-eight pts received 2L therapy (S 19, E 19). Median PFS in 2L with S was 1.8 mos (95% CI: 1.5, NA) and 4.3 mos with E (95% CI: 1.4, NA). A total of 27 pts have died (8 had S and 19 had E). Median OS with E in 1L was 10.5 mos (95% CI: 7.4, NA); median OS with S in 1L was not reached; p=0.01. Toxicity was consistent with previous reports of E and S.

Conclusions: Based on futility analysis for PFS and inferior OS with E compared to S in 1L, the DSMB recommended termination of further pt accrual on this trial. E cannot be recommended as 1L option in nccRCC. 

Pure clear cell or a clear cell component in RCC represent the great majority of cases of renal cancer (>80%). Therefore, very few trials have specifically addressed this population of patients with papillary, chromophome sarcomatoid and other rare non clear cell histology subtypes excluding urothelial origin.

In this trial, two targeted therapies known to be active in metastatic ccRCC for response and PFS were tested with the assumption that everolimus would fare better. This was hypothesized based on data obtained for sunitinib, from a phase II trial in a non-clear cell mRCC patient population showing limited efficacy and from a trial with an mTOR inhibitor other than everolimus showing efficacy that compared favorably. The presented study allowed cross-over to the other therapy and progression. This was a small trial with fewer than 100 patients, but a high event rate of progression and deaths.

Very few responses were seen in both treatment groups and mainly for chromophobe or translocation histology patients. No difference was seen in mPFS for first line or second line.

However, the HR for survival was statistically significant in advantage of sunitinib at the second interim analysis, but only shows a trend at the latest analysis. The OS advantage was more striking for patients with histologies other than sarcomatoid.

This trial therefore shows a negative endpoint as it did not demonstrate its primary objective of superiority of the mTOR inhibitor and that current targeted agents used for ccRCC have limited activity in patients suffering from metastatic non clear cell RCC, both for response, PFS and OS. However, it is reasonable to consider their use, with a possible preference for sunitinib. Moreover, it calls for more research with new agents for these patients.
— CARE Genitourinary Cancer Faculty