San Francisco, CA USA (UroToday.com) Dr. Escudier from Institut Gustave Roussy, Villejuif, France, presented subgroup analyses of METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in patients with advanced clear cell renal cell carcinoma (RCC). Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity against vascular endothelial growth factor receptor (VEGFR), MET and AXL, the latter two of which have been associated with resistance to VEGFR TKI therapy. This open-label, phase 3 study randomized 658 patients with previously treated advanced RCC with no limit to the number of prior therapies to cabozantinib (60mg orally once daily) or everolimus (10mg orally once daily).
The primary endpoint of improved progression free survival (PFS) with cabozantinib over everolimus [7.4 month versus 3.8 month; HR = 0.58, 95% CI (0.45 to 0.75); p < 0.001] was published by Choueiri TK et al. in the New England Journal of Medicine in 2015, and led to Food and Drug Administration breakthrough therapy designation for cabozantinib. Overall response rate (ORR), a secondary endpoint, was 21% with cabozantinib and 5% with everolimus (p < 0.001) in the general population. Though not statistically significant, an interim analysis of overall survival (OS) showed a trend towards improvement with cabozantinib over everolimus (HR 0.67; p = 0.005). Significantly more patients required dose-reductions of cabozantinib (60%) than everolimus (25%), though rates of treatment discontinuation in both arms were similar around 10%.
Dr. Escudier provided an updated analysis of PFS in patient subgroups based on a variety of baseline characteristics. While cabozantinib provided more PFS benefit than everolimus across subgroups, patients in the more favorable categories derived the more benefit. For example, the median PFS for Memorial Sloan Kettering Cancer Center (MSKCC) favorable and intermediate risk groups was 7.5 months {[HR 0.51; 95% CI (0.38-0.69) and [HR 0.47; 95% CI (0.35-0.65)], respectively}, while that for poor risk was 5.4 months [HR 0.70; 95% CI (0.42, 1.16)]. Similarly patients with ECOG performance status (PS) 0 had a median PFS of 9.1 months [HR 0.46; 95% CI (0.36-0.59)], while that for PS 1 was 5.6 months [HR 0.64; 95% CI (0.46-0.90)]. PFS based on measured tumor burden, number of involved organs, and presence of lung or liver metastases also favored cabozantinib, with a suggestion that cabozantinib had significantly more activity against bone metastases [HR 0.33; 95% CI (0.21-0.51)]. Patients who received 1 or more than 1 VEGFR TKI derived similar PFS benefit from cabozantinib; a trend towards longer PFS with longer duration of first TKI therapy and longer time to progression on last prior VEGFR TKI was observed. While limited to a very small subgroup (32 patients versus 626), the median PFS had not been reached for patients with prior PD-1/PD-L1 therapy [HR 0.22; 95% CI (0.07-0.65)], in contrast to 7.4 months [HR 0.54; 95% CI (0.44-0.66)] for patients without such prior therapy.
In summary, the benefit of cabozantinib over everolimus for previously treated advanced RCC is observed across pre-specified subgroups and is supported by the trend towards improved OS with cabozantinib at the time of the interim analysis. Future analyses will provide updated OS data.
Presented By:
Dr. Bernard J. Escudier, MD
Institut Gustave Roussy, Villejuif, France
Reported By:
Elizabeth A. Guancial, MD, at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Assistant Professor - Department of Medicine, Hematology/Oncology
University of Rochester Medical Center School of Medicine and Dentistry