mUC is genomically diverse. E/P combination targets the mTOR/PI3K/AKT pathway and selected kinases like FGFR, which are altered in up to 40% of mUC. We report the efficacy and toxicity results of mUC pts genomically profiled enrolled in the Phase I Study.
Previously treated mUC and ECOG PS ≤ 1 were eligible. The recommended dose (RD) for expansion was pazopanib 400mg and everolimus 5mg on a continuous 28 day cycle. Primary endpoint of the expanded cohort was response rate (RR) with secondary being safety, duration of response (MDR), progression free survival (PFS) and overall survival (OS). All pts were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes from institutional targeted next generation tumor only sequencing. Findings were correlated with clinical benefit.
21 pts registered; 9 solid tumors (5 mUC) entered in a 3 + 3 escalation to identify; RD. 12 additional pts with mUC included in the expansion cohort. 17 mUC are described. Median age 68, visceral disease 53%, median prior lines 1.5, median duration of treatment 3.7 m (0.4-13.8). Best radiographic responses: 3 progressive disease (PD), 8 stable disease (SD), 2 partial response (PR), 1 complete response (CR), and 3 non-evaluable (NE) for a RR of 18%. Table 1 summarizes adverse events (AEs) of clinical interest.3 pts with substantial clinical benefit (1CR,1SD, 1PR) had mutations in TSC1/TSC2 and the 4th with a PR did not have alterations in the mTOR pathway but a FGFR3-TACC3 fusion, predicting response to P. No PD had mTOR or FGFR pathways alterations in. Upon progression 2 pts were re-biopsied looking for resistance mechanisms. MDR was 7m and median PFS/OS 3.6 (95%CI 1.8-5.6) and 8m (95%CI: 4.9-10.3), respectively.
AEs of Clinical Interest
|Toxicity||Grade 1-2||Grade 3-4|
While overall E/P has moderate response rate in mUC, selected pts derive significant benefit. E/P is worth pursuing in a selected subset of mUC pts who have alterations in the mTOR or FGFR pathways.
Clinical trial identification
Legal entity responsible for the study
J. Bellmunt: Lectures and advisory board compensated from Novartis. T. Choueiri, J.E. Rosenberg: Research Funding Novartis. All other authors have declared no conflicts of interest.