Phase Ii Study Of Everolimus (E) With Imatinib (Im) In Patients With Previously-Treated Renal Carcinoma (Rcc)

e16075 Background: Inhibitors of mTOR improve progression-free survival (PFS) in advanced RCC. We hypothesized that co-administration of the mTOR inhibitor E with an upstream receptor tyrosine kinase inhibitor could augment activity in advanced RCC. We chose to study IM due to its inhibition of PDGFR, a relevant target for RCC with potential activity at both the tumor cell and the pericyte. Methods: Eligible patients had metastatic or unresectable clear cell renal carcinoma, at least one prior systemic therapy, no prior mTOR inhibitor therapy, performance status 0–2, and measurable disease. Treatment consisted of E 2.5 mg p.o. daily and IM 600 mg p.o. daily, a dose determined from a phase I study in GIST. A two-stage design was employed to test for a 3-month PFS of ≥ 70% vs. ≤ 50%. Results: 19 subjects were evaluable for toxicity and 18 for response. Median age 65; number of prior systemic therapies 1:2:3+ (47%:32%:21%); prior sorafenib and/or sunitinib 89%; MSKCC prognostic categories favorable:intermediate:poor (42%:47%:11%). There were no objective responses. Best response was stable disease (67%) and progressive disease (33%). The 3-month PFS rate was 49% (95% C.I. 23%, 72%). The median PFS was 2.9 months (95% C.I. 1.9, 6.2) and the median overall survival was 14.4 months (95% C.I. 11.3, N.R.). Toxicities and lab abnormalities affecting >50% of subjects were: nausea, elevated creatinine, edema, anemia, hypocalcemia, fatigue, diarrhea, vomiting, and dyspnea, and leucopenia. Most common grade 3+ events were: fatigue (16%), pleural effusion (16%), edema (11%), and renal failure (11%). The study was closed after the first stage as the 3-month PFS did not meet continuation criteria. Conclusions: The combination of E 2.5 mg with IM 600 mg in previously-treated patients with advanced RCC did not meet the study-defined level of activity to warrant further investigation. The natural history assumptions for this pretreated RCC population may have been overly optimistic. While the observed PFS is comparable to that reported with E 10mg monotherapy, there appears to be no advantage to combination IM therapy and the incidence of adverse events is high. Further development of this regimen for RCC is not recommended. [Table: see text]