Abstract
5111 Background: TEM, an inhibitor of mTOR complex 1 (TORC1), is approved for the treatment of metastatic RCC. BRYO inhibits protein kinase C, a downstream effector of mTOR complex 2 (TORC2). We observed additive effects of TEM and BRYO against RCC in vitro. Methods: Four cohorts of 3–6 patients (pts) received weekly BRYO (20 mcgm/m2) and TEM (10, 15, 25, or 37.5 mg,) in 28 day cycles. DLT was defined as 1st cycle toxicity ≥ grade 3. Results: Twenty-three pts have been enrolled. Eighteen pts had RCC: clear cell (12), papillary (3), clear cell with sarcomatoid/spindle features (2), unclassified (1), Among RCC pts, 3 had no prior therapy. 15 had a median of 2 prior therapies (immunotherapy, TKIs, and/or bevacizumab). To date, 22 pts have received 103 cycles across 4 dose levels. Five non-RCC pts (4 sarcoma, 1 paraganglioma) received up to 3 cycles of treatment. Two of these pts (both had prior cytotoxic therapy) experienced DLT at 15 mg (Gr 3 neutropenia and Gr 3 hypophosphatemia) Subsequently, pts with prior cytotoxic therapy were excluded. One additional non-RCC pt (prior radiation) experienced DLT (Gr 3 neutropenia) at TEM 37.5 mg. Among RCC pts, there were no 1st cycle DLT's. Significant toxicities during later cycles included Gr 3/4 thrombosis at TEM 37.5 mg (2), Gr 4 thrombus/Gr 4 LV dysfunction at TEM 15 mg (1), and Gr 3 dyspnea/Gr 3 pneumonitis at TEM 10mg (1). Gr 4 hypercholesterolemia (1) and Gr. 4 triglyceride elevation (1) were seen at TEM 37.5 mg, both reversed with treatment. One RCC pt withdrew prior to receiving treatment. Of the 17 remaining RCC pts, 3 had PRs and 9 had SD. One treatment naïve pt (TEM 15 mg) continues with PR for 2+ years after discontinuing treatment. One pt (had progressed on sunitinib) continues in a PR at 14+ months. Twelve pts received ≥4 cycles and 3 received >10 cycles. PR was seen in both clear cell and papillary histologies. Median PFS was 7.8 months for all pts and 5.7 months for previously treated pts. Two pts, both with PR, remain on treatment, having received 18 and 8 cycles. Conclusions: The TEM/Bryo combination is feasible for multiple cycles on a weekly schedule at full doses of each agent with durable PR and SD in RCC refractory to other therapies. Enrollment continues to further characterize safety and efficacy. [Table: see text]
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