A phase I-II study of everolimus (RAD001) in combination with imatinib in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (GIST).

10519 Background: Primary resistance to imatinib in pts with advanced GIST is uncommon but after durable benefit, most pts eventually develop secondary resistance. Molecular pathways of resistance may activate alternate oncogenic signaling mechanisms, including the AKT/mTOR pathway. Synergism in vitro between imatinib and RAD001 has been shown in human GIST cell lines resistant to imatinib, serving as the basis for this phase I/II trial. Phase 1 results were reported previously. This abstract reports phase 2 results.,Study follows a Simon's 2-stage design. Patients were enrolled into one of two strata. Stratum 1 (1-line failures): pts with progressive GIST on imatinib only (at least 4 mos treatment). Stratum 2 (post-2-line): patients with progressive GIST following imatinib and further therapies (e.g. sunitinib, investigational drugs) of which most pts received sunitinib. Main efficacy variable was 4 mo progression-free survival (PFS) with the criterion of interest being a 4 mo PFS rate of 20%, implying that at least 5/41 pts should be nonprogressive (α 0.046, 90% power). The passage from Simon stage 1 to 2 was dependent on a 4mo PFS rate of at least 5%, implying a 4 mo PFS in ≥ 2/21 pts. Each stratum was analyzed separately, but with the same criteria. All patients received imatinib 600 mg/d and RAD001 2.5 mg/d. The analysis was based on RECIST per investigator assessment.,Stratum 1: 23 of 28 enrolled pts (82.1%) were evaluable for 4 mo PFS, where 4 pts (17.4 %) were progression-free. Despite the criterion for continuing to stage 2 was met it was decided not to continue into stage 2 due to availability of new alternative treatment options. Stratum 2: 35 of 47 enrolled pts (74.5%) were evaluable for 4 mo PFS, where 13 pts (37.1 %) were progression-free.,The results suggest that GIST pts may benefit from combined treatment in case of 1- and 2-line treatment failure. However, randomized studies are needed to demonstrate the benefit associated with the combined therapy. [Table: see text].