Preliminary evaluation of response to combination of RAD001 and cetuximab using [18F]-fluorodeoxyglucose positron emission tomography (18FDG-PET).

14525 Background: RAD001 inhibits mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway. Preclinical studies suggest that RAD001 may restore sensitivity to EGFR inhibitors. 18FDG-PET has been used in pre-clinical studies as a pharmacodynamic marker of mTOR inhibition. In this phase I dose escalation study, 18FDG-PET was incorporated as a PD marker for RAD001, alone and with cetuximab.,Pts with EGFR-expressing solid tumors were randomized to a 3-week run-in of single agent RAD001 (30-70 mg PO) or cetuximab (400 mg/m IV loading, 250 mg/m IV maintenance) weekly, followed by the combination weekly. 18FDG-PET was performed at three timepoints (baseline, run-in, and combination), to assess for early changes in tumor metabolic activity, and for subsequent correlation to treatment response (CT or MRI evaluation after every two cycles of combination). Up to five target lesions/patient were identified based on qualitative assessment of 18FDG uptake, and the percentage difference in the sum of maximum standard uptake values (SUVmax) was calculated for each scan. Response by 18FDG-PET was determined by the EORTC PET Study Group Response Criteria.,13 pts were treated at three dose levels, with 3 per dose order. Observed toxicities were all grade 1-2. 9 patients are evaluable for response, including four with SD ranging from 4-12 mos (parotid, ovarian, and anal squamous cell CA). Mean % change in SUVmax from baseline for those treated with RAD001 during run-in (n=7) was -20 (-49 to +1.6), in comparison to pts treated with cetuximab (n=6), at +.33 (-30 to +32). Mean % change in SUVmax from baseline for the group with SD (n=4) were as follows: -12.85 (-49 to +4) during run-in, versus -39.75 (-59 to -13) during combination tx. Mean % change in SUVmax from baseline for the group with PD (n=5) was much lower during combination therapy.,Combined RAD001 and cetuximab are tolerated at full doses with minimal toxicity. Metabolic response by 18FDG-PET during early combination therapy may be associated with tumor response by RECIST. No significant financial relationships to disclose.