Pharmacodynamics of RAD001 measured by early FDG PET in patients with recurrent NSCLC

Abstract

14616 Background: RAD001 (everolimus) is a novel inhibitor of mTOR currently investigated as an anticancer agent. RAD001- induced inhibition of mTOR showed a prominent impact on glucose homeostasis with the transcription factor HIF-1 as one of the primary mediators and the inhibition of FDG uptake demonstrated by FDG-PET imaging in preclinical models treated with RAD001. We postulated that the glucose metabolism measured by 18F-FDG-PET might serve as pharmacodynamic marker of RAD001 treatment in lung cancer patients. Methods: Patients with previously treated advanced non-small cell lung cancer (NSCLC) were treatedwith a 10 mg daily dose of RAD001 in an open label, multi-centre phase II study. A subgroup of 8 pts enrolled in two of the study centres was evaluated by serial 18F-FDG-PET scans. 18F-FDG-PET was performed on day 1 and day 8 of RAD001 treatment in all 8 patients. In addition, in 5 out of these 8 pts FDG-PET was performed on day 28 of treatment. Percentage change of the sum of the maximum standardized uptake values (sSUVmax) from baseline was calculated on days 8 and 28. In addition, the computed tomography (CT) scans was obtained at baseline and on day 28 as a standard assessment of response. Results: Reduction of sSUVmax on day 8 was observed in all patients ranging from −1.4% to −89.1% (median −19.3). On day 28, the reduction of sSUVmax was much less in 4 patients and we found an increase versus baseline in 1 patient (median −9.7). On day 28, according to the PET response criteria, one patient achieved a PR and two each had SD or PD. TTP ranged from 12 to 191 days. Conclusions: Although based on evaluation of a small cohort of patients, the results suggest that (I) inhibition of glucose metabolism is an early effect of RAD001 treatment in lung cancer patients and (II) this early pharmacodynamic effect can be assessed by 18F-FDG-PET. The results indicate that 18F-FDG-PET may represent a suitable tool for early pharmacodynamic evaluation of mTOR inhibitors such as RAD001 in patients with NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis