Abstract LB-194: Window of opportunity preoperative interrogation of mTOR pathway in patients with resectable non-small cell lung cancer (NSCLC).
Authors: Owonikoko Taofeek Kunle , Miller Daniel L. , Force Seth , Sica Gabriel , Kono Scott , Behera Madhusmita , Mendel Jennifer , Chen Zhengjia , Pickens Allan , Fu Robert W. , Auffermann William F. , Rogerio Jaqueline , Torres William E. , Fu Haian , Hohneker John , Sun Shi-Yong , Gal Anthony A. , Ramalingam Suresh S. , Khuri Fadlo R. 
Published: August 2014

Abstract
Background: We conducted this ‘window- of-opportunity’ study to characterize the biologic activity of everolimus, an allosteric inhibitor of mTOR pathway, in patients with surgically resectable NSCLC.
Methods: Patients with surgically resectable NSCLC (Stage I-III) underwent baseline tumor biopsy and FDG PET/CT scan followed by treatment with everolimus (5 or 10mg daily for up to 28 days). A repeat PET/CT scan was obtained 24 hours prior to surgery. Blood samples for pharmacokinetic (PK) assay for drug levels were collected at 0.5, 1, 2, 5, 8 and 24 hours post drug ingestion on Days 1, 8 and 21. Control patients not treated with everolimus also had paired FDG PET/CT scans prior to surgery. Target modulation by everolimus was assessed in vivo by PET and ex vivo by immunohistochemical detection of total and phosphorylated mTOR, Akt, S6, eIF4e and 4EBP1 in pretreatment and posttreatment tissue samples. Alterations in common driver mutations in NSCLC were assessed using SnapShot minisequencing technique.
Results: We enrolled 33 patients; 23 on everolimus and 10 on the control arm. Median age: 64 yrs (range 36-77), gender: (14/19 -M/F), stage (I - 14; II - 13; IIIA - 6); histology (adenocarcinoma - 22; squamous - 7; others - 4). Treatment was tolerated well with mostly grade 1/2 toxicities (hyperglycemia, hypertriglyceridemia, anemia and fatigue) and 32 of 33 patients proceeded with surgery on schedule. Compared to controls, there was significant reduction in SUVmax and median anatomic tumor size in a dose-dependent manner in everolimus-treated patients (15.38 vs. -21.74 vs. -23.23; p=0.012 and 4.39 vs. 0 vs.-13.33; p=0.039 in the control, 5mg and 10mg cohorts respectively). There was a similar trend in reduced metabolic activity in Ras mutant tumors treated with 10mg everolimus compared to control (88% vs. -28%). Comparison of baseline biopsy samples and resected tumor specimens in control and everolimus-treated patients showed reduction of S6 (-27.38 vs. 0 vs. -78.95; p=0.0536), pS6 (-20 vs. -29.17 vs. -57.14; p=0.0233) and p4EBP1 (-45.83 vs. 0 vs. -75; p=0.057) with greatest reduction observed in patients treated with higher dose of everolimus.
Conclusions: Everolimus exerts a measurable, dose-dependent biologic activity in NSCLC tumors. ‘Window of opportunity’ studies in early stage NSCLC provide strong mechanistic insights and guide development of novel targeted agents.
Acknowledgements: This study was supported by NCI grant P01 CA116676. Everolimus was provided by Novartis Oncology. TKO, GS, SS, SSR and FRK are Georgia Cancer Coalition Distinguished Cancer Scholars.
Citation Format: Taofeek Kunle Owonikoko, Daniel L. Miller, Seth Force, Gabriel Sica, Scott Kono, Madhusmita Behera, Jennifer Mendel, Zhengjia Chen, Allan Pickens, Robert W. Fu, William F. Auffermann, Jaqueline Rogerio, William E. Torres, Haian Fu, John Hohneker, Shi-Yong Sun, Anthony A. Gal, Suresh S. Ramalingam, Fadlo R. Khuri. Window of opportunity preoperative interrogation of mTOR pathway in patients with resectable non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-194. doi:10.1158/1538-7445.AM2013-LB-194