TY - JOUR
T1 - A translational, pharmacodynamic, and pharmacokinetic phase IB clinical study of everolimus in resectable non-small cell lung cancer
AU - Owonikoko, Taofeek K.
AU - Ramalingam, Suresh S.
AU - Miller, Daniel L.
AU - Force, Seth D.
AU - Sica, Gabriel L.
AU - Mendel, Jennifer
AU - Chen, Zhengjia
AU - Rogatko, Andre
AU - Tighiouart, Mourad
AU - Harvey, R. Donald
AU - Kim, Sungjin
AU - Saba, Nabil F.
AU - Pickens, Allan
AU - Behera, Madhusmita
AU - Fu, Robert W.
AU - Rossi, Michael R.
AU - Auffermann, William F.
AU - Torres, William E.
AU - Bechara, Rabih
AU - Deng, Xingming
AU - Sun, Shi Yong
AU - Fu, Haian
AU - Gal, Anthony A.
AU - Khuri, Fadlo R.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/4/15
Y1 - 2015/4/15
N2 - Purpose: The altered PI3K/mTOR pathway is implicated in lung cancer, but mTOR inhibitors have failed to demonstrate efficacy in advanced lung cancer. We studied the pharmacodynamic effects of everolimus in resectable non-small cell lung cancer (NSCLC) to inform further development of these agents in lung cancer. Experimental Design: We enrolled 33 patients and obtained baseline tumor biopsy and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging followed by everolimus treatment (5 or 10 mg daily, up to 28 days), or without intervening treatment for controls. Target modulation by everolimus was quantified in vivo and ex vivo by comparing metabolic activity on paired PET scans and expression of active phosphorylated forms of mTOR, Akt, S6, eIF4e, p70S6K, 4EBP1, and total Bim protein between pretreatment and posttreatment tissue samples. Results: There were 23 patients on the treatment arm and 10 controls; median age 64 years; 22 tumors (67%) were adenocarcinomas. There was a dose-dependent reduction in metabolic activity (SUVmax: 29.0%, -21%, -24%; P = 0.014), tumor size (10.1%, 5.8%, -11.6%; P = 0.047), and modulation of S6 (-36.1, -13.7, -77.0; P = 0.071) and pS6 (-41.25, -61.57, -47.21; P = 0.063) in patients treated in the control, 5-mg, and 10-mg cohorts, respectively. Targeted DNA sequencing in all patients along with exome and whole transcriptome RNA-seq in an index patient with hypersensitive tumor was employed to further elucidate the mechanism of everolimus activity. Conclusions: This "window-of-opportunity" study demonstrated measurable, dose-dependent, biologic, metabolic, and antitumor activity of everolimus in early-stage NSCLC.
AB - Purpose: The altered PI3K/mTOR pathway is implicated in lung cancer, but mTOR inhibitors have failed to demonstrate efficacy in advanced lung cancer. We studied the pharmacodynamic effects of everolimus in resectable non-small cell lung cancer (NSCLC) to inform further development of these agents in lung cancer. Experimental Design: We enrolled 33 patients and obtained baseline tumor biopsy and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging followed by everolimus treatment (5 or 10 mg daily, up to 28 days), or without intervening treatment for controls. Target modulation by everolimus was quantified in vivo and ex vivo by comparing metabolic activity on paired PET scans and expression of active phosphorylated forms of mTOR, Akt, S6, eIF4e, p70S6K, 4EBP1, and total Bim protein between pretreatment and posttreatment tissue samples. Results: There were 23 patients on the treatment arm and 10 controls; median age 64 years; 22 tumors (67%) were adenocarcinomas. There was a dose-dependent reduction in metabolic activity (SUVmax: 29.0%, -21%, -24%; P = 0.014), tumor size (10.1%, 5.8%, -11.6%; P = 0.047), and modulation of S6 (-36.1, -13.7, -77.0; P = 0.071) and pS6 (-41.25, -61.57, -47.21; P = 0.063) in patients treated in the control, 5-mg, and 10-mg cohorts, respectively. Targeted DNA sequencing in all patients along with exome and whole transcriptome RNA-seq in an index patient with hypersensitive tumor was employed to further elucidate the mechanism of everolimus activity. Conclusions: This "window-of-opportunity" study demonstrated measurable, dose-dependent, biologic, metabolic, and antitumor activity of everolimus in early-stage NSCLC.
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U2 - 10.1158/1078-0432.CCR-14-1998
DO - 10.1158/1078-0432.CCR-14-1998
M3 - Article
C2 - 25673697
AN - SCOPUS:84927626238
SN - 1078-0432
VL - 21
SP - 1859
EP - 1868
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -