A translational, pharmacodynamic, and pharmacokinetic phase IB clinical study of everolimus in resectable non-small cell lung cancer

Taofeek K. Owonikoko, Suresh S. Ramalingam, Daniel L. Miller, Seth D. Force, Gabriel L. Sica, Jennifer Mendel, Zhengjia Chen, Andre Rogatko, Mourad Tighiouart, R. Donald Harvey, Sungjin Kim, Nabil F. Saba, Allan Pickens, Madhusmita Behera, Robert W. Fu, Michael R. Rossi, William F. Auffermann, William E. Torres, Rabih Bechara, Xingming DengShi Yong Sun, Haian Fu, Anthony A. Gal, Fadlo R. Khuri

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1859-1868
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number8
DOIs
StatePublished - Apr 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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