A phase I/II trial combining erlotinib with gamma secretase inhibitor RO4929097 in advanced non-small cell lung cancer (NSCLC).

8104 Background: All NSCLC patients treated with erlotinib (E) eventually develop resistance. Both the epithelial-mesenchymal transition (EMT) and cancer stem cells may contribute to resistance to E. The Notch pathway plays a key role in maintaining stem cell viability and in EMT. Gamma secretase inhibitors such as RO4929097 (R) inhibit Notch activity by preventing cleavage of Notch to its active form. In this CTEP-sponsored study, primary endpoint of phase I was to determine maximum tolerated dose (MTD) of the combination of E and R; primary endpoint of phase II was response rate. Methods: Eligible pts had incurable NSCLC, measurable disease, ECOG PS 0-1, and adequate laboratory parameters. There were no limits on prior therapy. All pts were required to have a tumor biopsy. Patients received E PO daily on a continuous schedule and R PO daily on days 1-3, 8-10, and 14-17 of a 21 day cycle. Dose cohorts (E/R both in mg) were as follows: 100 /20, 150/20, 150/30, 150/45. Imaging was performed every 6 weeks. ...