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

Abstract

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. Patients could remain on therapy until progression. Results: 21 pts were enrolled between 9/2010 and 3/2012. 5 were not eligible and did not receive treatment. For the 16 treated pts: median age was 61 yrs (40-75), 7 (44%) were male, 14 (88%) had adenocarcinoma. All pts had received prior chemotherapy (1-8 regimens); 7 (44%) had prior E. 3 pts had known EGFR mutations; 2 pts had KRAS mutations. Time on therapy ranged from 20 to 248 days. Median PFS was 42 days. Pts with prior progression on E had a median PFS of 64 days. 1 pt (6%) had a partial response, 4 (19%) had stable disease at 6 weeks. Median overall survival is 6.5 months (1.3 to 24.5+ months). Observed dose-limiting toxicity was hypophosphatemia in 1 pt in 150/45 cohort. Other toxicities included rash, neuropathic pain and nausea. MTD was determined to be 150/45. The study was halted early, after completion of the phase I cohort, as production of R was discontinued by the manufacturer. 12 pts (75%) have adequate tumor tissue for analyses. Biomarker studies are pending. Conclusions: Combination of R and E is safe and feasible in pts with NSCLC. Though development of R has been discontinued, other drugs targeting the Notch pathway are in development (NCI R21CA153017). Clinical trial information: NCT01193881.