Everolimus, an mTOR inhibitor, in combination with docetaxel for second- or third-line therapy of advanced-stage non-small cell lung cancer: A phase II study.

Abstract

e13601 Background: mTOR pathway activation is a critical oncogenic event in non-small cell lung cancer. We observed enhanced anti-cancer activity with the combination of docetaxel and everolimus (RAD 001) in pre-clinical and early phase clinical studies. Therefore a phase II study was conducted to evaluate the efficacy of this combination in advanced NSCLC. Methods: Advanced stage NSCLC patients with 1 or 2 prior systemic therapy regimens, ECOG performance status (PS) 0-2, and adequate organ function were eligible. Docetaxel (60 mg/m2) was given on day 1 of each cycle and everolimus (5 mg PO QD) was given on days 2-19 of each 3-week treatment cycle. The primary endpoint was response rate and secondary endpoints included PFS, OS and safety assessment. The Simon two-stage design was utilized. Archived tumor specimens were evaluated for upstream and downstream markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e and 4EBP1). Results: Twenty-eight patients were enrolled (median age- 64 years, male -13, Caucasian 19, adenocarcinoma-17, squamous-8, PS 0/1/2-4/20/2). A median of 3.5 cycles of therapy was administered. Grade 3/4 toxicities (n=11) included neutropenia, anemia, headache, fatigue, hyperglycemia, mucositis, and dyspepsia. Two patients experienced partial response and 13 had stable disease (clinical benefit rate 54%). The median PFS was 2.3 months and the median overall survival was 12 months. The study did not meet the efficacy criteria to proceed to full accrual. High pAkt expression correlated with objective tumor response (p=0.033) but not with PFS (p=0.261) or OS (p=0.467). Conclusions: The combination of everolimus and docetaxel was tolerated well, but there was no clear signal of enhanced efficacy in an unselected population of NSCLC patients. Supported by NCI P01 CA116676. FRK, TKO, SS, and SSR are Georgia Cancer Coalition Distinguished Cancer Scholars.