A phase II NCCTG “Window of Opportunity Front-line” study of the mTOR Inhibitor, CCI-779 (Temsirolimus) given as a single agent in patients with advanced NSCLC Molina, Julian R.1 Mandrekar, Sumithra J.1 Rowland, Kendrith2 Reuter, Nicholas F.3 Jett, James R.1 Marks, Randolph1 Schild, Steven E.4 Adjei, Alex A.5 1 Mayo Clinic, Rochester, MN, USA 2 NCCTG, Danville, USA 3 NCCTG, Sait Cloud, USA 4 Mayo Clinic Arizona, Scottsdale, AR, USA 5 Roswell Park Cancer Institute, Buffalo, NY, USA Background: Over-expression of Akt and loss of PTEN are frequent events in non-small cell lung cancer (NSCLC). The mammalian target of rapamycin (mTOR) is a protein downstream to Akt in the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. CCI-779 (temsirolimus), an ester of sirolimus, is an inhibitor of mTOR with growth inhibitory activity in a variety of tumor cells. In an effort to evaluate the single agent activity of CCI-779 in previously untreated NSCLC, the NCCTG undertook a front-line “window of opportunity” study. Methods: N0323 was a two-stage single arm phase II trial which evaluated the response and toxicity rates of CCI-779 administered as a front line single agent treatment for stage IIIB (pleural effusion) or IV NSCLC. Fresh tumor biopsies were obtain to evaluate predictive markers of CCI-779 activity and target inhibition such as phospho AKT expression and loss of PTEN. Patients received 25 mg of CCI-779 administered intravenously as a 30 minute infusion on days 1, 8, 15, and 22 in4 week cycles. Based on a two-stage Fleming design with an exact significance level of 0.05 and 94% power to detect an effective treatment if the true CRR was at least 20%, this treatment would be promising if at least 4 of the first 25 evaluable patients in Stage I or at least 6 of the 50 evaluable patients at the end of Stage II have a confirmed response. Results: A total of 55 patients were accrued from February 2004 to November 2006 and results from the first 50 evaluable patients are reported here. Patient characteristics included a median age of 64 years (range: 44-85); 38% of patients were female; 84% had stage IV disease, and 89% were ECOG PS of 0 or 1. Median number of cycles administrated was 2 (range 1-18). One patient is still receiving active treatment (28 weeks). The most common grade 3/4 events were dyspnea (12%), fatigue (10%), hyperglycemia (8%), hypoxia (8%), nausea (8%), and rash/desquamation (6%). The clinical benefit rate was 38% with 4 (8%: 95% CI: 0.03-0.22) confirmed partial responses and 15 (30%: 95% CI: 0.14-0.48) stable disease for a minimum of 56 days. The 24-week progression-free survival (PFS) rate was 22% (11/50; 95% CI: 0.120.36). The median PFS and overall survival were respectively 2.3 and 6.6 months. Sixteen (32%) patients received subsequent treatment after progressing on CCI-779. Conclusions: CCI-779 (Temsirolimus) given as a single agent front line therapy in patients with NSCLC produced a clinical benefit rate of 38% (8% PR, 30% SD). While the study did not meet the predefined success criteria, single agent CCI-779 has activity similar to other signal transduction inhibitors and had good tolerability. Proper patient selection may enhance efficacy. The potential predictive markers of efficacy such as p70S-kinase phosphorylation and PTEN expression are being evaluated and these results will be presented. Poster Discussion Abstracts