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	NSCLC Trial: Dual-Action Kinase Inhibitor and Unique Study Design Yield Encouraging Results Abstract #8014: A randomized discontinuation phase II study of sorafenib (Nexavar®, Bayer HealthCare and Onyx Pharmaceuticals, Inc.) versus placebo in patients with NSCLC who have failed at least two prior chemotherapy regimens: ECOG 2501, was presented during a lung cancer oral presentation at the 2008 ASCO Annual Meeting. Sorafenib (S) inhibits Raf kinase and is an inhibitor of angiogenesis (VEGF receptors) as well. Since other angiogenic inhibitors have activity in NSCLC, sorafenib was chosen for this randomized, placebo (P) controlled phase II study in third-line and beyond disease. The investigators utilized a unique study design, known as a randomized discontinuation trial (RDT). Why use the randomized discontinuation design? Optimal for agents with cytostatic activity, where the primary clinical benefit might be stabilization of disease. It represents an enrichment design, in which all patients receive study drug (sorafenib) for an initial “run-in” period, followed by random assignment of patients with stable disease (SD) to either the study drug or placebo. Patients with rapidly progressive disease (PD) go off study before randomization. Based on the hypothesis that patients with rapidly progressive disease may not stay on drug long enough to derive a benefit. It enriches for patients with slower progressing disease, who might be more likely to benefit. All patients received 400mg of S orally twice daily for 2 cycles (2 months); the “run-in” phase called Step 1. Responding patients on Step 1 continued on S; progressing patients went off study, and patients with stable disease were randomized to sorafenib (S) or placebo (Step 2). Patients randomized to placebo (P) were allowed to cross over to S on progression (PD). The primary endpoint of the study was the proportion of patients having stable or responding disease 2 months (8 weeks) after randomization. Eligibility: PS 0-1, progressive disease, and at least 2 prior chemotherapy regimens; however, prior treatment with biologics (EGFR, TKIs, and anti-angiogenics) did not count as a “line of therapy”. In fact, most patients were on their third, fourth, and fifth line of therapy, thus a heavily pre-treated population. Results: 342 patients enrolled in Step 1; 97 eligible patients were subsequently randomized to Step 2 and treated; 36 of 41 patients receiving P on Step 2 were crossed over to S. Primary endpoint: 83 patients evaluable overall (32 placebo, 51 sorafenib). The number of patients with stable or responding disease 2 months after randomization were placebo 6 (19%), sorafenib 24 (47%) (p=0.01). Outcomes: Step 2; for median PFS: 2.0 months placebo vs. 3.6 months for sorafenib (p=0.009; HR 2.16). For median survival: 9.0 months P vs. 11.9 months for S (HR= 1.50, p=0.18). Best overall response (Step 2): placebo CR 0%, PR 3%, stable 16%; sorafenib CR 0%, PR 2%, stable 47% (p=0.01 for CR, PR, + stable disease). Conclusions: This trial met its primary endpoint of disease stabilization at 8 weeks (2 months) following randomization compared to placebo. Single agent sorafenib significantly improves PFS and maintains stable disease in a heavily pre-treated, enriched NSCLC patient population. Trend toward improvement in survival promising. Major toxicities manageable and as expected. Too few patients with squamous cell histology to make any definitive conclusions regarding either toxicity or efficacy in this single agent trial. These results warrant further investigations in larger randomized studies.