Background: Efatutazone, a highly-selective peroxisome proliferator-activated receptor gamma (PPARδ) agonist, has demonstrated antitumor activity in multiple preclinical cancer models, including NSCLC, and has shown anticancer effects and a favorable toxicity profile in Phase 1 trials. The current study evaluated the safety and efficacy of efatutazone in combination with carboplatin and paclitaxel as first-line therapy for NSCLC. Methods: Patients with histologically/cytologically confirmed, untreated metastatic NSCLC, with no significant pleural effusion or pleural involvement from the tumor and an ECOG score of 0-1 participated in this 2-part, multinational study. Part 1 comprised a single-arm portion evaluating safety; Part 2, a double-blind, placebo-controlled, randomized Phase 2 portion evaluating safety and efficacy. Efatutazone (0.5 mg) or placebo was administered orally BID, continuously. Carboplatin was administered at a projected AUC of 6 mg/ml*min and paclitaxel at 200 mg/m2. In Part 1, patients were evaluated for treatment-related dose-limiting toxicities (DLTs). In Part 2, the primary endpoint was the progression-free survival (PFS) rate at Week 18, assessed by the investigators using RECIST. Results: 3 patients enrolled in Part 1; no DLTs were observed. 108 patients were randomized into Part 2. Demographic characteristics were generally similar between treatment arms with fewer patients in the efatutazone arm aged > 65 years (11% vs 28%), female (24% vs 32%), ECOG = 0 (30% vs 35%), and with squamous histology (26% vs 37%). Efatutazone was associated with a lower PFS rate at Week 18 vs placebo (41.1% [95% CI: 26.3, 55.3%] vs 64.9% [95% CI: 50.1, 76.3%]; P < 0.001) and a shorter PFS (102 vs 142 days; HR = 1.62, P = 0.04). There was no difference in overall survival (HR = 1.11, P = 0.71) at a median duration of follow-up of 6.7 months. Most adverse events more frequent with efatutazone were consistent with fluid retention, a known side effect of PPARδ agonists, and included edema, weight gain, pleural effusion, dyspnea, and anemia. In addition, a higher incidence of febrile neutropenia, nausea, and pain in extremity occurred in the efatutazone arm. Exploratory analyses are ongoing to try to understand the reason for the unexpected negative effect on PFS. The higher incidence of pleural effusion with efatutazone, which might be related to a treatment side effect rather than tumor progression, may provide some explanation: in some cases, pleural effusion was judged as progressive disease, whereas other target lesions were stable; no cytology was obtained in these cases. Interpretation: The efatutazone safety profile in this trial was largely consistent with prior studies and known effects of PPARδ agonists. Efatutazone does not improve the efficacy of carboplatin/paclitaxel as first-line therapy of unselected patients with NSCLC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4606. doi:1538-7445.AM2012-4606