Phase 2 randomized study of enzastaurin (LY317615) for lung cancer prevention in former smokers

BACKGROUND: Chemoprevention for lung cancer with nutraceutical or anti‐inflammatory agents has had mixed clinical benefit. Novel targeted agents hold the promise of greater efficacy and selectivity. The authors of this report evaluated enzastaurin, a selective protein kinase C‐β (PKC‐β) inhibitor with antiproliferative and proapoptotic properties, in former smokers. METHODS: The primary objective of this study was to compare the average fraction of Ki‐67–stained cells (the Ki‐67 labeling index [LI]) in bronchial biopsy specimens that were collected before and after treatment. Participants were randomized (2:1) to receive either 6 months of daily oral enzastaurin (500 mg) or placebo. Stratification was based on morphology, history of lung cancer, and airway obstruction. RESULTS: In pretrial investigations, the rationale for PKC‐β inhibition and pathway interrogation was established in premalignant lesions and early stage lung cancer. In an intent‐to‐treat analysis, of 40 randomized participants, there was no significant difference in the pretreatment/post‐treatment change in the Ki‐67 LI between the enzastaurin group and the placebo group (P = .53). Six participants discontinued enzastaurin, including 4 participants who had adverse events, including abdominal distension, deep vein thrombosis, hyponatremia, and rash, and 2 participants who decided to discontinue. One participant in the placebo group was discontinued on the study because of noncompliance. Two participants had ≥1 serious adverse event (bradycardia, deep vein thrombosis, and hypotension). CONCLUSIONS: To the authors' knowledge, this represents the first chemoprevention trial with a non‐US Food and Drug Administration‐approved, oral, small‐molecule–targeted agent. Although the primary endpoint was not met, enzastaurin was tolerable for 6 months by 75% of participants, and there was a suggestion of response in a subset analysis that was restricted to those who had metaplastic or dysplastic lesions. Cancer 2013. © 2012 American Cancer Society. This chemoprevention trial is the first using a non‐US Food and Drug Administration‐approved, oral, small‐molecule–targeted agent. Although the primary endpoint has not been met, the results indicate that enzastaurin is tolerable for 6 months by 75% of participants with a 19% positive response rate in all metaplastic or dysplastic lesions post‐treatment.