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.