In the first chemoprevention trial with a non-FDA-approved, oral, small-molecule-targeted agent, enzastaurin did not meet a primary endpoint but showed reasonable tolerability and some success in subgroup analyses.
“In lung cancer, several [chemoprevention] compounds have been tested, but trials have been either negative or, in the case of those evaluating B-carotene in smokers, deleterious,” wrote researchers led by Jhanelle E. Gray, MD, of the Moffitt Cancer Center in Tampa, Florida. “Because of the large number of required participants and long interventions and follow-up times, trials that use lung cancer incidence as a primary endpoint pose a formidable challenge from a logistic and financial perspective.”
To avoid that issue, the current study used a surrogate endpoint of Ki-67, which can be found in normal and premalignant lung lesions; a high fraction of tumor cells that stain positive for Ki-67 correlates with poorer survival in non–small-cell lung cancer patients. The phase II, randomized, double-blind study included 40 patients, 25 of whom received the oral serine/threonine kinase inhibitor enzastaurin; the other 15 received placebo. Results were published online ahead of print on October 12 in Cancer.
The included patients had at least a 30 pack-year history of smoking, though all had quit at least 1 year prior to the study. Patients were free of malignancies for the previous 5 years with several exceptions. Staining for Ki-67 was done at baseline and after 6 months of treatment.
There was no significant difference between the placebo and enzastaurin groups in terms of pretreatment to post-treatment change in Ki-67 staining (P = .53). Six patients discontinued the study drug, including four with adverse events that included abdominal distension, deep vein thrombosis, hyponatremia, and rash. The original study design called for 186 participants yielding 138 evaluable patients, but the planned interim efficacy analysis at 40 patients was required to show positive results in order to continue recruiting patients.
Though that analysis did fail, leading to the end of the study, there was some suggestion of success in a subgroup analysis of only metaplastic and dysplastic samples; 19% of patients receiving enzastaurin had a reduction of greater than 50% in Ki-67 response compared to none of the participants receiving placebo.
The authors concluded that “Ki-67 or other biomarkers of proliferation should be used only in tissues with high baseline levels, such as metaplastic/dysplastic lesions, if the inhibitory activity of an agent is being investigated. Further studies with enzastaurin or similar agents that take these considerations into account are warranted to advance cancer prevention with targeted agents.”