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Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer

Yun Oh, Roy S. Herbst, Howard Burris, Ann Cleverly, Luna Musib, Michael Lahn, Gerold Bepler

From the M.D. Anderson Cancer Center, Houston, TX; The Sarah Cannon Cancer Center, Nashville, TN; Eli Lilly and Company, Indianapolis, IN; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and Eli Lilly and Company, Erlwood, United Kingdom

Corresponding author: Gerold Bepler, MD, PhD, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL 33612; e-mail: gerold.bepler{at}moffitt.org

Purpose: Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses protein kinase C (PKC) and protein kinase B/AK transforming (AKT) signaling, induces tumor cell apoptosis, and inhibits proliferation and angiogenesis. Increased PKC and AKT activity is associated with poor prognosis in non–small-cell lung cancer (NSCLC). This phase II trial of enzastaurin was conducted to determine the 6-month progression-free survival (PFS) rate in advanced, metastatic NSCLC.

Patients and Methods: Patients with metastatic (stage IV and wet IIIB) NSCLC, Eastern Cooperative Oncology Group performance status 2, and two prior systemic regimens (including one or more platinum-based chemotherapy regimens) received 500 mg of enzastaurin administered once daily.

Results: Fifty-five patients were enrolled (55% male patients, 45% female patients; median age, 63 years; range, 44 to 82 years; 78% of patients having stage IV disease). Adenocarcinoma was the most common diagnosis (65%). Prior therapies included radiotherapy (73%) and epidermal growth factor inhibitors (29%). Median PFS was 1.8 months (95% CI, 1.7 to 1.9). Six-month PFS rate was 13% (95% CI, 3.9% to 21.5%). Median overall survival (OS) was 8.4 months (95% CI, 6.0 to 13.6 months). The 12-month OS rate was 44% (95% CI, 30.5% to 57.3%). Nineteen patients (35%) had stable disease. No objective responses were observed. Seven patients (13%) had PFS 6 months, three of whom continued for more than 10 months. The most common toxicity was fatigue (grade 3; n = 17). Grade 3 or worse toxicities were fatigue (n = 2), thromboembolism (n = 1), ataxia (n = 1), and anemia (n = 1). Two patients discontinued treatment because of drug-related fatigue and dizziness. Five patients died while enrolled in the study (non drug-related).

Conclusion: Although the primary end point of a 20% PFS rate was not achieved, 13% of the patients had PFS for 6 months. Given the tolerability and survival data, evaluation of enzastaurin in combination with cytotoxic drugs is warranted in NSCLC.

Sponsored by Eli Lilly and Company.

Presented in part at the 18th European Organization for Research and Treatment of Cancer–National Cancer Institute–American Association for Cancer Research Symposia, Prague, Czech Republic, November 7-10, 2006, and at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.