Some long-term stablization in NSCLC with enzastaurin

ASCO—Long-term disease stabilization in some patients who had progressed after one or two prior therapies suggests possible activity for the investigational agent enzastaurin (Eli Lilly) in non-small-cell lung cancer (NSCLC), Gerold Bepler, MD, PhD, of H. Lee Moffitt Cancer Center & Research Institute, reported at ASCO 2007 (abstract 7543)

Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways, inducing tumor apoptosis, inhibiting tumor cell proliferation and suppressing tumor-induced angiogenesis. Both PKC and PI3K/AKT are overexpressed and overactive in lung cancer tissues and cell lines.

"It would be good if we could reverse the proliferation process and slow down cancer growth by blocking apoptosis," Dr. Bepler said in an interview. He noted that in early clinical studies of enzastaurin, several patients with advanced cancers had stable disease for up to 12 months.

The primary objective of Dr. Bepler's phase II study was to estimate progression-free survival (PFS) at 6 months. A total of 55 patients with progressive advanced or metastatic NSCLC (stage IIIB and IV) received oral enzastaurin 500 mg once daily for a planned maximum duration of six cycles (28 days each). A number of patients also received post-study chemotherapy, including 14 (25.5%) who received erlotinib (Tarceva).

Included patients had received at least one prior platinum-based regimen, with 42% having two to three prior regimens; 29% had received a prior EGFR-TKI, and 54.5% had received at least one radiotherapy course.

Dr. Bepler reported that at the 6 month interim analysis, median PFS was 1.8 months, and the PFS rate was 13%. Best overall response assessment was stable disease in 19 patients (34%), including three with stable disease for 10 or more cycles. There were no objective responses. Progressive disease occurred in 29 (53%), and 7 patients (13%) discontinued treatment before assessment. Median overall survival was 8.4 months, with a 1-year overall survival rate of 44%.

Enzastaurin was well tolerated, with the most common drug-related toxicity being fatigue. Dr. Bepler noted that fatigue was observed in patients who progressed, but not in patients who had disease stabilization.

Dr. Bepler concluded, "Long-term disease stabilization in three patients who had progressed after one or two prior therapies suggests enzastaurin may have activity in NSCLC." He pointed out that although the disease stabilization rate was modest, one patient was treated for 20 months before progression, and six were treated for more than 6 months.

"This is an oral drug with only minor fatigue. With molecular markers, perhaps PKC via immunohistochemistry, we may be able to select those patients more likely to respond," Dr. Bepler said.

ASCO discussant

ASCO reviewer Chandra P. Belani, MD, of the University of Pittsburgh Cancer Institute, commented that with no evidence of single-agent activity for enzastaurin in recurrent NSCLC, "the survival duration was probably related to post-study therapy."

The question as to whether there is a chemotherapy-enhancing effect for enzastaurin is being addressed, Dr. Belani said, in an ECOG phase II study of carboplatin, gemcitabine (Gemzar), and enzastaurin with or without bevacizumab (Avastin).