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Addition of enzastaurin to erlotinib did not improve survival in NSCLC
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The addition of enzastaurin to erlotinib did not improve survival or response in patients with previously treated, unselected, advanced non–small cell lung cancer, according to study results.
Enzastaurin (LY317615), an oral serine/threonine kinase inhibitor, targets protein kinase C (PKC) and phosphatidylinositol-3-kinase (PI3K) pathways. It affects signal transduction linked with angiogenesis, apoptosis and cellular proliferation, inducing inhibition of tumor growth.
Enzastaurin was considered a promising agent to add to erlotinib (Tarceva; Genentech, Astellas), the researchers wrote.
“The combination of erlotinib with the anti-VEGF agent bevacizumab has been shown to increase response rate and PFS, but not OS, beyond that seen with erlotinib alone,” the researchers wrote. “There is also preclinical evidence supporting the ability of enzastaurin to overcome resistance to the EGFR inhibitor gefitinib (Iressa, AstraZeneca), a drug very similar to the EGFR tyrosine kinase inhibitor erlotinib used in this trial.”
To determine the efficacy and safety profile of the enzastaurin/erlotinib combination in patients with previously treated NSCLC, the researchers enrolled 49 patients with advanced NSCLC (stage IIIB or IV).
All patients had failed at least one prior systemic treatment regimen, and they had undergone at least one prior chemotherapy regimen.
Fifty-nine percent of patients were men, 78% were white and 71% were former smokers. Six patients (12%) had stage IIIB disease and 43 (88%) had stage IV disease. Adenocarcinoma, observed in 65% of patients, was the most common histologic type.
All patients received erlotinib 150 mg/day and enzastaurin 500 mg/day, both orally in 28-day cycles. The primary endpoint was PFS.
The combination regimen did not improve survival and response when compared with historical data of single-agent erlotinib, the researchers wrote. In the current study, median PFS was 1.7 months (one-sided 90% CI, 1.5-NA) and median OS was 8.3 months (85% CI, 5.3-14.3). The overall response rate of 10.2%, and the disease control rate was 30.6%.
The combination was well tolerated. Grade-3/grade-4 drug-related adverse events that occurred in ≥5% of patients were diarrhea, acne and nausea. One patient died from interstitial lung disease that could be related to the treatment, the researchers said.
Enzastaurin has not demonstrated clear single-agent activity in NSCLC. Prior trials showed the addition of enzastaurin to pemetrexed (Alimta, Lilly) did not increase response or PFS in NSCLC patients, and no benefit was observed when enzastaurin was added to a bevacizumab-containing first-line NSCLC regimen, the researchers said.
“It is possible that enzastaurin does increase efficacy for a subset of patients with NSCLC, but specific markers for efficacy have yet to be identified,” the researchers wrote.
Disclosure: The researchers report grant support from Eli Lilly and Co. and Genentech for clinical trial work. Researchers also report employment relationships with and stock ownership in Eli Lilly and Co.
Perspective
Back to TopPatrick C. Ma, MD, MS
The study report by Clement-Duchene et al. on “A phase 2 study of enzastaurin in combination with erlotinib in patients with previously treated advanced NSCLC” unfortunately showed no added benefit in the addition of enzastaurin, an oral serine/threonine kinase inhibitor of PKC and PIK3/AKT pathway, in an unselected advanced NSCLC patient population with unknown EGFR mutation genotype status. This study was conducted at the time when EGFR mutation test has not been performed in a routine pre-therapy fashion. However, there is no report of retrospective analysis of the EGFR mutation status in the tumor tissue in this trial study. Hence, no conclusion can be made regarding if the 10.2% responders in this study are from patients with EGFR mutations. Since the inhibitor enzastaurin targets separate signaling cascades that is thought to play key roles in NSCLC, namely the PKC and PI3K/AKT pathways, it would be hoped that one would at least observe some activities that could indicate additive benefits in addition to erlotinib alone.
A limitation of the study here is that it is a single arm trial comparing to historic control of erlotinib alone treated patients. Despite being well-tolerated, the combination of erlotinib plus enzastaurin did not seem to yield more superior response rates, PFS or OS. This is rather disappointing. Clearly, there is still much room to improve in the clinical outcome of the advanced NSCLC patients, whether they have mutations in EGFR or not. We still have not “cured” mutated EGFR driven NSCLC, and non-mutated EGFR NSCLC is now known to be a heterogeneous group of molecular disease rather than one disease. Further attempts of combination targeted therapeutic clinical trials evaluating novel targeted drugs would best be designed for patients with known specific genotype background. Clear and specific objectives should be pursued with examples being goals to prevent or overcome resistance in a responder population to another targeted drug in combination use, or whether to enhance primary response in a non-responder population by invoking a synergistic inhibition by the two novel drugs in combination. The underlying mechanism of action could be quite different in the two scenarios. Moreover, it is becoming clearer and more essential now to develop companion diagnostics for identifying predictive and prognostic biomarkers in novel targeted therapeutics trials. It is equally important to design such trials vigorously based on mechanistic insights of the drug(s) to be tested whether alone or in combination. Robust preclinical in vivo models for drug combination testing could play very important role to guide the clinical therapeutic development strategies and are really indispensable.
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