A phase II study of enzastaurin in combination with erlotinib in patients with previously treated advanced non-small cell lung cancer

Stanford University, Stanford Cancer Institute, Stanford, CA, USA
Lung cancer (Amsterdam, Netherlands) (Impact Factor: 3.96). 07/2012; 78(1):57-62. DOI: 10.1016/j.lungcan.2012.06.003
Source: PubMed


Regardless of epidermal growth factor receptor (EGFR) mutation status, erlotinib improves survival for patients with advanced non-small cell lung cancer (NSCLC) after one or more chemotherapy regimens. Enzastaurin is an oral serine/threonine kinase inhibitor. This phase II study was designed to evaluate the efficacy and safety of erlotinib and enzastaurin in NSCLC, a combination with promise to overcome EGFR resistance based on preclinical models.
Eligible patients with advanced NSCLC (IIIB or IV) who had failed one or two prior systemic treatment regimen(s) were enrolled and received erlotinib 150mg/day and enzastaurin 500mg/day (after a 1125-mg loading dose on day 1, cycle 1), both orally in 28-day cycles. The primary endpoint was progression-free survival (PFS).
From January 2008 to July 2009, 49 patients were enrolled: 29 (59%) men and 20 (41%) women; 8 (16%) were non-smokers. The median PFS was 1.7months (one-sided 90% CI: 1.5-NA) and median overall survival (OS) was 8.3months (95% CI: 5.3-14.3). Five patients had partial response, for an overall response rate of 10.2%; the disease control rate was 30.6% (responders+10 patients with stable disease). Grade 3-4 drug-related adverse events in ≥5% of patients were diarrhea, acne, and nausea. One possibly drug-related death due to interstitial lung disease occurred during the study.
In previously treated, unselected, advanced NSCLC patients, the addition of enzastaurin to erlotinib did not improve PFS, response, or OS compared with historical data of single-agent erlotinib, but was well tolerated.

Download full-text


Available from: Heather A Wakelee, Dec 13, 2014
  • Source
    • "Erlotinib has been also tested in combination with enzastaurin, a selective protein kinase Cβ inhibitor, and bortezomib, a proteasome inhibitor, without improving PFS and OS when compared to erlotinib alone,75–77 as well as entinostat, an HDAC inhibitor.78 Two Phase I/II trials of HDAC inhibitor vorinostat (NCT00503971) and belinostat (NCT01188707) in combination with erlotinib have been terminated but results are still to come. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the last decade, better understanding of the role of epidermal growth factor receptor in the pathogenesis and progression of non-small cell lung cancer has led to a revolution in the work-up of these neoplasms. Tyrosine kinase inhibitors, such as erlotinib and gefitinib, have been approved for the treatment of non-small cell lung cancer, demonstrating an improvement in progression-free and overall survival, particularly in patients harboring activating EGFR mutations. Nevertheless, despite initial responses and long-lasting remissions, resistance to tyrosine kinase inhibitors invariably develops, most commonly due to the emergence of secondary T790M mutations or to the amplification of mesenchymal-epithelial transition factor (c-Met), which inevitably leads to treatment failure. Several clinical studies are ongoing (http://www.clinicaltrials.gov), aimed to evaluate the efficacy and toxicity of combined approaches and to develop novel irreversible or multitargeted tyrosine kinase inhibitors and mutant-selective inhibitors to overcome such resistance. This review is an overview of ongoing Phase I, II, and III trials of novel small molecule epidermal growth factor receptor inhibitors and combinations in non-small cell lung cancer patients.
    OncoTargets and Therapy 05/2013; 6:563-76. DOI:10.2147/OTT.S28155 · 2.31 Impact Factor
  • Source
    • "A current study that explored the treatment of patients with advanced stage IIIB or IV NSCLC with erlotinib and enzastaurin. Results revealed that while the enzastaurin did not help improve the patient response to chemotherapy, it did not worsen usual results either (Clement-Duchene et al., 2012). Overall, the combination therapy presented to be well tolerated in the NSCLC patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lung cancer is the most common cancer in the world. Despite modern advancements in surgeries, chemotherapies, and radiotherapies over the past few years, lung cancer still remains a very difficult disease to treat. This has left the death rate from lung cancer victims largely unchanged throughout the past few decades. A key cause for the high mortality rate is the drug resistance that builds up for patients being currently treated with the chemotherapeutic agents. Although certain chemotherapeutic agents may initially effectively treat lung cancer patients, there is a high probability that there will be a reoccurrence of the cancer after the patient develops resistance to the drug. Erlotinib, the epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor, has been approved for localized as well as metastatic non-small cell lung cancer where it seems to be more effective in patients with EGFR mutations. Resistance to erlotinib is a common observation in clinics and this review details our current knowledge on the subject. We discuss the causes of such resistance as well as innovative research to overcome it. Evidently, new chemotherapy strategies are desperately needed in order to better treat lung cancer patients. Current research is investigating alternative treatment plans to enhance the chemotherapy that is already offered. Better insight into the molecular mechanisms behind combination therapy pathways and even single molecular pathways may help improve the efficacy of the current treatment options.
    Frontiers in Pharmacology 02/2013; 4:15. DOI:10.3389/fphar.2013.00015 · 3.80 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The ocean occupies three-fourths of the Earth's surface and hosts approximately 80% of all living species. In fact, some areas of the sea such as coral reefs possess a biodiversity density greater than that of tropical rainforests. A recent census of marine life by 2700 scientists from more than 80 countries assessed the diversity, distribution, and abundance of marine life and reported over 6000 potentially novel species. Molecules with potential biomedical applications include alkaloids, terpenoids, steroids, polypeptides, polyethers, macrolides, and polysaccharides. Marine organisms produce secondary metabolites that are structurally distinct from those produced by terrestrial organisms, due to the unique biosynthetic milieu, and unusual functional groups such as isocyanate, isonitrile, dichloroimine, and halogenated functionalities that are predominantly found in marine metabolites.
    Chemical Reviews 05/2013; 113(8). DOI:10.1021/cr300410v · 46.57 Impact Factor
Show more