Originally published as JCO Early Release 10.1200/JCO.2008.18.9514 on December 1 2008

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Oral mTOR Inhibitor Everolimus in Patients With Gemcitabine-Refractory Metastatic Pancreatic Cancer

Brian M. Wolpin, Aram F. Hezel, Thomas Abrams, Lawrence S. Blaszkowsky, Jeffrey A. Meyerhardt, Jennifer A. Chan, Peter C. Enzinger, Brittany Allen, Jeffrey W. Clark, David P. Ryan, Charles S. Fuchs

From the Department of Medical Oncology, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital; Division of Hematology/Oncology, Massachusetts General Hospital; and Harvard Medical School, Boston, MA

Corresponding author: Brian Wolpin, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: bwolpin{at}partners.org

Purpose The PI3K/Akt/mTOR pathway is activated in the majority of pancreatic cancers, and inhibition of this pathway has antitumor effects in preclinical studies. We performed a multi-institutional, single-arm, phase II study of RAD001(everolimus), an oral inhibitor of mTOR, in patients who experienced treatment failure on first-line therapy with gemcitabine.

Patients and Methods Thirty-three patients with gemcitabine-refractory, metastatic pancreatic cancer were treated continuously with RAD001 at 10 mg daily. Prior treatment with fluorouracil in the perioperative setting was allowed. Patients were observed for toxicity, treatment response, and survival.

Results Treatment with single-agent RAD001 was well-tolerated; the most common adverse events were mild hyperglycemia and thrombocytopenia. No patients were removed from the study because of drug-related adverse events. No complete or partial treatment responses were noted, and only seven patients (21%) had stable disease at the first restaging scans performed at 2 months. Median progression-free survival and overall survival were 1.8 months and 4.5 months, respectively. One patient (3%) had a biochemical response, defined as 50% reduction in serum CA19-9.

Conclusion Although well-tolerated, RAD001 administered as a single-agent had minimal clinical activity in patients with gemcitabine-refractory, metastatic pancreatic cancer. Future studies in metastatic pancreatic cancer should assess the combination of mTOR inhibitors with other agents and/or examine inhibitors of other components of the PI3K/Akt/mTOR pathway.

published online ahead of print at www.jco.org on December 1, 2008

Supported by Novartis Pharmaceuticals and Grants No. P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908, and T32 CA09001 from the National Cancer Institute, National Institutes of Health.

Previously presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL.

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

Clinical trial information can be found for the following: NCT00409292 [ClinicalTrials.gov]

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