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Efficacy of RAD001 (Everolimus) and Octreotide LAR in Advanced Low- to Intermediate-Grade Neuroendocrine Tumors: Results of a Phase II Study

James C. Yao, Alexandria T. Phan, David Z. Chang, Robert A. Wolff, Kenneth Hess, Sanjay Gupta, Carmen Jacobs, Jeannette E. Mares, Andrea N. Landgraf, Asif Rashid, Funda Meric-Bernstam

From the Departments of Gastrointestinal Medical Oncology, Biostatistics, Radiology, Pathology, and Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX

Corresponding author: James Yao, MD, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jyao{at}mdanderson.org

Purpose Evaluate the activity of everolimus (RAD001) in combination with octreotide long-acting repeatable (LAR) in patients with advanced low- to intermediate-grade neuroendocrine tumors.

Methods Treatment consisted of RAD001 5 mg/d (30 patients) or 10 mg/d (30 patients) and octreotide LAR 30 mg every 28 days. Thirty carcinoid and 30 islet cell patients were enrolled.

Results Intent-to-treat response rate was 20%. Per protocol, there were 13 with partial responses (22%), 42 with stable disease (SD; 70%), and five patients with progressive disease (8%). Overall median progression-free survival (PFS) was 60 weeks. Median PFS for patients with known SD at entry was longer than for those who had progressive disease (74 v 50 weeks; P < .01). Median overall survival has not been reached. One-, 2-, and 3-year survival rates were 83%, 81%, and 78%, respectively. Among 37 patients with elevated chromogranin A, 26 (70%) achieved normalization or more than 50% reduction. Most common toxicity was mild aphthous ulceration. Grade 3/4 toxicities occurring in 10% of patients included hypophosphatemia (11%), fatigue (11%), and diarrhea (11%). Treatment was associated with a dose-dependent rise in lactate dehydrogenase (LDH). Those with lower than 109 U/L rise in LDH at week 4 had shorter PFS (38 v 69 weeks; P = .01). Treatment was also associated with a decrease in proliferation marker Ki-67 among patients who underwent optional paired pre- and post-treatment biopsy (P = .04).

Conclusion RAD001 at 5 or 10 mg/d was well tolerated in combination with octreotide LAR, with promising antitumor activity. Confirmatory studies are ongoing.

Supported in part by a grant from Novartis Oncology (East Hanover, NJ) and Grant No. R01 CA112199 from the National Institutes of Health.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA; Chemotherapy Foundation Symposium, November 8-11, New York, NY; 4th Annual European Neuroendocrine Tumor Society Conference, March 15-17, 2007, Barcelona, Spain; 43rd Annual Meeting of the American Society of Clinical Oncology, June 2-5, 2007, Chicago, IL; and at the 9th World Congress on Gastrointestinal Cancer, June 27-30, 2008, Barcelona, Spain.

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

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