Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study.
OBJECTIVE
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 >or= 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).


CONCLUSIONS
RAD001 at 5 or 10 mg/d was well tolerated in combination with octreotide LAR, with promising antitumor activity. Confirmatory studies are ongoing.
Yao
James C
JC
Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. jyao@mdanderson.org
Phan
Alexandria T
AT
Chang
David Z
DZ
Wolff
Robert A
RA
Hess
Kenneth
K
Gupta
Sanjay
S
Jacobs
Carmen
C
Mares
Jeannette E
JE
Landgraf
Andrea N
AN
Rashid
Asif
A
Meric-Bernstam
Funda
F
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002276:Carcinoid Tumor / Q000188:drug therapy; D018273:Carcinoma, Islet Cell / Q000188:drug therapy; D003692:Delayed-Action Preparations; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy*; D015282:Octreotide / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use
D003692:Delayed-Action Preparations; D000068338:Everolimus; D015282:Octreotide; D020123:Sirolimus
Eur J Surg Oncol. 1996 Jun;22(3):298-301
8654616
Acta Pathol Jpn. 1991 Nov;41(11):847-56
1686137
Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8573-8
15937108
Urol Res. 2003 Feb;30(6):380-6
12599018
J Clin Oncol. 2006 Jan 20;24(3):401-6
16421420
Clin Cancer Res. 2007 Jan 1;13(1):234-40
17200360
Acta Oncol. 2003;42(7):672-92
14690153
J Clin Oncol. 2004 Dec 1;22(23):4762-71
15570077
Cancer Res. 2006 Feb 1;66(3):1500-8
16452206
Cancer Res. 2006 Jun 1;66(11):5549-54
16740688
Endocr Relat Cancer. 2008 Mar;15(1):257-66
18310292
Genes Chromosomes Cancer. 2008 Jan;47(1):84-92
17943967
J Clin Oncol. 2008 Mar 10;26(8):1316-23
18323556
Mod Pathol. 2007 Jul;20(7):802-10
17483816
Anticancer Res. 1989 Jul-Aug;9(4):889-91
2817814
Ann Oncol. 1997 Jul;8(7):685-90
9296223
Cancer. 2003 Feb 15;97(4):934-59
12569593
Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6111-8
15447997
Neth J Med. 1994 Jun;44(6):202-6
8052343
Ann Surg Oncol. 2007 Feb;14(2):780-5
17146740
Virchows Arch. 2007 Oct;451(4):757-62
17674042
Mod Pathol. 1999 May;12(5):539-45
10349994
J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
10655437
Endocr Pract. 2002 Mar-Apr;8(2):109-12
11942775
Pharmacogenomics. 2007 Dec;8(12):1705-13
18086000
Cancer Res. 2000 Aug 15;60(16):4573-81
10969809
Acta Oncol. 2008;47(5):941-7
17906983
Mod Pathol. 2005 Aug;18(8):1079-87
15920555
Eur J Pediatr. 1999 Apr;158(4):284-7
10206124