title: Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial.
abstract: PURPOSE No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. PATIENTS AND METHODS This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. CONCLUSION Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, USA. jyao@mdanderson.org
authors.forename: James C
authors.initials: JC
authors.lastname: Yao
authors.forename: Catherine
authors.initials: C
authors.lastname: Lombard-Bohas
authors.forename: Eric
authors.initials: E
authors.lastname: Baudin
authors.forename: Larry K
authors.initials: LK
authors.lastname: Kvols
authors.forename: Philippe
authors.initials: P
authors.lastname: Rougier
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruszniewski
authors.forename: Sakina
authors.initials: S
authors.lastname: Hoosen
authors.forename: Jessica
authors.initials: J
authors.lastname: St Peter
authors.forename: Tomas
authors.initials: T
authors.lastname: Haas
authors.forename: David
authors.initials: D
authors.lastname: Lebwohl
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Kulke
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hobday
authors.forename: Thomas M
authors.initials: TM
authors.lastname: O'Dorisio
authors.forename: Manisha H
authors.initials: MH
authors.lastname: Shah
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cadiot
authors.forename: Gabriele
authors.initials: G
authors.lastname: Luppi
authors.forename: James A
authors.initials: JA
authors.lastname: Posey
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D053379:Chromogranin A / Q000097:blood; D018572:Disease-Free Survival; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000401:mortality; D015282:Octreotide / Q000008:administration & dosage / Q000009:adverse effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D010751:Phosphopyruvate Hydratase / Q000097:blood; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D017211:Treatment Failure
chemical_list: D053379:Chromogranin A; D000068338:Everolimus; D010751:Phosphopyruvate Hydratase; D015282:Octreotide; D020123:Sirolimus