Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial.
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.
Yao
James C
JC
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
Lombard-Bohas
Catherine
C
Baudin
Eric
E
Kvols
Larry K
LK
Rougier
Philippe
P
Ruszniewski
Philippe
P
Hoosen
Sakina
S
St Peter
Jessica
J
Haas
Tomas
T
Lebwohl
David
D
Van Cutsem
Eric
E
Kulke
Matthew H
MH
Hobday
Timothy J
TJ
O'Dorisio
Thomas M
TM
Shah
Manisha H
MH
Cadiot
Guillaume
G
Luppi
Gabriele
G
Posey
James A
JA
Wiedenmann
Bertram
B
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
D053379:Chromogranin A; D000068338:Everolimus; D010751:Phosphopyruvate Hydratase; D015282:Octreotide; D020123:Sirolimus