Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study.
BACKGROUND
In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib.


METHODS
In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan-Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses.


RESULTS
Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1-20.6) months for sunitinib and 5.8 (3.8-7.2) months for placebo (HR, 0.32; 95% CI 0.18-0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (HR, 0.73; 95% CI 0.50-1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib.


CONCLUSIONS
BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib.


BACKGROUND
NCT00428597.
Medical Oncology and Gastroenterology Department, Service Inter-Hospitalier de Cancérologie, Hôpital Beaujon and Paris Diderot University, Clichy.
S
S
Faivre
Cancer Care, Institut Paoli-Calmettes, and RENATEN Network, Marseille, France.
P
P
Niccoli
Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
D
D
Castellano
Medical Oncology Department, The University of Manchester/The Christie NHS Foundation Trust, Manchester, UK.
J W
JW
Valle
Medical Oncology and Gastroenterology Department, Service Inter-Hospitalier de Cancérologie, Hôpital Beaujon and Paris Diderot University, Clichy.
P
P
Hammel
Translational Medicine - Digestive Cancers, Institut Paoli-Calmettes and RENATEN Network, Marseille, France.
J-L
JL
Raoul
Eastern Virginia Medical School Streilitz Diabetes Research Center and Neuroendocrine Unit, Norfolk, USA.
A
A
Vinik
Digestive Oncology Unit, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
E
E
Van Cutsem
Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Y-J
YJ
Bang
Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
S-H
SH
Lee
Hepato-Gastroenterology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
I
I
Borbath
Medical Oncology Department, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
C
C
Lombard-Bohas
McGill University Hospital Centre, Montreal, Canada.
P
P
Metrakos
Oncology Department, University Hospital, Bordeaux, France.
D
D
Smith
Linkou Chang Gung Memorial Hospital and Chang Gung University, Tao-Yuan, Taiwan.
J-S
JS
Chen
Medical Oncology and Gastroenterology Department, Service Inter-Hospitalier de Cancérologie, Hôpital Beaujon and Paris Diderot University, Clichy.
P
P
Ruszniewski
Centre Hospitalier Universitaire Timone, Assistance Publique-Hôpitaux de Marseille, Aix-Marseille Université, and RENATEN Network, Marseille, France.
J-F
JF
Seitz
Pfizer Oncology, La Jolla, USA.
S
S
Patyna
Pfizer Oncology, La Jolla, USA.
D R
DR
Lu
Department of Evidera, St-Laurent, Canada.
K J
KJ
Ishak
Medical Oncology and Gastroenterology Department, Service Inter-Hospitalier de Cancérologie, Hôpital Beaujon and Paris Diderot University, Clichy.
E
E
Raymond
D000970:Antineoplastic Agents / Q000008:administration & dosage; D003430:Cross-Sectional Studies; D018572:Disease-Free Survival; D004311:Double-Blind Method; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D053208:Kaplan-Meier Estimate; D018358:Neuroendocrine Tumors / Q000000981:diagnostic imaging / Q000188:drug therapy*; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D016016:Proportional Hazards Models; D011758:Pyrroles / Q000008:administration & dosage*; D000077210:Sunitinib; D015996:Survival Rate
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
VEGFR inhibitor; antiangiogenics; blinded independent central review; crossover; rank-preserving structural failure time (RPSFT)