TY - JOUR
T1 - Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma
AU - De Jesus-Acosta, Ana
AU - Sugar, Elizabeth A.
AU - O’Dwyer, Peter J.
AU - Ramanathan, Ramesh K.
AU - Von Hoff, Daniel D.
AU - Rasheed, Zeshaan
AU - Zheng, Lei
AU - Begum, Asma
AU - Anders, Robert
AU - Maitra, Anirban
AU - McAllister, Florencia
AU - Rajeshkumar, N. V.
AU - Yabuuchi, Shinichi
AU - de Wilde, Roeland F.
AU - Batukbhai, Bhavina
AU - Sahin, Ismet
AU - Laheru, Daniel A.
N1 - Funding Information:
Competing interests A.D.J.A.—consulting: Merck; clinical trials grant support: Merck, AstraZeneca. P.J.O.—consulting: Genentech; clinical trials grant support: Genentech. L.Z.—consulting: NovaRock Biological, Datareve; research grant: Halozyme, iTeos, BMS, Merck, Amgen and NovaRock Biological; advisory board: Biosynergics, Alphamab, Mingrui and Foundation Medicine; shareholder: Mingrui; Aduro: under a licencing agreement between Aduro BioTech, Inc. and the Johns Hopkins University, the university and investigators are entitled to milestone payments and royalty on sales of the vaccine products. L.Z. had declined personal royalty. Z.R.: full-time employee of AstraZeneca. Remaining authors have no competing interests.
Funding Information:
Funding information The study was sponsored by a Stand Up to Cancer Dream Team Translational Cancer Research Grant (SU2C grant AACR-DT0509), Viragh Clinical Cancer Research and the Lustgarten Foundation. Genentech provided drug support.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Cancer Research UK.
PY - 2020/2/18
Y1 - 2020/2/18
N2 - Background: The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling. Methods: Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib). Results: Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37–6.97) and 9.79 months (95% CI: 7.85–10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment. Conclusions: Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population. Trial registration: ClinicalTrials.gov Identifier: NCT01088815.
AB - Background: The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling. Methods: Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib). Results: Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37–6.97) and 9.79 months (95% CI: 7.85–10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment. Conclusions: Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population. Trial registration: ClinicalTrials.gov Identifier: NCT01088815.
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U2 - 10.1038/s41416-019-0683-3
DO - 10.1038/s41416-019-0683-3
M3 - Article
C2 - 31857726
AN - SCOPUS:85077066628
SN - 0007-0920
VL - 122
SP - 498
EP - 505
JO - British journal of cancer
JF - British journal of cancer
IS - 4
ER -