Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma

Ana De Jesus-Acosta, Elizabeth A Sugar, Peter J O'Dwyer, Ramesh K Ramanathan, Daniel D Von Hoff, Zeshaan Rasheed, Lei Zheng, Asma Begum, Robert Anders, Anirban Maitra, Florencia McAllister, N V Rajeshkumar, Shinichi Yabuuchi, Roeland F de Wilde, Bhavina Batukbhai, Ismet Sahin, Daniel A Laheru, Ana De Jesus-Acosta, Elizabeth A Sugar, Peter J O'Dwyer, Ramesh K Ramanathan, Daniel D Von Hoff, Zeshaan Rasheed, Lei Zheng, Asma Begum, Robert Anders, Anirban Maitra, Florencia McAllister, N V Rajeshkumar, Shinichi Yabuuchi, Roeland F de Wilde, Bhavina Batukbhai, Ismet Sahin, Daniel A Laheru

Abstract

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.

Conflict of interest statement

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.

Figures

Fig. 1. Kaplan–Meier estimates of survival. The…
Fig. 1. Kaplan–Meier estimates of survival. The estimate is represented with a solid line and the 95% confidence interval is represented with dotted lines.
Kaplan–Meier estimates of (a) progression-free survival and (b) overall survival. The estimate is represented with a solid line and the 95% confidence interval is represented with dotted lines.
Fig. 2. RT-PCR for GLI-1 and PATCH…
Fig. 2. RT-PCR for GLI-1 and PATCH comparing baseline pre-treatment and post- treatment expression.
The post-treatment samples were collected following exposure to vismodegib therapy. a GLI-1. b PATCH.

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