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

doi:10.1038/s41416-019-0683-3

Abstract

BackgroundThe 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.MethodsPatients 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).ResultsSeventy-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.ConclusionsAdding 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 registrationClinicalTrials.gov Identifier: NCT01088815.

Highlights

The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA)
Our approach of an initial cycle chemotherapy prior to administration of vismodegib starting on cycle 2 of chemotherapy was based on one of these preclinical studies that showed sequencing of chemotherapy first to deplete the bulk of tumour cells followed by the administration of a Hh inhibitor decreased the number of chemotherapy-resistant pancreatic cancer stem cells (pCSC).[30]
Our findings suggest that the Hh pathway as the only molecular target for pCSC is not sufficient to deplete the stem cell compartment

Summary

Introduction

The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). In the United States, an estimated total of 55,440 pancreatic cancer diagnoses are expected to occur in 2018 with 44,330 expected deaths.[1,2] Standard regimens for patients with metastatic pancreatic ductal adenocarcinoma (PDA) include single agent gemcitabine or combination regimens, such as gemcitabine with nab-paclitaxel[3] and the FOLFIRINOX4 regimen. Patients treated with these regimens have an estimated survival ranging from 6 to 11 months, depending upon the therapy. Signal transduction by SMO leads to the activation and nuclear localisation of GLI-1 transcription factors and induction of Hh target genes, many of which are involved in proliferation, survival and angiogenesis in different malignancies

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Conclusion