A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma

Highlights

• Patients with previously treated pleural mesothelioma were treated with AZD4547.

• 12 % of patients were progression free at 6 months.

• There were no confirmed objective responses to treatment.

• There was no association between tumour BAP1 protein expression and treatment outcome.

• This study did not meet its primary endpoint.

Abstract

Objectives

Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1–3 inhibitor, as a second or third-line treatment.

Materials and Methods

We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon’s two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients.

Results

3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes.

Conclusions

The FGFR 1–3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.

Introduction

Systemic chemotherapy remains the mainstay of treatment for patients with unresectable malignant pleural mesothelioma (MPM). In 2003, the EMPHACIS trial established cisplatin and pemetrexed as the standard of care for first-line treatment of advanced mesothelioma [1]. More recently, the MAPS trial provided the first randomised demonstration of efficacy of a targeted therapy in mesothelioma, with the addition of bevacizumab to cisplatin and pemetrexed chemotherapy providing a small incremental survival benefit over chemotherapy alone, increasing median survival from 16.1 to 18.8 months [2]. This regimen is not FDA approved and has therefore not been uniformly adopted. Currently, there is no clinical consensus about salvage therapy when patients relapse after first-line treatment. Treatment options post-relapse include reintroduction of a platinum and pemetrexed [3], single agent chemotherapy such as vinorelbine or gemcitabine [4], or checkpoint inhibitors including pembrolizumab [5] or nivolumab with/without ipilimumab [6,7], although none of these have yet been demonstrated to improve survival in a randomised controlled trial. Nevertheless, only a small proportion of patients achieve a progression free survival of more than a year. These poor outcomes motivate the need for novel therapies for relapsed mesothelioma.

In recent years, fibroblast growth factor receptor signalling has been recognised as increasingly important, both in cancer pathogenesis and as a potential therapeutic target [8,9]. There is strong preclinical data to suggest that fibroblast growth factor (FGF) signalling is important in mesothelioma. In mesothelial cell lines, FGFR1 and FGF2 are co-expressed and expression is significantly associated with sensitivity to FGFR-active tyrosine kinase inhibitor (TKI) [10]. Inhibiting FGF autocrine signalling using an FGF-ligand trap reduces proliferation in mesothelioma cell lines and reduces tumour growth in xenografts [11]. In our own work, FGFR-targeted tyrosine kinase inhibitors strikingly reduced tumour burden in three separate murine models of mesothelioma [12].

AZD4547 is a potent, orally bioavailable and highly selective FGFR-1, 2, and 3 tyrosine kinase inhibitor [13]. Preclinical data, both from human tumour cell lines and patient-derived xenograft models, demonstrates that AZD4547 has anti-proliferative activity against a broad range of tumours, including gastric, pancreatic, colorectal and lung cancers [[14], [15], [16]]. Two phase I dose escalation studies have established a tolerable recommended dose (RD) of 80 mg twice daily. Clinical data on AZD4547 monotherapy demonstrates a consistent toxicity profile with dysgeusia, dry-mouth, stomatitis and hyperphosphatemia and fatigue as common side effects, which are generally well-tolerated [15,17,18]. The available preclinical and clinical data on AZD4547, combined with its strong scientific rationale in preclinical studies of mesothelioma made it an attractive candidate for a clinical trial in progressive disease.