Elsevier

Lung Cancer

Volume 104, February 2017, Pages 65-69
Lung Cancer

A phase II trial of dovitinib in previously-treated advanced pleural mesothelioma: The Ontario Clinical Oncology Group

https://doi.org/10.1016/j.lungcan.2016.12.004Get rights and content

Highlights

  • Treatment of MPM at progression after platinum-antifolate is an unmet need.

  • The role of the FGFR pathway in MPM has not been fully elucidated.

  • Dovitinib is a multi-targeted tyrosine kinase inhibitor of VEGFR and FGFR.

  • In pre-treated MPM dovitinib had no significant activity and was poorly tolerated.

  • It is unclear if at the doses administered FGFR was effectively inhibited.

Abstract

Objectives

Following failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFRs, and could be active in MPM.

Methods

This open-label multicentre phase II trial [NCT01769547] enrolled fit, consenting adult patients with advanced MPM who had previously received platinum-antifolate combination chemotherapy and up to one additional line of systemic therapy. Dovitinib was administered orally at 500 mg/day for 5 days on, 2 days off, in 28-day cycles. Response was assessed every 2 cycles using RECIST 1.1 criteria modified for MPM. Correlative studies included FGFR-1 amplification on archival tumour and serum samples for circulating angiogenesis factors. The primary end-point was the proportion of patients progression-free at 3 months (PF3) using a two-stage design.

Results

12 patients (10 males, median age 67) were enrolled. The median number of cycles administered was 2.5 (range 1–8). One unconfirmed partial response was observed. PF3 was 50% (95% confidence interval 28.4% to 88.0%); although the criterion for proceeding to stage II accrual was met, the trial was halted due to a combination of minimal activity with several early progression events and poor tolerability in this patient population. One of 12 tumour specimens had low amplification of FGFR-1.

Conclusions

Dovitinib has minimal activity in previously-treated MPM. The role of the FGFR pathway in MPM remains unclear.

Introduction

Malignant pleural mesothelioma (MPM) presents with advanced, incurable disease in the majority of patients. The combination of cisplatin with an anti-folate, either raltitrexed [1] or pemetrexed [2], is standard first-line chemotherapy. In select patients, the addition of bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF)-A, has been shown to lead to modestly improved outcomes [3]. Patients with MPM have among the highest levels of circulating angiogenesis factors, such as VEGF when compared to those patients with other malignancies [4], and high microvessel density is negatively prognostic [5]. This suggests that tyrosine kinase inhibitors targeting the VEGF receptors (VEGFR) may be of potential benefit in the treatment of MPM. However, other VEGFR inhibitors, such as sunitinib [6], [7] and sorafenib [8] have been studied in MPM, and while occasional objective responses have been observed, these agents have not demonstrated compelling single-agent activity.

Dovitinib [Novartis AG] is a multitargeted oral tyrosine kinase inhibitor which inhibits all three VEGFR at nanomolar concentrations, in addition to platelet-derived growth factor receptor β, KIT, ret and fetal liver tyrosine kinase 3. Further, dovitinib inhibits the fibroblast growth factor receptors (FGFR) 1–3 [9]. At the time of initiation of this trial, agents targeted the FGFR family had not been studied in MPM, and the role of the FGFR pathway in the pathogenesis of MPM had not been extensively evaluated. This trial was designed to evaluate an agent targeting both VEGFR and FGFR, and to perform a preliminary evaluation of the FGFR pathway in MPM tumour specimens.

Section snippets

Patients

This open-label multi-centre phase II trial [NCT01769547] enrolled adult patients with histologically-proven advanced MPM. Patients had previously received combination chemotherapy with platinum and an antifolate (either raltitrexed or pemetrexed); up to one additional line of systemic therapy, not including agents targeting the VEGF or FGFR pathways, was permitted. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2, adequate hematological,

Results

Between February 2013 and August 2014, 12 patients were enrolled at 5 centres in Canada; their characteristics are summarized in Table 1. The median age of these patients was 67 (range 50–75) and 10 were male. All patients had previously received platinum-antifolate doublet chemotherapy; 4 received dovitinib as their third-line therapy.

Discussion

There are no approved agents for use in patients with MPM with progressive disease following first-line platinum-antifolate chemotherapy. On the basis of phase II data, other agents such as vinorelbine are commonly used off-label in this setting [15]. In randomized trials of previously-treated patients, neither vorinostat [16] nor tremelumumab [17] improved survival compared to placebo.

In the current study, the use of single-agent dovitinib, a multi-targeted tyrosine kinase inhibitor, did not

Conflicts of interest

NL reports that her institution received support from Novartis Canada in 2014 for an investigator-initiated clinical trial. The other authors report no relevant conflicts of interest.

Acknowledgments

We thank the patients who participated in this trial, and the trials staff at the sites and OCOG central office for their help in the conduct of this trial.

OCOG received funding and drug from Novartis for the conduct of this study.

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