Treatment options are limited after first line platinum-based therapy for malignant pleural mesothelioma (MPM). FGFR-9 is a mitogenic ligand that activates the FGF-receptor (FGFR) family and is overexpressed in pleural fluid and tumour samples from mesothelioma patients. In mesothelioma mouse models, FGF-receptor inhibitors reduce tumour burden. Hence, we examined the efficacy of the FGFR tyrosine kinase inhibitor, AZD4547 as second/third line therapy in MPM.
From April 2016 to August 2018, we conducted a single-site, single arm, open-label study of AZD4547 in patients with MPM. Eligible patients had measurable disease and had progressed after first or second line therapy. Patients received oral 80mg twice-daily AZD4547 with protocol dose reductions as required. The primary end point was 6-month progression free survival (PFS6). Using a Simons' two-stage design, 26 patients would be recruited to the first stage and the study would be declared negative if fewer than 7 (27%) of 26 patients achieved PFS6.
24 patients (21 (87%) male), median age 69.5 (range 53-84) were recruited. Histological subtype was epithelioid (83.3%), biphasic (8.3%), sarcomatoid (8.3%). Most patients had one prior regimen (14; 58%). Common toxicities included grade 1 and 2 hyperphosphataemia, nail changes, stomatitis, and ophthalmological changes, consistent with reported toxicities of this drug class. No adverse events required hospitalisation. There were two partial responses (8%); 16 patients (63%) had stable disease (SD) for at least 6 weeks, and 7 patients (29%) had progressive disease as their best response. Three of 24 patients (12%) were progression free at 6 months, hence, the study fulfils stopping criteria regardless of further recruitment and warrants discontinuation. One patient remains on study with SD at 321 days.
The FGFR inhibitor AZD4547 was ineffective for patients with MPM who had progressed on first or second line therapy.