Journal of Thoracic Oncology 2017 December [Epub ahead of print] [Link]

Tsao AS


Window-of-opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent. We treated MPM patients (n=24) with 4 weeks of oral dasatinib followed by surgery with or without radiotherapy and then an optional 2 years of maintenance dasatinib. The primary endpoint was biomarker modulation of p-SrcTyr419. For all patients, the median PFS was 7.5 months and OS 19.1 months. No significant responses were seen after 4 weeks of dasatinib therapy, however, modulation of p-SrcTyr419 immunohistochemistry (IHC) scores (median (interquartile range) = 70 (37.5, 110) and 41.9 (4.2, 60) for pre and post treatment, respectively, p=0.004) was seen. A decrease in p-SrcTyr419 levels post-dasatinib correlated to improved median PFS (6.9 months vs 0.94 months, p=0.03), suggesting that p-SrcTyr419 is a viable pharmacodynamic biomarker for dasatinib in MPM. PDGFR pathway analysis correlated high PDGFRβ [cytoplasm (HR=2.54, p=0.05), stroma (HR=2.79, p=0.03), and nucleus (HR=6.79, p=0.023)] with a shorter PFS. Low (less than the median) cytoplasmic p-PDGFRα IHC levels was predictive of a decrease in PET/CT standard uptake values (SUV) levels after dasatinib therapy (p=0.04); whereas higher-than-median IHC scores of PDGFRβ [cytoplasmic (HR=2.8, p=0.03), nuclear (HR=6.795, p=0.02)] were correlated to rising SUV levels. In conclusion, there was no significant efficacy signal and dasatinib monotherapy will not continue to be studied in MPM. However, our study demonstrated that PDGFR subtypes (α, β) may have differential roles in prognosis and resistance to anti-angiogenic tyrosine kinase inhibitors and are important potential therapeutic targets that require further investigation.