P2.06-029 Pilot Window-Of-Opportunity Study of Pembrolizumab in Patients with Resectable Malignant Pleural Mesothelioma (MPM): Topic: Mesothelioma and SCLC

Abstract

Although PD-1 inhibitors have demonstrated significant activity in MPM (Alley, WCLC 2015; Kindler, WCLC 2016), not all patients benefit. About 1/3 of MPM have high PD-L1 expression and a CD8+ infiltrative pattern with a gamma-interferon gene expression profile; this phenotype has been employed in tumors such as melanoma to predict for benefit from immune checkpoint blockade (Ribas, ASCO 2015; Seiwert, ASCO 2015). The mechanisms of anti-tumor response in a disease with a low mutational burden and a distinct macrophage-dominant immune microenvironment remain poorly understood. Due to the anatomy of MPM, access to tumor tissue for correlative studies can be problematic without surgery. We therefore initiated a window-of-opportunity study of pembrolizumab in patients with resectable MPM (NCT02707666) to better understand the dynamic changes occurring with PD-1 checkpoint blockade. Eligible patients have previously untreated, histologically confirmed, epithelial or biphasic MPM amenable to maximal surgical debulking via extended pleurectomy/decortication. Measurable or evaluable disease, PS 0-1, no extra-thoracic disease, adequate pulmonary and cardiac function, and a free pleural space for video-thoracoscopy (VATS) are required. PET/CT and VATS to obtain tissue for correlative studies are performed at baseline. Patients receive 3 cycles of pembrolizumab, 200 mg IV Q21 days followed by repeat PET/CT. Extended pleurectomy/decortication is performed at least 4 weeks later. Adjuvant cisplatin/pemetrexed x 4 cycles is administered 6-8 weeks after surgery, followed by optional adjuvant pembrolizumab x 1 year. The primary objective is to assess an increase in gamma-interferon, measured via a gene expression profile (GEP), comparing matched pre- and post-treatment samples (IFN-G GEP response), and to identify additional candidate biomarkers that may predict benefit or constitutive resistance to pembrolizumab. Correlative studies include: a) multi-color immunofluorescence (CD8, CD4, PD-L1, FOXP3), b) evaluation of immune-related gene expression signatures (using Nanostring/RNAseq), c) evaluation of alternative immune checkpoints, d) determination of mutations in antigen presenting machinery, and e) assessment of activation of immunosuppressive signaling pathways. Radiologic correlatives use image-based texture analysis on PET/CT scans to evaluate therapy-induced changes in tumor composition. This is an exploratory trial. Fifteen patients will be enrolled, which provides a standard error for the estimated IFN-G GEP response rate of approximately 10% (assuming the true response rate is close to 20%). This will also provide 80% power to detect a 0.8 standard deviation change in pre-post treatment biomarker levels, using a paired t-test at the 0.05 alpha level. Section not applicable. Section not applicable.