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T. Seiwert



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    OA13 - Immunotherapy in Malignant Pleural Mesothelioma: Current Status of Trials and New Approaches (ID 392)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      OA13.02 - Phase II Trial of Pembrolizumab in Patients with Malignant Mesothelioma (MM): Interim Analysis (ID 6232)

      14:30 - 14:40  |  Author(s): T. Seiwert

      • Abstract
      • Presentation
      • Slides

      Background:
      Pembrolizumab showed significant activity in PD-L1+ MM in a phase IB study (Alley, 2015). We are conducting a phase II trial (NCT02399371) of pembrolizumab in previously-treated MM patients to further characterize its activity in a larger, non-selected population, determine a PD-L1 expression threshold, and interrogate the microenvironment.

      Methods:
      Eligible patients have histologically-confirmed pleural or peritoneal MM, measurable disease, PS 0-1, disease progression on/after pemetrexed/platinum, 1-2 prior regimens, normal organ function, and available tissue. Patients receive 200 mg pembrolizumab IV Q21 days and CT scans Q9 weeks. Primary objectives: 1) determine the objective response rate in: A] an unselected population and, B] a PD-L1 positive population; 2) determine the optimal threshold for PD-L1 expression using the 22C3 antibody-based IHC assay (Qualtek). Exploratory correlatives profile the inflammatory microenvironment via: a) multi-color immunofluorescence of tumor infiltrating lymphocytes (TILs) and macrophages, b) RNA-based inflammation signatures/pathway activation, c) characterizing underlying mutations/copy number changes. Proceeding to a 2[nd] stage requires ≥3 responses in 35 patients. If an optimal threshold for PD-L1 expression is determined, the 2[nd] stage only enrolls above that threshold.

      Results:
      35 patients enrolled 5/15-2/16. 1 withdrew. Male 82%; median age 63 (range 26-85); PS 0/1 63%/37%; epithelial/sarcomatoid/biphasic/NOS: 69%/26%/3%/3%; pleural/peritoneal 86%/14%; 1 prior regimen: 60%. Mean cycles: 8.5 (range 1-18). Median progression-free survival: 6.2 months (95% CI: 3.2, 8.2). Median overall survival has not been reached. Partial response: 7 (21%), stable disease (SD): 19 (56%); progression: 6 (18%); early death: 2 (6%). Ten patients received treatment beyond progression; 20% subsequently achieved SD. Grade 3/4 toxicity: pneumonitis 6%, fatigue 6%, adrenal insufficiency 6%, colitis 3%, confusion 3%, hyponatremia 3%, neutropenia 3%. Grade 1/2 immune-related toxicities: hypothyroidism 17%, rash 14%, pruritus 11%, diarrhea 9%, uveitis 6%, arthralgia 6%, hepatitis 3%, infusion reaction 3%, mucositis 3%. Grade 5 toxicities: autoimmune hepatitis 3%, unknown 3%. PD-L1 expression by tumor proportion score (N=31): none (< 1%): 55%; low (1%-49%): 19%; high (≥ 50%): 26%. PD-L1 expression did not correlate with response (ROC area 0.62; 95% CI: 0.32, 0.94).

      Conclusion:
      Pembrolizumab has robust activity in PD-L1 unselected, previously-treated MM patients, with a response rate of 21% and a disease control rate of 76%. An optimal PD-L1 threshold could not be established in this small sample. The 2nd stage is enrolling an additional 30 patients without PD-L1 pre-selection. Correlative studies including CD8 TILs, macrophage characterization, and presence of T-regulatory cells will be presented. Funded by a grant from the Mesothelioma Applied Research Foundation.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 1
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      P2.06-029 - Pilot Window-Of-Opportunity Study of Pembrolizumab in Patients with Resectable Malignant Pleural Mesothelioma (MPM) (ID 6268)

      14:30 - 14:30  |  Author(s): T. Seiwert

      • Abstract

      Background:
      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.

      Methods:
      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.

      Results:
      Section not applicable.

      Conclusion:
      Section not applicable.