Phase II study of olaparib in malignant mesothelioma (MM) to correlate efficacy with germline and somatic mutations in DNA repair genes.

作者：Raffit Hassan, Idrees Mian, Cathy Wagner, Yvonne Mallory, Maria Agra, Emerson Padiernos, Manjistha Sengupta, Betsy Morrow, Jun S. Wei, Anish Thomas, Seth M. Steinberg, Javed Khan, Azam Ghafoor · 发表于：Journal of Clinical Oncology · 年份：2020 · DOI：10.1200/jco.2020.38.15_suppl.9054 · 被引用次数：22 · 研究领域：Occupational and environmental lung diseases

9054 Background: BRCA1 associated protein 1 ( BAP1), a nuclear deubiquitinase involved in DNA double-strand break repair is frequently mutated in MM. Because poly(ADP-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we sought to evaluate efficacy of olaparib in patients with MM and correlate it with pathogenic germline and somatic mutations in DNA repair genes. Methods: Phase II single-center study (NCT03531840) enrolled patients with advanced pleural or peritoneal mesothelioma who had progressed on prior therapies, age >18 years, ECOG performance status <1, adequate organ and bone marrow function. Olaparib 300mg was given twice daily orally in 3 week cycles until disease progression or toxicity. Efficacy was assessed by CT scan every 6 weeks using RECIST criteria. Whole exome sequencing (WES) was performed on blood and tumor samples to identify pathogenic germline and somatic mutations in DNA repair genes. Primary objective was to determine response rate based on germline or somatic mutation status of DNA repair genes. Results: Between July 2018 to May 2019, 23 patients were enrolled, 15 pleural and 8 peritoneal MM [14 male; median age 63 (range 41-75 years); median number of prior treatments 3 (range 1-5)]. Median olaparib cycles received was 4 (2-21). WES to identify pathogenic mutations in the germline and tumor was performed in 23 and 17 patients respectively. Four patients had germline BAP1, 1 germline MRE11A, and 5 had ...