Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial

Nat Med. 2021 Nov;27(11):1910-1920. doi: 10.1038/s41591-021-01541-0. Epub 2021 Nov 8.


Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. Here we report the results of the phase 2 PrE0505 trial ( NCT02899195 ) of the anti-PD-L1 antibody durvalumab plus platinum-pemetrexed chemotherapy for 55 patients with previously untreated, unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historical control with cisplatin and pemetrexed chemotherapy; secondary and exploratory endpoints included safety, progression-free survival and biomarkers of response. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint, reaching a median survival of 20.4 months versus 12.1 months with historical control. Treatment-emergent adverse events were consistent with known side effects of chemotherapy, and all adverse events due to immunotherapy were grade 2 or lower. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire was linked to favorable clinical outcome. Structural genome-wide analyses showed a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to achieve long-term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents, Immunological / adverse effects
  • Antineoplastic Agents, Immunological / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Carboplatin / therapeutic use
  • Cisplatin / therapeutic use*
  • DNA Repair / genetics
  • Female
  • Genetic Predisposition to Disease / genetics
  • Germ-Line Mutation / genetics
  • Humans
  • Male
  • Mesothelioma, Malignant / drug therapy*
  • Mesothelioma, Malignant / genetics
  • Mesothelioma, Malignant / mortality
  • Middle Aged
  • Nucleic Acid Synthesis Inhibitors / adverse effects
  • Nucleic Acid Synthesis Inhibitors / therapeutic use*
  • Pemetrexed / adverse effects
  • Pemetrexed / therapeutic use*
  • Progression-Free Survival
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics


  • Antibodies, Monoclonal
  • Antineoplastic Agents, Immunological
  • BAP1 protein, human
  • Nucleic Acid Synthesis Inhibitors
  • Tumor Suppressor Proteins
  • Pemetrexed
  • durvalumab
  • Carboplatin
  • Ubiquitin Thiolesterase
  • Cisplatin

Associated data

  • ClinicalTrials.gov/NCT02899195