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Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial.
- Source :
-
Nature medicine [Nat Med] 2021 Nov; Vol. 27 (11), pp. 1910-1920. Date of Electronic Publication: 2021 Nov 08. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (© 2021. The Author(s).)
- Subjects :
- Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal adverse effects
Antineoplastic Agents, Immunological adverse effects
Antineoplastic Combined Chemotherapy Protocols adverse effects
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Carboplatin therapeutic use
DNA Repair genetics
Female
Genetic Predisposition to Disease genetics
Germ-Line Mutation genetics
Humans
Male
Mesothelioma, Malignant genetics
Mesothelioma, Malignant mortality
Middle Aged
Nucleic Acid Synthesis Inhibitors adverse effects
Pemetrexed adverse effects
Progression-Free Survival
Tumor Suppressor Proteins genetics
Ubiquitin Thiolesterase genetics
Antibodies, Monoclonal therapeutic use
Antineoplastic Agents, Immunological therapeutic use
Cisplatin therapeutic use
Mesothelioma, Malignant drug therapy
Nucleic Acid Synthesis Inhibitors therapeutic use
Pemetrexed therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 27
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 34750557
- Full Text :
- https://doi.org/10.1038/s41591-021-01541-0