A Prospective Phase II Single-arm Study of Niraparib Plus Dostarlimab in Patients With Advanced Non–small-cell Lung Cancer and/or Malignant Pleural Mesothelioma, Positive for PD-L1 Expression and Germline or Somatic Mutations in the DNA Repair Genes: Rationale and Study Design
| Autor: | Silvia Novello, Luisella Righi, Angela Listì, F. Arizio, Paolo Bironzo, Marco Volante, Giorgio V. Scagliotti, Francesco Passiglia |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine PD-L1 Cancer Research Indazoles Lung Neoplasms Treatment combinations DNA damage DNA repair Pleural Neoplasms Poly ADP ribose polymerase Synthetic lethality Antibodies Monoclonal Humanized B7-H1 Antigen 03 medical and health sciences Clinical Trials Phase II as Topic 0302 clinical medicine Germline mutation Piperidines Carcinoma Non-Small-Cell Lung Antineoplastic Combined Chemotherapy Protocols Homologous recombination repair deficiency PARP inhbitors PD-1 inhibitors Humans Medicine Prospective Studies Lung cancer Germ-Line Mutation biology business.industry Mesothelioma Malignant Prognosis medicine.disease DNA Repair Enzymes 030104 developmental biology Oncology 030220 oncology & carcinogenesis Mutation Cancer cell biology.protein Cancer research business |
| Popis: | Treatment with poly ADP ribose polymerase (PARP)1/2 inhibitors represents a novel opportunity to selectively kill a subset of cancer cell types by exploiting their deficiencies in DNA repair, thus leading to synthetic lethality. Treatment of homologous recombination deficient (HRD)-tumors with PARP inhibitors generates significant levels of DNA damage, which has the potential to further increasing tumor mutational burden, promoting neoantigen release, and upregulating both interferons and programmed death ligand-1 (PD-L1) expression, suggesting a potential complementary and synergistic role with immune checkpoint inhibitors in cancer treatment. Here we present the design and rationale of a prospective, phase II, single-arm study aiming to investigate the safety and antitumor activity of the combination of niraparib and dostarlimab in patients with HRD-positive and PD-L1 ≥ 1% advanced non–small-cell lung cancer (NSCLC) and/or malignant pleural mesothelioma (MPM). Considering the prevalence of pathogenetic germline mutations in DNA repair genes, reported to be around 5% to 10% in patients with MPM and NSCLC, a total of 700 to 1000 cases will be screened to identify 70 patients who are HRD-positive/PD-L1 ≥ 1% (N = 35 NSCLC; N = 35 MPM) to be included. Patients will receive the combination of niraparib orally once daily and dostarlimab intravenously. The primary endpoint is progression-free survival. Secondary endpoints are objective response, duration of response, overall survival, and safety. The results of this study will provide evidence on the safety and antitumor activity of niraparib and dostarlimab combination in patients with advanced, HRD-positive and PD-L1 ≥ 1% NSCLC and/or MPM. |
| Databáze: | OpenAIRE |
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