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

Our plain-English summary of 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, by F. Passiglia, P. Bironzo, L. Righi, et al (Clinical Lung Cancer, 2021).

The study

• Authors: F. Passiglia, P. Bironzo, L. Righi, A. Listì, F. Arizio, S. Novello, M. Volante, G.V. Scagliotti
• Journal: Clinical Lung Cancer
• Published: 2021;22(1):e63-e66
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

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In plain English

This article described the plan for a clinical trial. It reported no patient results. The authors designed a single-arm, prospective phase II study of two cancer drugs given together. Niraparib was to be taken by mouth once daily, and dostarlimab given by intravenous infusion. The trial was planned for about 70 previously treated patients: 35 with advanced non-small-cell lung cancer and 35 with metastatic malignant pleural mesothelioma. Each patient's tumor had to show a DNA repair defect (homologous recombination deficiency, from germline or somatic mutations) and PD-L1 expression of at least 1%. The authors planned to screen 700 to 1000 cases to find these patients. The main measure was progression-free survival. The study was sized to detect an improvement in median progression-free survival from 4 months, the figure the authors assumed from historical data for single-agent immune checkpoint inhibitors, to 7 months. Other measures were response, duration of response, overall survival and safety. The authors hypothesized that the combination may be synergistic. The study did not examine asbestos exposure. It was supported by GlaxoSmithKline.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Description of the rationale and design of a planned single-arm, prospective, interventional phase II trial (no results reported)
• Who was studied: Planned: about 70 previously treated patients whose tumors are HRD-positive and PD-L1-positive (tumor proportion score of at least 1%). Cohort A is 35 patients with advanced NSCLC and Cohort B is 35 patients with advanced or metastatic malignant pleural mesothelioma. 700 to 1000 cases are to be screened to find them.
• Exposure: Treatment, not asbestos exposure, was studied. Niraparib is given orally once daily at 300 mg (for patients weighing at least 77 kg with a platelet count of at least 150,000) or 200 mg otherwise. Dostarlimab is given as a 30-minute intravenous infusion: 500 mg on day 1 of every 21-day cycle for the first 4 doses, then 1000 mg on day 1 of every 42-day cycle.
• The authors' conclusion: The authors hypothesized that combining niraparib with dostarlimab may be synergistic, with the potential to prolong survival and increase tumor response in these molecularly selected patients. They stated that the study's results will provide evidence on the combination's safety and antitumor activity.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Pleural Mesothelioma, PD-L1, Somatic Mutation, Tumor Mutational Burden (TMB), checkpoint inhibitors, Germline Mutation, Progression-Free Survival.

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