Dual antitumor immunomodulatory effects of PARP inhibitor on the tumor microenvironment: A counterbalance between anti-tumor and pro-tumor.

Poly (ADP-ribose)-polymerases (PARPs) play an essential role in the maintenance of genome integrity, DNA repair, and apoptosis. PARP inhibitors (PARPi) exert antitumor effects via synthetic lethality and PARP trapping. PARPi impact the antitumor immune response by modulating the tumor microenvironment, and their effect has dual properties of promoting and inhibiting the antitumor immune response. PARPi promote M1 macrophage polarization, antigen presentation by dendritic cells, infiltration of B and T cells and their killing capacity and inhibit tumor angiogenesis. PARPi can also inhibit the activation and function of immune cells by upregulating PD-L1. In this review, we summarize the dual immunomodulatory effects and possible underlying mechanisms of PARPi, providing a basis for the design of combination regimens for clinical treatment and the identification of populations who may benefit from these therapies.

Efficacy and safety of combined immunotherapy and antiangiogenesis with or without chemotherapy for advanced non-small-cell lung cancer: A systematic review and pooled analysis from 23 prospective studies.

Purpose: Immune checkpoint and antiangiogenic inhibitors have a potentially synergistic antitumor effect. We aimed to assess the efficacy and safety of immunotherapy in combination with antiangiogenesis therapy with or without chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Methods: PubMed, Embase, the Cochrane library, Google Scholar, Ovid, Scopus, and Web of Science were searched for eligible trials. ClinicalTrials.gov and meeting abstracts were also searched for qualified clinical studies. The inclusion criteria were as follows: prospective studies (including single-arm studies) that evaluated efficacy and/or toxicity of immunotherapy combined with antiangiogenic agents (A + I) with or without chemotherapy (A + I + chemo) in patients with advanced or metastatic NSCLC; and primary outcome of each study reported at least one of these endpoints: progression-free survival (PFS), overall survival, objective response rate (ORR), disease control rate (DCR), or adverse events (AEs). Results: Twenty three prospective studies comprising 1,856 patients with advanced NSCLC were included. The pooled ORR, median PFS and estimated overall survival were 39%, 6.8 months [95% confidence interval (CI), 5.53-8.13], and 18.6 months in the overall group. Similar ORR and median PFS with A + I + chemo versus A + I were observed in patients treated in first-line setting [59% and 9.47 months (95% CI, 6.45-12.49) versus 52% and 10.9 months (95% CI, 1.81-19.98), respectively]. We also observed improved ORR and mPFS with A + I + chemo versus A + I in subsequent-line setting [56% and 8.1 months (95% CI, 5.00-11.26) versus 22% and 5.1 months (95% CI, 4.01-6.15), respectively]. Efficacy of A + I + chemo therapy was evident across different PD-L1 subgroups, especially in patients with EGFR mutations [ORR: 59%; mPFS: 8.13 months (95% CI: 5.00-11.26)] or baseline liver metastases. The incidence of AEs with a major grade of ≥3 in the overall, A + I, and A + I + chemo groups were 4.1% vs. 5.5% vs. 3.4% for proteinuria, 13.7% vs. 16.2% vs. 9.7% for hypertension, and 1.9% vs. 1.2% vs. 2.8% for rash, respectively. No new safety signals were identified in this pooled analysis. Conclusion: Immunotherapy combined with antiangiogenic agents with or without chemotherapy showed encouraging antitumor activity and an acceptable toxicity profile in treatment-naïve or pretreated patients with advanced NSCLC. Doublet treatment with immunotherapy and antiangiogenic agents might be a new option for patients with advanced NSCLC, especially those who are treatment-naive or cannot tolerate chemotherapy.

Efficacy of Osimertinib in EGFR-Mutated Advanced Non-small-Cell Lung Cancer With Different T790M Status Following Resistance to Prior EGFR-TKIs: A Systematic Review and Meta-analysis.

Purpose: Epidermal growth factor receptor (EGFR) T790M-negative/unknown advanced non-small cell lung cancer (NSCLC) patients lack subsequent approved targeted therapies. This meta-analysis aimed to assess the efficacy of osimertinib in advanced NSCLC patients with different T790M status after resistance to prior first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and to predict the subgroups that may benefit beside T790M-positive disease. Methods: PubMed, Embase, Web of Science, and Cochrane Library databases were searched for relevant trials. Meeting abstracts were also reviewed to identify appropriate studies. Studies evaluating the efficacy and/or survival outcomes of osimertinib in patients with different T790M status (positive, negative, or unknown) after resistance to prior first- or second-generation EGFR-TKIs were enrolled, and data were pooled to assess hazard ratios (HRs) or relative risk ratios (RRs) in terms of overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: A total of 1,313 EGFR-mutated NSCLC patients from 10 retrospective and one prospective studies treated with osimertinib after resistance to first- or second-generation EGFR-TKIs were included. In overall groups, T790M-positive patients showed an improved OS (HR=0.574, p=0.015), PFS (HR = 0.476, p = 0.017), and ORR (RR = 2.025, p = 0.000) compared with T790M-negative patients. In the brain metastases subgroup, no significant difference in OS was observed between T790M-positive and T790M-negative patients (HR = 0.75, p = 0.449) or between T790M-positive and T790M-unknown patients (HR = 0.90, p = 0.673). In the plasma genotyping subgroup, PFS was similar between T790M-positive and T790M-negative patients (HR = 1.033, p = 0.959). Conclusion: Patients with progressive brain metastases on first- or second-generation EGFR-TKIs can benefit from subsequent osimertinib therapy regardless of T790M status. Patients with plasma T790M-negative status and lack of tissue genotyping should be allowed to receive osimertinib treatment.