Efficacy and safety of immune checkpoint inhibitors in patients with advanced non–small cell lung cancer (NSCLC): a systematic literature review

Abstract

Background: Therapeutic strategies with immune checkpoint inhibitors (ICIs) counteract the immunosuppressive effects of programmed cell death protein-1 (PD-1) and ligand-1 (PD-L1). ICI treatment has emerged in first-and second-line therapy of non-small cell lung cancer (NSCLC). As immunotherapeutic treatment with ICIs is a dynamic field where new drugs and combinations are constantly evaluated, we conducted an up-to-date systematic review on comparative efficacy and safety in patients with advanced NSCLC. Methods: We searched PubMed up to February 2020 and Embase, CENTRAL, and clinical trial registries up to August 2018. Additionally, we checked reference lists. We dually screened titles, abstracts and, subsequently, full-texts for eligibility. Two reviewers assessed the risk of bias and graded the certainty of evidence following GRADE (Grading of Recommendations Assessment, Development and Evaluation). For second-line therapy, we performed random-effects meta-analyses. Due to considerable clinical heterogeneity, we reported first-line results narratively. Results: Of 1497 references, we identified 22 relevant publications of 16 studies. For first-line therapy, a combination of an ICI with chemotherapy improved progression-free survival and overall survival compared to chemotherapy but increased the risk of serious adverse events. Single-agent pembrolizumab increased overall and progression-free survival in patients with PD-L1 expression of ≥50% and resulted in less TRAE than chemotherapy. Compared to placebo, maintenance therapy with durvalumab increased overall and progression-free survival at the downside of higher risk of TRAE. For second-line therapy, a random-effects metaanalysis yielded a statistically significantly improved overall survival (OS) and progression-free survival (PFS) for ICIs compared to docetaxel (HR 0.69; 95% CI: 0.63-0.75 for OS; HR 0.85; 95% CI: 0.77 − 0.93 for PFS; 6 studies, 3478 patients; median OS benefit in months: 2.4 to 4.2). In meta-analysis, risk of any treatment-related adverse events of any grade was lower for ICI than docetaxel as second-line therapy (RR 0.76, 95% CI: 0.73-0.79; 6 studies, 3763 patients). Conclusion: In first-line therapy of patients with advanced NSCLC, ICI is effective when combined with chemotherapy not depending on PD-L1 expression, or as monotherapy in high PD-L1 expressing tumors. For second-line therapy, single-agent ICI improves efficacy and safety compared to docetaxel.

Effectiveness and Safety of Immune Checkpoint Inhibitors for Patients with Advanced Non Small-Cell Lung Cancer in Real-World: Review and Meta-Analysis

“…Immunotherapy with checkpoint inhibitors (ICIs) that target the PD-1/PD-L1 (programmed death-1/programmed death ligand-1) pathway is considered the new standard treatment of advanced and metastatic squamous and non-squamous lung cancers, with or without chemotherapy [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Nevertheless, cancer patients enrolled in randomized clinical trials (RCT) meet strict eligibility criteria allowing for the treatment of patients that do not reflect the more heterogeneous population of oncologic patients.…”

Establishment and Characterization of Patient-Derived Xenografts (PDXs) of Different Histology from Malignant Pleural Mesothelioma Patients

“…MPMs are relatively rare, aggressive tumors for which new therapeutic strategies are particularly warranted due to the very poor prognosis these patients have [ 15 , 16 , 17 , 18 , 19 , 20 ]. Data obtained so far with immunotherapy (in particular with the use of immune checkpoint inhibitors) were below the expectancies [ 7 , 21 , 22 , 23 , 24 , 25 ], particularly when we consider that their use vastly improves the outcome in other tumor types [ 26 , 27 , 28 , 29 , 30 ]. One of the factors limiting the discovery of new drugs and/or combinations potentially active in MPM is the scarce availability of models able to recapitulate the malignancy.…”

Case Report: PD-1 Inhibitor Is Active in Lung Adenocarcinoma With B Cell Deficiency

“…The frequency and severity of adverse effects related to PD-1 inhibitor might be decreased when B cells are depleted in NSCLC patients. NSCLC patients receiving PD-1 inhibitor often have adverse effects, including autoimmune hypophysitis, thyroiditis, colitis, hepatitis, pneumonitis, and rash, sometimes appearing as systemic diseases (11). Thus, patients with NSCLC and concurrent autoimmune disease have typically been excluded from clinical trials using PD-1 inhibitor due to their underlying immune disorders.…”