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. 2020 Jun 16;9(1):1774314.
doi: 10.1080/2162402X.2020.1774314.

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

Gernot Wagner  1 , Hannah Karolina Stollenwerk  2 , Irma Klerings  1 , Martin Pecherstorfer  3 , Gerald Gartlehner  1   4 , Josef Singer  3
Affiliations

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

Gernot Wagner et al. Oncoimmunology. .

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 meta-analysis 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.

Keywords: Immune checkpoint inhibitors; advanced non-small cell lung cancer; meta-analysis; nsclc; pd-1; pd-L1; systematic review.

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Figures

Figure 1.
Figure 1.
PRISMA flow diagram modified from Moher et al.
Figure 2.
Figure 2.
Forest plots for (a) overall survival and (b) progression-free survival in studies assessing immune checkpoint inhibitors as first-line therapy.
Figure 3.
Figure 3.
Forest plots for (a) overall survival and (b) progression-free survival in studies assessing immune checkpoint inhibitors as second-line therapy.
Figure 4.
Figure 4.
Forest plots for adverse events in studies assessing immune checkpoint inhibitors as (a) first-line and (b) second-line therapy.
Figure 4.
Figure 4.
(Continued).
See this image and copyright information in PMC

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There was no funding for this work. JS declares honorarium payments from Janssen and Roche as an invited speaker and from Amgen, Janssen, Merck, Roche and Pfizer for expert consulting on other topics than immune checkpoint inhibition and NSCLC. MP declares financial support from Roche for research projects other than immune checkpoint inhibition and NSCLC.