AUTHOR=Lin Li , Xiao Lu , Li Lei , Chen Chen , Zhang Haorong , Yu Changyan , Zhang Lanfang , Wei Anhua , Li Wei 

TITLE=A meta-analysis of the efficacy of programmed cell death 1/its ligand inhibitors plus cytotoxic T-lymphocyte-associated antigen 4 inhibitors in non-small cell lung cancer

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1267763

DOI=10.3389/fphar.2024.1267763

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Immune checkpoint inhibitors (ICIs), either as monotherapy or in combination with chemotherapy, have improved the therapeutic outcome for non-small cell lung cancer (NSCLC). However, the efficacy of combination therapies, such as programmed cell death 1(PD-1)/its ligand (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, in targeting different pathways remains unclear. We performed a meta-analysis to determine whether the addition of a CTLA-4 inhibitor to PD-1/PD-L1 therapy improves the efficacy of PD-1/PD-L1 monotherapy in NSCLC.</p><p><bold>Methods:</bold> We systematically searched various electronic databases for suitable trials. Only randomized controlled trials (RCTs) comparing the clinical efficacy of PD-1/PD-L1 with and without CTLA-4 were included in the analyses. The meta-analysis software RevMan 5.3 was used for statistical analyses.</p><p><bold>Results:</bold> A total of seven RCTs were retrieved. The results suggested that the combination of CTLA-4 and PD-1/PDL-1 inhibitors did not show enhanced efficacy over PD1/PDL-1 inhibitor monotherapy as determined by overall survival (OS) (HR = 0.98, 95% CI = 0.84–1.14, <italic>p</italic> = 0.79), progression-free survival (PFS) (HR = 0.92, 95% CI = 0.81–1.06, <italic>p</italic> = 0.25), and objective response rate (ORR) (HR = 1.08, 95% CI = 0.96–1.21, <italic>p</italic> = 0.19). Furthermore, the combination immunotherapy was associated increased toxicity as evidenced by increased incidence of any type adverse events (AEs) (RR = 1.06, 95% CI = 1.00–1.13, <italic>p</italic> = 0.03), grade ≥3 immune-mediated AEs (RR = 1.58, 95% CI = 1.36–1.82, <italic>p</italic> &lt; 0.05), and treatment discontinuation (RR = 1.83, 95% CI = 1.46–2.28, <italic>p</italic> &lt; 0.05).</p><p><bold>Conclusion:</bold> Combining anti-CTLA-4 with anti-PD-1/PD-L1 therapy did not improve the therapeutic efficacy, and was associated with greater toxicity than anti-PD-1/PD-L1 monotherapy in patients with advanced NSCLC. Further investigation of the combination immunotherapy in specific subsets of patients is warranted to identify and define the patient-specific benefits of this combination.</p><p><bold>Systematic Review Registration:</bold><ext-link ext-link-type="uri" xlink:href="https://www.crd.york.ac.uk/prospero/" xmlns:xlink="http://www.w3.org/1999/xlink">https://www.crd.york.ac.uk/prospero/</ext-link>, identifier CRD42023435399</p>