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Review
. 2020 Jul 15;12(7):1905.
doi: 10.3390/cancers12071905.

Nivolumab plus Ipilimumab versus Existing Immunotherapies in Patients with PD-L1-Positive Advanced Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis

Koichi Ando  1 , Yasunari Kishino  1 , Tetsuya Homma  1 , Sojiro Kusumoto  1 , Toshimitsu Yamaoka  2 , Akihiko Tanaka  1 , Tohru Ohmori  1 , Tsukasa Ohnishi  1 , Hironori Sagara  1
Affiliations
Review

Nivolumab plus Ipilimumab versus Existing Immunotherapies in Patients with PD-L1-Positive Advanced Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis

Koichi Ando et al. Cancers (Basel). .

Abstract

No head-to-head trials have compared the efficacy and safety of nivolumab (Niv) plus ipilimumab (Ipi) combination therapy (Niv+Ipi) and existing regimens with immunotherapies approved as first-line treatment in patients with programmed cell death ligand 1 (PD-L1)-positive previously untreated advanced non-small cell lung cancer (NSCLC). We conducted a network meta-analysis of four relevant Phase Ⅲ trials to compare the efficacy and safety of Niv+Ipi, pembrolizumab (Pem) plus platinum-based chemotherapy (PBC) (Pem+PBC), Pem, Niv, or PBC using Bayesian analysis. The primary efficacy endpoint was progression-free survival (PFS) in patients with advanced NSCLC with PD-L1 expression ≥1%. The primary safety endpoint was the incidence of Grade 3-5 drug-related adverse events (G3-5AEs). Efficacy and safety were ranked using surface under the cumulative ranking curve (SUCRA). With regard to PFS, Niv+Ipi was inferior to Pem+PBC, and superior to Pem, Niv, or PBC alone. SUCRA ranking showed Pem+PBC had the highest efficacy for PFS, followed by Niv+Ipi, Niv, PBC, and Pem. The safety outcome analysis revealed Niv+Ipi was generally well tolerated compared to existing immunotherapy regimens. These results provide clinical information regarding the efficacy and safety of Niv+Ipi and indicate the possibility of the Niv+Ipi combination as a new therapeutic option in PD-L1-positive advanced NSCLC.

Keywords: indirect treatment comparison; ipilimumab; network meta-analysis; nivolumab; non-small cell lung cancer; overall survival; pembrolizumab; programmed cell death ligand 1; progression-free survival; systematic review.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Flow diagram of the study selection process. RCT, randomized controlled trial.
Figure 2
Figure 2
Network map of the network meta-analysis performed in this study. The randomized controlled trials (RCTs) included in this analysis are represented by solid lines, and the thickness of solid line indicates the number of included studies. The dashed line indicates a relationship where no RCT exists but an indirect comparison could be attempted. s.c., subcutaneous; RCT, randomized controlled trial; Niv, nivolumab; Ipi, ipilimumab; Pem, pembrolizumab; PBC, platinum-based chemotherapy.
Figure 3
Figure 3
Comparative efficacy for progression-free survival (PFS) among five therapeutic regimens (Niv+Ipi, Pem+PBC, Pem, Niv, PBC) in patients with programmed cell death ligand 1 (PD-L1) expression levels of 1% or more. Comparisons were expressed as Treatment A versus Treatment B. Data are expressed in terms of hazard ratio (HR) and 95% credible intervals (CrIs); Niv, nivolumab; PBC, platinum-based chemotherapy; Pem, pembrolizumab; Ipi, ipilimumab.
Figure 4
Figure 4
Comparative efficacy for progression-free survival (PFS) among the five therapeutic regimens (Niv+Ipi, Pem+PBC, Pem, Niv, and PBC) in patients with programmed cell death ligand 1 (PD-L1) expression levels of 50% or more. Comparisons were expressed as Treatment A versus Treatment B. Data are expressed in terms of hazard ratio (HR) and 95% credible intervals (CrIs); Niv, nivolumab; PBC, platinum-based chemotherapy; Pem, pembrolizumab; Ipi, ipilimumab.
Figure 5
Figure 5
Comparative efficacy for overall survival (OS) among the five therapeutic regimens (Niv+Ipi, Pem+PBC, Pem, Niv, and PBC) in patients with programmed cell death ligand 1 (PD-L1) expression levels of 1% or more. Comparisons were expressed as Treatment A versus Treatment B. Data are expressed in terms of hazard ratio (HR) and 95% credible intervals (CrIs); Niv, nivolumab; PBC, platinum-based chemotherapy; Pem, pembrolizumab; Ipi, ipilimumab.
Figure 6
Figure 6
Comparative efficacy for overall survival (OS) among the five therapeutic regimens (Niv+Ipi, Pem+PBC, Pem, Niv, and PBC) in patients with programmed cell death ligand 1 (PD-L1) expression levels of 50% or more. Comparisons were expressed as Treatment A versus Treatment B. Data are expressed in terms of hazard ratio (HR) and 95% credible intervals (CrIs); Niv, nivolumab; PBC, platinum-based chemotherapy; Pem, pembrolizumab; Ipi, ipilimumab.
Figure 7
Figure 7
Comparative efficacy among the five therapeutic regimens (Niv+Ipi, Pem+PBC, Pem, Niv, and PBC) in terms of incidence of any Grade 3–5 drug-related adverse events (G3–5AEs) in the overall patient group. Comparisons were expressed as Treatment A versus Treatment B. Data are expressed in terms of odds ratio (OR) and 95% credible intervals (CrIs); Niv, nivolumab; PBC, platinum-based chemotherapy; Pem, pembrolizumab; Ipi, ipilimumab.
Figure 8
Figure 8
The surface under the cumulative ranking curve (SUCRA) of the efficacy in progression-free survival (PFS) in a group of patients with programmed cell death ligand 1 (PD-L1) expression levels of 1% or more (presented as red crosses), in a group of patients with PD-L1 expression levels of 50% or more (presented as blue circles), and safety in any Grade 3–5 drug-related adverse events (G3–5AEs) in the overall population of the five therapeutic regimens (Niv+Ipi, Pem+PBC, Pem, Niv, and PBC). Data are presented as (SUCRA in PFS and SUCRA in G3–5AEs) with each plot of the five therapeutic regimens. In terms of efficacy in patients with PD-L1 expression levels of 1% or more (presented as red crosses), Pem+PBC ranked the highest, followed by Niv+Ipi, PBC, Niv, and, finally, Pem. In terms of efficacy in patients with PD-L1 expression levels of 50% or more (presented as blue circles), Pem+PBC ranked the highest, followed by Niv+Ipi, Niv, Pem, and, finally, PBC. However, Pem ranked the highest in safety, followed by Niv, Niv+Ipi, PBC, and, finally, Pem+PBC. Niv, nivolumab; PBC, platinum-based chemotherapy; Pem, pembrolizumab; Ipi, ipilimumab.
Figure 9
Figure 9
The surface under the cumulative ranking curve (SUCRA) of the efficacy in overall survival (OS) in a group of patients with programmed cell death ligand 1 (PD-L1) expression levels of 1% or more (presented as red crosses), in a group of patients with PD-L1 expression levels of 50% or more (presented as blue circles), and safety in any Grade 3–5 drug-related adverse events (G3–5AEs) in the overall population of the five therapeutic regimens (Niv+Ipi, Pem+PBC, Pem, Niv, and PBC). Data are presented as (SUCRA in OS and SUCRA in G3–5AEs) with each plot of the five therapeutic regimens. In terms of efficacy in patients with PD-L1 expression levels of 1% or more (presented as red crosses), Pem+PBC ranked the highest, followed by Niv+Ipi, Pem, Niv, and, finally, PBC. In terms of efficacy in patients with PD-L1 expression levels of 50% or more (presented as blue circles), Pem+PBC ranked the highest, followed by Niv+Ipi, Pem, Niv, and, finally, PBC. However, Pem ranked the highest in safety, followed by Niv, Niv+Ipi, PBC, and, finally, Pem+PBC. Niv, nivolumab; PBC, platinum-based chemotherapy; Pem, pembrolizumab; Ipi, ipilimumab.
Figure 10
Figure 10
Ipilimumab releases T lymphocytes from suppression caused by CD80/CD86-expressing dendritic cells by competing for binding to CTLA-4 on T lymphocytes, and induces T lymphocyte activation and proliferation. Nivolumab releases T lymphocytes from suppression caused by PD-L1-expressing cancer cells by binding to the PD-1 molecule. These properties of ipilimumab and nivolumab contribute to the restoration of the antitumor effect of T lymphocytes; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand 1; CTLA-4, cytotoxic T lymphocyte antigen-4.
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