Elsevier

Lung Cancer

Volume 162, December 2021, Pages 175-184
Lung Cancer

Impact of treatment timing and sequence of immune checkpoint inhibitors and anti-angiogenic agents for advanced non-small cell lung cancer: A systematic review and meta-analysis

https://doi.org/10.1016/j.lungcan.2021.11.008Get rights and content

Highlights

  • Clinical effects of ICI and AA therapy are evaluated in comparison with either monotherapy for advanced non-small cell lung cancer.

  • ICI and AA therapy showed a higher objective response rate than either monotherapy.

  • AA administered concomitantly or immediately after ICI can provide favorable survival benefits compared to either monotherapy.

  • ICI administered immediately after AA may show no survival benefits compared to ICI monotherapy.

Abstract

Objective

Several studies have demonstrated that anti-angiogenic agents (AAs) have the ability to regulate immune-related cells in the tumor microenvironment and may affect the clinical effect of immune checkpoint inhibitors (ICIs). Therefore, we investigated the drug interaction between ICI and AA for advanced non-small cell lung cancer (NSCLC).

Materials and methods

We systematically searched PubMed-MEDLINE, Embase-Scopus, and ISI Web of Science before August 23, 2021. ICI and AA therapy included the concomitant and sequential use of ICIs and AAs. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of patients who received ICI and AA therapy were evaluated and compared to those of patients who received either monotherapy. Subgroup analyses were performed to clarify the cause of heterogeneity; the timing and sequence of ICI and AA administration were predefined as the subgroups.

Results

Thirteen studies involving 2414 patients were included in the meta-analysis. ICI and AA therapy had significantly higher ORR than either monotherapy (OR [95% CI]: 0.61 [0.50–0.74]; p < 0.001; I2 = 29%). PFS and OS were favorable benefits in ICI and AA therapy; however, significant heterogeneity was identified in these analyses (I2 = 80% and 59%, respectively). According to the administration timing and sequence, ICI immediately after AA showed no PFS and OS benefits compared to ICI monotherapy (HR [95 % CI]: 1.54 [1.14–2.08] and 1.50 [1.04–2.15], respectively), whereas favorable PFS and OS were demonstrated when AA was concomitantly administered with ICI (HR [95 % CI]: 0.57 [0.43–0.76] and 0.80 [0.61–1.05], respectively) or when AA was administered immediately after ICI (HR [95 % CI]: 0.58 [0.34–1.00] and 0.56 [0.40–0.80], respectively).

Conclusion

ICI and AA therapy can provide favorable clinical effects compared to either monotherapy; however, ICI administered immediately after AA may not show survival benefits.

Introduction

Currently, anti-angiogenic agents (AAs) and immunotherapy are major components of standard therapies for patients with advanced non-small cell lung cancer (NSCLC). Several molecular-targeted agents that target the receptors of vascular endothelial growth factor (VEGF) have achieved positive outcomes. Bevacizumab plus platinum-doublet chemotherapy has become the standard treatment for patients with treatment-naïve advanced NSCLC [1]. Further, ramucirumab or nintedanib plus chemotherapy have been approved by the Food and Drug Administration for previously treated advanced NSCLC [2], [3]. However, the combined use of AA and chemotherapy would lead to drug resistance in most patients, barely prolonging survival by a few months, compared to using chemotherapy alone.

In recent years, immune checkpoint inhibitors (ICIs), a breakthrough treatment, have been continuously developed for NSCLC, allowing durable survival for several years [4], [5]. Once patients respond to treatment, they can continue to survive for long periods; however, patients who experience such benefits are limited. High tumor mutation burden and programmed death ligand-1 were found to be biomarkers [6], [7]. Most patients experience disease progression immediately after ICI administration or develop resistance after a short duration of treatment, similar to what is experienced with AAs.

Some studies have demonstrated that AAs have the ability to regulate immune-related cells in the tumor microenvironment (TME), and the combination of AAs with ICIs may theoretically enhance the clinical effect of the ICI monotherapy [8]. Several clinical trials have demonstrated that ICIs combined with AAs improved the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of patients with various solid tumors [9], [10], and a meta-analysis showed positive results in patients with metastatic renal cell carcinoma [11]. Patients with advanced NSCLC who concomitantly received ICIs with AAs also demonstrated significantly prolonged survival time compared to those who received AAs alone [12]. In recent years, sequential treatment with ICIs and AAs were reported to provide potential survival benefits for patients with advanced NSCLC [13]. Such studies, including basic and clinical research, have been reviewed extensively; however, there has been no reports of an integrated analysis. Thus, we performed a meta-analysis of available clinical studies to evaluate the drug interaction between ICI and AA for advanced NSCLC. We present the following article in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist.

Section snippets

Search strategy

The study protocol was registered in the International Prospective Register of Systematic Reviews (CRD 42021268286). Our systematic review and meta-analysis followed PRISMA guidelines [14]. Some databases, including PubMed-MEDLINE, Embase-Scopus, and Web of Science were searched for eligible studies published before August 23, 2021. The following search terms were used for the literature search: “immune checkpoint inhibitor” OR “immunotherapy” OR “nivolumab” OR “pembrolizumab” OR “atezolizumab”

Search results

The PRISMA flowchart for this meta-analysis is shown in Fig. 2. Duplicates and irrelevant studies were removed from a total of 1156 titles. We screened 788 records and ruled out 749 through their titles and abstracts. All investigators fully assessed the remaining 39 articles and agreed to include 13 eligible studies with 2414 patients in our meta-analysis [12], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31].

Study characteristics

The extracted data are summarized in Table 1. Two randomized

Discussion

This systematic review and meta-analysis demonstrated that ICI and AA therapy was associated with better treatment outcomes compared to either monotherapy in patients with advanced NSCLC. Importantly, clinical effects of ICI and AA were observed when AA were administered concomitantly and immediately after ICI, but not when ICI were administered immediately after AA. Thus, our findings provide further evidence of the clinical efficacy of ICI and AA therapy for advanced NSCLC. To the best of our

Conclusion

Our systematic review and meta-analysis demonstrated that ICI and AA therapy had favorable clinical effects compared to either monotherapy. Significant heterogeneity was identified in PFS and OS; therefore, subgroup analyses were required to elucidate the clinical effects of administration timing and sequence. We suggest that AA concomitantly or immediately after ICI can provide favorable survival benefits compared to either monotherapy; however, ICI administered immediately after AA may show

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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