Non-small-cell lung cancer (NSCLC), which makes up around 80–85% of each diagnosis, is the most common kind of lung cancer and the leading cause of cancer-related death globally. The most recent “Global Cancer Statistics 2020” data from the World Health Organization show that its incidence rate is more than 1/10 of the world’s malignant tumors (1). Approximately 70% of patients with stage I to stage III non-small cell lung cancer are surgically curable (2). Only 5% of patients with advanced non-small cell lung cancer survived 5 years (3). About 62 percent of non-small cell lung cancer patients are given a stage IV diagnosis at their initial diagnosis because they don’t exhibit the typical signs of lung cancer (4). Chemotherapy, targeted therapy, and immunotherapy are the three most widely used therapies for persons with advanced non-small cell lung cancer (5).

Since the introduction of immunotherapy, the area of therapeutic approaches for NSCLC has taken on a whole new perspective and demonstrated considerable promise. Jianwei Zhu presented a review (6) of immunotherapy, which found that immunotherapies other than immune checkpoint inhibitor therapy, the current literature does not provide evidence that suggests a survival benefit from adding immunotherapy (excluding checkpoint inhibitors) to conventional curative surgery or radiotherapy, for people with localized NSCLC (stages I to III). However, patients with metastatic NSCLC who receive treatment with checkpoint inhibitors that target programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have shown improved disease response rates and longer lifetime (7–9). The benefit of PD-1/PD-L1 inhibitor monotherapy is limited, a systematic review (10) was conducted by Fausto Petrelli et al. The study showed that the addition of immune checkpoint inhibitors to chemotherapy may improve both OS compared with chemotherapy alone, it is critically necessary to investigate the efficacy of combination treatment modalities to help doctors optimize their treatment regimens.

Anti-angiogenic agents, including monoclonal antibodies like bevacizumab and small molecule inhibitors like anlotinib, apatinib, and lenvatinib, inhibit the VEGF signaling pathway, exhibiting anti-tumor effects. Clinical studies have demonstrated the efficacy of this family of drugs in the treatment of advanced non-small cell lung cancer, including BEYOND (11) and ALTER0303 (12). Results from several clinical trials have been reported on the potential efficacy of PD-1/PD-L1 inhibitors in combination with anti-angiogenic drugs. Atezolizumab was shown to be beneficial in prolonging progression-free survival and overall survival in patients with advanced non-small cell lung cancer in IMpower150 (13) when used in conjunction with chemotherapy and bevacizumab. Pembrolizumab with lenvatinib was shown to have an objective response rate (ORR) of 33.3% when used as the first-line therapy for advanced non-small cell lung cancer in KEYNOTE-524 (14). These findings offer a scientific rationale for the PD-1/PD-L1 inhibitor plus anti-angiogenic drug therapy regimen.

Although various effective compounds for the second or later-line treatment of advanced non-small cell lung cancer improved the overall survival, the optimal regimen remains controversial. Due to the paucity of scientific evidence supporting the use of PD-1/PD-L1 inhibitors in combination with other drugs in the second or later-line treatment of patients with advanced non-small cell lung cancer, a number of clinical studies are being conducted worldwide to further examine the viability of combination regimens. However, almost all studies on the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer are non-randomized controlled trials with small sample sizes, which might lead to a lack of effective metrics to assess the effectiveness and safety of the therapeutic regimen. Here, this meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer

Single-arm meta-analysis is in accordance with PRISMA(Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines (15) and has been registered with PROSPERO (ID: CRD42023407559, https://www.crd.york.ac.uk/prospero/).

In this era of numerous drugs, the treatment of lung cancer has evolved fast. The availability of second or later-line treatment for advanced non-small cell lung cancer is still constrained. Docetaxel was established as the standard chemotherapy regimen for second-line treatment of NSCLC in the TAX317/TAX320 studies (37, 38) and the results of the TAX317 study demonstrated that it significantly increased overall survival when used in the treatment of driver-negative advanced NSCLC compared to best supportive care (7 months vs. 4.6 months). The advent of immunotherapeutic medications has further changed the paradigm of second or later-line therapy for patients with advanced NSCLC. Based on the results of KEYNOTE-010, CheckMate 078 and OAK (9, 39, 40). PD-1/PD-L1 inhibitors monotherapy have been approved by the Food and Drug Administration (FDA) and the National Medical Products Administration (NMPA) of China for the second or later-line treatment of patients with driver-negative advanced non-small cell lung cancer. Alfredo Tartarone also conducted a Meta-analysis (41), this meta-analysis confirms the superiority of ICIs over docetaxel in pretreated non-small-cell lung cancer patients and would indicate a slight benefit from anti-PD-1 than from anti-PD-L1 inhibitors. The ALTER0303 study (12) demonstrated a median OS extension of 3.3 months for patients in the anlotinib arm compared to the placebo arm (9.6 months vs. 6.3 months); and a median PFS extension of 4.0 months (5.4 months vs. 1.4 months). Based on the results of this study, anlotinib was approved for third-line treatment of patients with driver-negative advanced non-small cell lung cancer. There is a dearth of scientific data to support the use of combination regimens in the second or later-line therapy of patients with advanced non-small cell lung cancer, hence several clinical trials are being carried out globally to further investigate the viability of combination regimens.

Combination regimen based on small molecule VEGF signaling pathway inhibitors like anlotinib, apatinib, and lenvatinib is a popular issue in current research. Many academics have provided compelling justifications for the mechanisms at work when small molecule VEGF signaling pathway inhibitors are taken with additional medications, of these, the treatment options with the most established grounded theory were PD-1/PD-L1 inhibitors plus anti-angiogenic agents. A blockade of the VEGF signaling pathway with anti-angiogenic agents can have an enhanced anti-tumor immune effect because prior research has demonstrated that the Vascular Endothelial Growth Factors (VEGF)/VEGFR signaling pathway inhibits anti-tumor immune responses not only by producing a hypoxic microenvironment but also through other complex mechanisms to produce immunosuppressive effects (42–45). Activated immune cells can inhibit tumor angiogenesis both directly and indirectly, according to studies (46–48), resulting in a positive feedback loop between immunotherapy and anti-angiogenic treatment. A growing number of clinical studies focus on PD-1/PD-L1 inhibitors plus anti-angiogenic agents.

In our meta-analysis, nineteen clinical trials with 931 patients were included to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors plus anti-angiogenic agents as second or later-line treatment for patients with advanced non-small cell lung cancer. The pooled analyses presented that PD-1/PD-L1 inhibitors plus anti-angiogenic agents exhibited efficacy and manageable safety with promising ORR, DCR, OS, and PFS. The pooled results showed that the ORR and DCR were 22.4% and 76.8%, respectively, and the median OS and PFS were 14.09 months and 5.20 months, respectively. The subgroup analysis indicated that it was likely that combination of chemotherapy resulted in an increased ORR and DCR. The pooled median PFS of patients receiving small molecule VEGF signaling pathway inhibitors as treatment was lower than that of patients who received recombinant human endostatin and bevacizumab as treatment. In the meantime, our research shows that the pooled AE≥ grade 3 was 47.6%, and the most commonly reported adverse event was hypertension. Xiaoying Sun et al. conducted a meta-analysis (49) to assess the immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer, study showed only a 4% probability of serious adverse events. However, that study included data from a large number of patients and addressed adverse reactions associated with PD-1 and PD-L1 drugs, whereas our study addressed a smaller number of patients in the study and addressed data from a combination anti-vascular drug regimen. And a large number of in our meta-analysis have shown that serious adverse events are hypertensive, and associated with anti-vascular drugs, the adverse events are relatively safe and manageable.

In monotherapy, nivolumab’s effectiveness and safety in treating advanced non-small-cell lung cancer after prior treatment were evaluated by a meta-analysis (50). According to the research, the pooled ORR of the 817 patients who received nivolumab was 20%, and the pooled DCR of the 657 patients who received nivolumab was 36%. According to OAK (9) data, the ORR of 425 patients in the atezolizumab group was 14%, while the DCR was 49%. According to ALTER 0303’s results (12), the ORR of 437 patients in the anlotinib group was 9.2%, and the DCR was 81%. The ORR of 353 patients in the nintedanib group was 9.1%, and the DCR was 60.9%, according to the results of LUME-Lung 2 (51). And the data from our study suggest that PD-1/PD-L1 inhibitors plus anti-angiogenic agents have more promising efficacy as second or later-line treatment in patients with advanced non-small cell lung cancer.

Another hot topic in current research is the use of chemotherapy plus PD-1/PD-L1 inhibitors combination regimens as second or later-line treatment for patients with advanced non-small cell lung cancer. The effectiveness of nivolumab with docetaxel in the second or later-line therapy of patients with advanced non-small cell lung cancer was examined in a clinical study (52). According to the results of the trial, the ORR was 41.8% and the DCR was 80% in the nivolumab plus docetaxel group. As second-line treatment for advanced non-small cell lung cancer without targetable mutations, sintilimab with docetaxel showed promising outcomes, according to Zhang et al. (53). The ORR was 36.7%, the DCR was 76.6%, the median PFS was 5.0 months, and the median OS was 13.4 months. The effectiveness of these two trials’ findings was comparable to that of PD-1/PD-L1 inhibitors combined with anti-angiogenic medicines in this meta-analysis. Real-world data from our hospitals were analyzed by our team, and the findings of the study demonstrated that PD-1/PD-L1 inhibitors plus anti-angiogenic medicines were superior than PD-1/PD-L1 inhibitors plus chemotherapy (54). According to the data indicated above, PD-1/PD-L1 inhibitors combined with anti-angiogenic drugs had a satisfactory impact when used as a second or later-line treatment for patients with advanced non-small cell lung cancer. Our study is based on data from second and later line therapy, a population for which most existing clinical studies have not focused on PD-L1 expression in a timely manner, and which is therefore not mentioned in the extensive literature. Even the available studies agree that different countries and different populations will have different PD-L1 expressions, but it is unknown whether this difference causes differences in therapeutic efficacy. This also suggests that studying the relationship between PD-L1 expression and drug efficacy after treatment with various drugs is a key research direction for the future.

In conclusion, our study has a number of advantages: First and foremost, our meta-analysis was conducted on better quality clinical trials, and a sufficient number of clinical trials were included. Second, we carry out rigorous statistical analysis of the data to ensure the stability and reliability of the results. The last but not least, we compared the results of previous studies to confirm the effectiveness of the treatment options. The meta-analysis’s findings are valuable for physicians in that they may be used to create more effective treatment strategies for various individuals in a clinical environment.

The present meta-analysis had some shortcomings. First, the included studies showed significant heterogeneity. Despite our best efforts, we were unable to accurately identify the source of heterogeneity using meta-regression and subgroup analysis. Second, because all of the included studies had small sample sizes and were noncontrolled trials, we were only able to assess the effectiveness and risk without drawing any firm conclusions. Third, we haven’t been able to thoroughly analyze the AE in further depth. In order to validate the clinical function of PD-1/PD-L1 inhibitors in combination with anti-angiogenic medicines in contrast to other medications and the general population, further large-scale RCTs need be developed.

PD-1/PD-L1 inhibitors plus anti-angiogenic agents has promising efficacy and safety as second or later-line treatment in patients with advanced non-small cell lung cancer.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

Material preparation, data collection, analysis and writing were performed by SC and WM. WJ and SZ given some constructive discussions make revisions to the paper. QY and HG conceptualized the research process and guided its conduct. All authors contributed to the article and approved the submitted version.