Efficacy and safety of PD‑1/PD‑L1 inhibitors combined
with chemotherapy in patients with advanced gastric or gastro‑esophageal junction cancer: A systematic review and meta‑analysis
- Authors:
- Published online on: July 17, 2023 https://doi.org/10.3892/ol.2023.13960
- Article Number: 373
-
Copyright: © Su . This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Gastric cancer, including gastro-esophageal junction cancer (GC/GEJC), is the fourth leading cause of cancer-related death worldwide (1). Patients with newly diagnosed advanced GC/GEJC often have a poor prognosis, with a life expectancy of ~1 year (2). For advanced GC/GEJC, chemotherapy with platinum and fluoro-pyrimidine is currently the standard first-line therapy (3,4). However, initial chemotherapy is frequently unsuccessful, and the majority of patients will experience a relapse with a tendency of systemic metastasis, necessitating second-line treatments (2). Second-line treatment options for advanced or metastatic GC/GEJC patients include docetaxel, paclitaxel, or irinotecan, and the anti-vascular endothelial growth factor receptor 2 antibody ramucirumab as either monotherapy or in combination with paclitaxel (5–7). Although chemotherapy regimens for these patients have recently developed, the prognosis of advanced GC/GEJC is still disappointing. Thus, novel treatment options for patients with advanced gastric or gastroesophageal junction cancer are urgently required.
Immune checkpoint inhibitors (ICIs) such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been recommended as treatments for GC/GEJC, which overexpress immune checkpoint ligands (8–10). A previous meta-analysis investigated the efficacy and safety of anti-PD-1/PD-L1 agents vs. chemotherapy in patients with GC/GEJC (11). Additionally, Zheng et al (12) also pooled data on the efficacy and safety of PD-1/PD-L1 inhibitor combined with chemotherapy in patients with advanced GC/GEJC. However, the patients examined in these two previous meta-analyses included both PD-L1-positive and negative patients. Notably, PD-1/PD-L1 inhibitors inhibit T cell activation by blocking the binding of the PD-1 receptor, an immune checkpoint protein expressed on tumor cells, to PD-1 on the surface of T cells, leading to tumor immune escape (13). Therefore, the present systematic review and meta-analysis focused on comparing the efficacy and safety of PD-1/PD-L1 inhibitors or PD-1/PD-L1 inhibitors combined with chemotherapy vs. chemotherapy alone in PD-L1 positive GC/GEJC patients, defined as patients whose tumors had a PD-L1 combined positive score (CPS) of ≥1, aiming to provide more precise guidance for the clinical treatment of GC/GEJC patients.
Materials and methods
Literature search
The inclusion criteria were: Study object, patients with advanced GC/GEJC; intervention measures, PD-1/PD-L1 inhibitors, PD-1/PD-L1 inhibitors combined with chemotherapy, or chemotherapy alone. All included studies were randomized controlled trials (RCTs) limited to English. Outcome indicators included were: Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), stable disease (SD) rate, progressive disease (PD) rate, and incidence of adverse events.
The exclusion criteria were: Studies where full text could not be obtained, lacking information, studies on which data could not be extracted, studies using animal experiments, reviews, and systematic reviews.
Search strategy
PubMed, Embase, and Cochrane Library databases were searched from the establishment of the database till June 2022, with the following search terms: ‘Stomach Neoplasm’, ‘gastric cancer’, ‘stomach cancer’, ‘gastroesophageal cancer’ AND ‘Nivolumab’, ‘Pembrolizumab’, ‘Durvalumab’, ‘Tremelimumab’, ‘Avelumab’, ‘Atezolizumab’, ‘PD-1’, ‘PD-L1’ AND ‘Chemotherapy’, ‘Chemotherapeutics’.
Literature screening and data extraction
Relevant studies were independently identified by two researchers, with disagreements being resolved through discussion with a third investigator. Information extracted from relevant studies included the experiment name, study design, sample size of all patients, sex, age, Eastern Cooperative Oncology Group ECOG performance status, the sample size of patients that were PD-L1 positive, interventions, and outcome indicators including OS, PFS, ORR, SD rate, PD rate, and incidence of adverse events.
Literature quality assessment
RevMan 5.3 (The Cochrane Collaboration) risk assessment tool was used by two investigators to independently assess study quality based upon the Cochrane risk assessment scale (14), which assesses study quality based on random sequence generation, allocation concealment, blinding method, whether research results were evaluated in a blinded manner, and the completeness of reported data. Studies were also examined for potential selective reporting, sex bias, and other biases. This meta-analysis was executed in compliance with the PRISMA statement (15).
Data synthesis and statistical analysis
All data were analyzed using STATA (version 15.1, Stata Corporation) (16). OS and PFS were evaluated based on the hazard ratio (HR) with 95% confidence intervals (CIs), while ORR, SD rate, PD rate, and incidence of adverse events were assessed based on risk ratio (RR) and 95% CI. Heterogeneity was evaluated based on the I2 statistic, with fixed effects models being used to analyze normally distributed data (P≥0.1 and I2≤50%), whereas a random-effects model or descriptive statistics, were used in cases where the data were not normally distributed (P<0.1, I2>50%) and the sources of such heterogeneity could not be determined through sensitivity analyses. Since the literature included in the indicators evaluated in this study were all <3, the publication bias of the literature was not evaluated.
Results
Results of the literature search
In this meta-analysis, a total of 797 studies from PubMed, Embase, and Cochrane Library were obtained. After eliminating duplicate studies, 536 studies remained. After reading the titles and abstracts, 434 studies were retained. After browsing the full text, 6 studies were obtained and excluded any that did not report the outcomes of interest and other ablation methods. Finally, 6 studies were included in the final meta-analysis (Fig. 1).
Baseline characteristics and quality assessment of the included studies
Baseline characteristics of the included studiesIn total, 6 RCTs (16–21) were included in this meta-analysis. The patient sample size totaled 5,030, including 2,518 in the experimental group and 2,512 in the control group. The median age of the patients ranged from 59–64. The sample size of patients with PD-L1 positive cancer totaled 3,286, including 1,640 in the experimental group and 1,646 in the control group. Interventions include PD-1/PD-L1 inhibitors or PD-1/PD-L1 inhibitors combined with chemotherapy (Table I).
Quality assessment of the included studies
All the studies included in this meta-analysis described their random sequence generation strategies; three studies were double-blinded, whereas the other three did not use any blinding methods (Figs. 2 and 3). Additionally, allocation concealment was performed in 5 studies. Overall, the quality of the included studies was relatively high.
Efficacy for all patients
OSOnly 2 studies reported on the OS of all patients that underwent PD-1/PD-L1 inhibitors vs. chemotherapy. Since there was no significant heterogeneity (I2=36.1%, P=0.211), a fixed effects model was used. The pooled results indicated that the PD-1/PD-L1 inhibitors did not improve the OS compared with patients that underwent chemotherapy alone (HR=0.98; 95% CI, 0.86–1.13; P=0.817; Fig. 4). In addition, 3 studies reported on the OS of all patients that underwent chemotherapeutic treatment alone or combined with PD-1/PD-L1 inhibitors. Since there was no significant heterogeneity (I2=28.7%, P=0.246), the fixed effects model was used. The OS of PD-1/PD-L1 inhibitors combined with chemotherapy for patients with advanced GC/GEJC was significantly longer than that of chemotherapy alone (HR=0.80; 95% CI, 0.73–0.88; P≤0.001; Fig. 4). These results suggest that chemotherapy combined with immunotherapy prolongs OS in patients with advanced GC/GEJC.
PFS
The JAVELIN Gastric 300 study (19) reported that the PFS of patients with advanced GC/GEJC treated with PD-1/PD-L1 inhibitors was significantly lower than that of patients treated with chemotherapy alone (HR=1.73, 95% CI, 1.38–2.17; P≤0.001; Fig. 5). In addition, 3 studies reported on the PFS of all patients that underwent chemotherapeutic treatment alone or combined with PD-1/PD-L1 inhibitors. Since there was no significant heterogeneity (I2=0.0%, P=0.246), a fixed effects model was used. The PFS of PD-1/PD-L1 inhibitors combined with chemotherapy for advanced GC/GEJC was significantly longer than that of chemotherapy alone (HR=0.80, 95% CI, 0.73–0.88; P≤0.001; Fig. 5). The above results showed that for advanced GC/GEJC, the PFS with PD-1/PD-L1 inhibitors alone or in combination with chemotherapy was improved compared with chemotherapy.
Efficacy for patients with PD-L1 positive cancer
ORRFirst, the ORR of PD1/PD-L1 inhibitors vs. chemotherapy was compared for patients with PD-L1 CPS≥1, and three studies reported on the ORR of patients with PD-L1 CPS≥1 that underwent PD-1/PD-L1 inhibitors vs. chemotherapy. Since there was significant heterogeneity (I2=85.8%, P=0.001) (Fig. S1), sensitivity analysis was performed, and it was found that the KEYNOTE-62 had a notable impact on the results of this study. Heterogeneity was significantly reduced after excluding this study (I2=0.0%, P=0.728). The pooled results indicated that the PD-1/PD-L1 inhibitors did not improve the ORR in patients with PD-L1 CPS≥1 that underwent chemotherapy (RR=1.18, 95% CI: 0.74–1.86, P=0.481; Fig. 6A). Additionally, the KEYNOTE-61 study (17) reported that there was no significant difference in the ORR between PD1/PD-L1 inhibitors and chemotherapy for patients with PD-L1 CPS≥5 (RR=1.40, 95% CI: 0.74–2.67, P=0.306; Fig. 6A). There were also two studies that reported on the ORR of patients with PD-L1 CPS≥10 that underwent PD-1/PD-L1 inhibitors vs. chemotherapy. Since there was significant heterogeneity (I2=85.6%, P=0.008), the analysis was performed using the random effects model. The pooled results showed that there was no significant difference in ORR between PD1/PD-L1 inhibitors and chemotherapy for patients with PD-L1 CPS≥10 (RR=0.92, 95% CI: 0.62–1.35, P=0.751; Fig. 6A). These results suggest that PD1/PD-L1 inhibitors do not significantly increase ORR in PD-L1-positive patients compared with chemotherapy.
Two studies reported on the ORR of patients with PD-L1 CPS≥1 that underwent PD-1/PD-L1 inhibitors combined with chemotherapy vs. chemotherapy. Since there was no significant heterogeneity (I2=0.0%, P=0.998), the analysis was performed using a fixed effects model. The pooled results showed that the ORR of PD-1/PD-L1 inhibitors combined with chemotherapy in patients with PD-L1 CPS≥1 was significantly higher than that of chemotherapy alone (RR=1.31, 95% CI: 1.19–1.43, P≤0.001; Fig. 6B). In addition, the results of CheckMate 649 (20) and KEYNOTE-062 (18) showed that PD-1/PD-L1 inhibitor combined with chemotherapy significantly increased ORR compared with chemotherapy alone in patients with PD-L1 CPS≥5 (RR=1.32, 95% CI: 1.15–1.51, P≤0.001; Fig. 6B) and PD-L1 CPS≥10 (RR=1.50, 95% CI: 1.09–2.06, P=0.014; Fig. 6B), respectively. The above results suggest that for PD-L1-positive patients, the ORR of PD1/PD-L1 inhibitors combined with chemotherapy was significantly higher than that of chemotherapy.
SD rate
Two studies reported on the SD rate of patients with PD-L1 CPS≥1 that underwent PD-1/PD-L1 inhibitors vs. chemotherapy. Since there was no significant heterogeneity (I2=43.9%, P=0.182), the analysis was performed using a fixed effects model. The pooled results showed that the SD rate of PD-1/PD-L1 inhibitors in patients with PD-L1 CPS≥1 was significantly lower than that of chemotherapy (RR=0.58, 95% CI: 0.48–0.70, P≤0.001; Fig. 7A). Notably, the results of KEYNOTE-061 (17) showed that PD-1/PD-L1 inhibitor had a significantly lower SD rate than chemotherapy in patients with PD-L1 CPS≥5 (RR=0.52, 95% CI: 0.37–0.73, P=0.003; Fig. 7A). Furthermore, the pooled results also showed that the SD rate of PD-1/PD-L1 inhibitors in patients with PD-L1 CPS≥10 was significantly lower than that of chemotherapy (RR=0.52, 95% CI: 0.37–0.73, P≤0.001; Fig. 7A). In summary, PD-1/PD-L1 inhibitors have higher SD rates compared to chemotherapy in PD-L1-positive patients.
As for the SD rate of patients with PD-L1 positive cancer who underwent PD1/PD-L1 inhibitor combined with chemotherapy vs. chemotherapy, the results of CheckMate 649 (20) showed that there was no significant difference in the SD rate of patients with PD-L1 CPS≥5 between PD-1/PD-L1 inhibitor combined with chemotherapy and chemotherapy alone (RR=0.81, 95% CI: 0.66–1.01, P=0.062; Fig. 7B).
PD rate
Two studies reported on the PD rate of patients with PD-L1 CPS≥1 that underwent treatment with PD-1/PD-L1 inhibitors vs. chemotherapy. Since there was significant heterogeneity (I2=90.5%, P=0.001), the analysis was performed using a random effects model. The pooled results showed that the PD rate of PD-1/PD-L1 inhibitors in patients with PD-L1 CPS≥1 was significantly higher than that of chemotherapy (RR=3.15, 95% CI: 1.35–7.37, P=0.008; Fig. 8A). In addition, the results of KEYNOTE-061 (17) showed that PD-1/PD-L1 inhibitors significantly increased the PD rate compared with chemotherapy in patients with PD-L1 CPS≥5 (RR=2.16, 95% CI: 1.39–3.35, P=0.001; Fig. 8A). Furthermore, the pooled results also showed that the PD rate of PD-1/PD-L1 inhibitors in patients with PD-L1 CPS≥10 was significantly higher than that of chemotherapy (RR=2.78, 95% CI: 1.73–4.41, P≤0.001; Fig. 8A). In summary, PD-1/PD-L1 inhibitors had higher PD rates compared to chemotherapy in PD-L1-positive patients.
As for the PD rates of patients with PD-L1 positive cancer undergoing PD1/PD-L1 inhibitor combined with chemotherapy vs. chemotherapy alone, the results of CheckMate 649 (20) showed that there was no significant difference in the PD rate of patients with PD-L1 CPS≥5 when treated with PD-1/PD-L1 inhibitors combined with chemotherapy vs. chemotherapy alone (RR=0.64, 95% CI: 0.40–1.02, P=0.062; Fig. 8B).
OS
Three studies reported on the OS of patients with PD-L1 CPS≥1 that underwent treatment with PD-1/PD-L1 inhibitors vs. chemotherapy. Since there was no significant heterogeneity (I2=0.0%, P=0.739), the analysis was performed using a fixed effects model. The pooled results showed that the OS of PD-1/PD-L1 inhibitors in patients with PD-L1 CPS≥1 was significantly longer than that of chemotherapy (HR=0.85, 95% CI: 0.73–1.00, P=0.049; Fig. 9A). In addition, the results of KEYNOTE-061 (17) showed that PD-1/PD-L1 inhibitor-treated group had a significantly longer OS than chemotherapy in patients with PD-L1 CPS≥5 (HR=0.72, 95% CI: 0.53–0.98, P=0.039; Fig. 9A). As for the OS of patients with PD-L1 CPS≥10, the pooled results also showed that the OS of PD-1/PD-L1 inhibitors in patients with PD-L1 CPS≥10 was significantly longer than that of chemotherapy (HR=0.69, 95% CI: 0.53–0.90, P=0.006; I2=0.0%, P=1.000; Fig. 9A). Altogether, in PD-L1-positive patients, PD-1/PD-L1 inhibitors increased OS compared with chemotherapy.
Three studies reported on the OS of patients with PD-L1 CPS≥1 that underwent treatment with PD-1/PD-L1 inhibitors combined with chemotherapy vs. chemotherapy alone. Since there was no significant heterogeneity (I2=0.0%, P=0.513), the analysis was performed using a fixed effects model. The pooled results showed that the OS of PD-1/PD-L1 inhibitors combined with chemotherapy in patients with PD-L1 CPS≥1 was significantly longer than that of chemotherapy alone (HR=0.83, 95% CI: 0.74–0.94, P=0.003; Fig. 9B). In addition, the results of CheckMate 649 (20) showed that PD-1/PD-L1 inhibitor-treated group combined with chemotherapy had a significantly longer OS than chemotherapy alone in patients with PD-L1 CPS≥5 (HR=0.71, 95% CI: 0.59–0.86, P≤0.001; Fig. 9B). As for the OS of patients with PD-L1 CPS≥10, the pooled results also showed that the OS of the PD-1/PD-L1 inhibitors combined with chemotherapy in patients with PD-L1 CPS≥10 was significantly longer than that of chemotherapy alone (HR=0.71, 95% CI: 0.52–0.97, P=0.030; I2=59.5%, P=0.116; Fig. 9B). In conclusion, in PD-L1-positive patients, PD-1/PD-L1 inhibitors combined with chemotherapy also prolonged OS compared with chemotherapy alone.
PFS
Three studies reported on the PFS of patients with PD-L1 CPS≥1 that underwent treatment with PD-1/PD-L1 inhibitors vs. chemotherapy alone. Since there was significant heterogeneity (I2=53.7%, P=0.116), the analysis was performed using a random effects model. The pooled results showed that the PFS of PD-1/PD-L1 inhibitors in patients with PD-L1 CPS≥1 was significantly shorter than that of chemotherapy (HR=1.48, 95% CI: 1.19–1.86, P=0.001; Fig. 10A). However, the results of KEYNOTE-061 (17) showed that there was no significant difference between PD-1/PD-L1 inhibitors and chemotherapy in patients with PD-L1 CPS≥5 (HR=0.98, 95% CI: 0.71–1.35, P=0.901; Fig. 10A). As for the PFS of patients with PD-L1 CPS≥10, the pooled results also showed that there was no significant difference between treatment with PD-1/PD-L1 inhibitors and chemotherapy in patients with PD-L1 CPS≥10 (HR=0.98, 95% CI: 0.75–1.27, P=0.857; I2=30.7%, P=0.230; Fig. 10A). The results suggest that PD-1/PD-L1 inhibitors can prolong PFS in patients with PD-L1 CPS≥1 compared with chemotherapy, but this conclusion does not hold in patients with PD-L1 CPS≥5 or 10, indicating that there was a potential correlation between the CPS and drug efficacy.
The pooled results showed that the PFS of PD-1/PD-L1 inhibitors combined with chemotherapy in patients with PD-L1 CPS≥1 was significantly longer than that of chemotherapy alone (HR=0.76, 95% CI: 0.67–0.86, P≤0.001; I2=20.5%, P=0.284; based on three studies; Fig. 10B). Additionally, the results of CheckMate 649 (20) showed that the PFS of PD-1/PD-L1 inhibitors combined with chemotherapy in patients with PD-L1 CPS≥5 was significantly longer than that of chemotherapy alone (HR=0.77, 95% CI: 0.68–0.87, P≤0.001; Fig. 10B). As for the PFS of patients with PD-L1 CPS≥10, the pooled results also showed that the PFS of PD-1/PD-L1 inhibitors combined with chemotherapy was significantly longer than that of chemotherapy alone (HR=0.60, 95% CI: 0.42–0.85, P=0.004; I2=68.9%, P=0.073; Fig. 10B). These results suggest that PD1/PD-L1 inhibitors combined with chemotherapy can prolong PFS regardless of the CPS.
Adverse events for patients with PD-L1 positive cancer
The incidence of adverse events of PD-1/PD-L1 inhibitors vs. chemotherapy in patients with PD-L1 positive cancer was also analyzed. Since there was significant heterogeneity (I2=53.7%, P=0.116), the analysis was performed using a random effects model. The pooled results showed that the incidence of adverse events of PD-1/PD-L1 inhibitors in patients with PD-L1 positive cancer was significantly lower than that of chemotherapy (RR=0.34, 95% CI: 0.18–0.62, P≤0.001; Fig. 11).
Sensitivity analysis
To assess whether any individual study included in this meta-analysis had an undue impact on the overall results, sensitivity analysis was performed wherein individual studies were sequentially excluded from the summary analysis. This approach indicated that none of the included studies biased the overall results of the meta-analysis, as evidenced by the stability of the results, further emphasizing the reliability of these findings (Fig. S2, Fig. S3, Fig. S4, Fig. S5, Fig. S6).
Discussion
Patients diagnosed with advanced GC/GEJC often have poor outcomes despite the use of standard treatments, such as chemotherapy and biologic agents. Previous studies have focused on evaluating combinations of ICIs, standard chemotherapy, and biologic agents as well as novel biomarkers to prolong survival and improve quality of life. However, most chemotherapy therapeutic approaches fail to provide substantial efficacy benefits (22). The present systematic review and meta-analysis included 6 studies consisting of 3,286 PD-L1 positive patients, comparing the OS, PFS, ORR, SD, PD, and incidence of adverse events of PD-1/PD-L1 inhibitor or PD-1/PD-L1 inhibitor combined with chemotherapy vs. chemotherapy in PD-L1-positive GC/GEJC patients, aiming to provide more precise guidance for the clinical treatment of GC/GEJC patients.
The present study first analyzed the OS and PFS rates of PD1/PD-L1 inhibitors or PD1/PD-L1 inhibitors combined with chemotherapy vs. chemotherapy alone for advanced gastric or gastro-esophageal junction cancer. The pooled results showed that single-agent PD-1/PD-L1 inhibitor did not result in a relative improvement in OS compared with chemotherapy in the treatment of patients with advanced GC/GEJC, which was consistent with the conclusions of Wang et al (11). Conversely, in the analysis of PFS, the JAVELIN Gastric 300 study (18) reported that the PFS of PD-1/PD-L1 inhibitors for advanced GC/GEJC was significantly lower than that of chemotherapy. Notably, Wang et al (11) also reported that GC/GEJC patients treated with PD-1/PD-L1 inhibitors had an improved PFS compared with chemotherapy. These data suggest that PD-1/PD-L1 antagonists may not be superior to chemotherapy in the treatment of patients with advanced GC/GEJC. However, insufficient clinical trials analyzing PFS made it impossible to obtain objective evidence-based medical evidence. In addition, the results showed that the OS and PFS of PD-1/PD-L1 inhibitors combined with chemotherapy were both significantly longer than that of chemotherapy alone.
Next, the analysis of OS, PFS, ORR, SD, and PD, as well as the incidence of adverse events of PD-1/PD-L1 inhibitors or PD-1/PD-L1 inhibitors combined with chemotherapy vs. chemotherapy alone in PD-L1 positive GC/GEJC patients were considered. Pooled results suggested that single-agent PD1/PD-L1 inhibitor did not improve the ORR of patients with PD-L1 positive cancer compared to chemotherapy. However, single-agent PD1/PD-L1 inhibitor did lower the SD rate and increase the PD rate, regardless of CPS level. This showed that the single use of PD1/PD-L1 inhibitors had no advantage in the short-term efficacy of the tumor; that is, in the short term, the disappearance or regression of the tumor, compared with chemotherapy did not notably differ. Encouragingly, in the evaluation of long-term efficacy, the findings found that the OS of PD-1/PD-L1 inhibitors in patients with PD-L1 CPS≥1, 5, and 10 were all significantly longer than that of chemotherapy. Additionally, the HRs of patients with PD-L1 CPS≥1, 5, and 10 were 0.85, 0.72, and 0.69, respectively. Despite the lack of statistical evidence for differential analysis, it is hypothesized that OS may be prolonged with increased PD-L1 expression. Additionally, the pooled results showed that the incidence of adverse events of PD-1/PD-L1 inhibitors in patients with PD-L1 positive was significantly lower than that of chemotherapy. Therefore, it can be suggested that anti-PD1/PD-L1 treatment was safer than chemotherapy.
As for the comparison of PD-1/PD-L1 inhibitor combined with chemotherapy vs. chemotherapy alone in PD-L1 positive GC/GEJC patients, the pooled results first showed that the ORR of PD-1/PD-L1 inhibitors combined with chemotherapy in patients with PD-L1 CPS≥1 was significantly higher than that of chemotherapy alone. In addition, the results of CheckMate 649 (20) and KEYNOTE-062 (18) showed that patients treated with PD-1/PD-L1 inhibitor combined with chemotherapy had a significantly higher ORR than chemotherapy alone in patients with PD-L1 CPS≥5 and PD-L1 CPS≥10. The results of CheckMate 649 (20) showed that there was no significant difference in the SD and PD rates of patients with PD-L1 CPS≥5 between the patients treated with PD-1/PD-L1 inhibitor combined with chemotherapy vs. chemotherapy alone. Although the lack of more clinical trial results challenges the objectivity of the SD and PD rate analysis, the pooled results still suggest that PD-1/PD-L1 inhibitor combined with chemotherapy had better short-term efficacy than chemotherapy alone in patients with PD-L1 positive cancer. Furthermore, the findings suggest that the OS and PFS of PD-1/PD-L1 inhibitors combined with chemotherapy in patients with PD-L1 CPS≥1, 5, and 10 were all significantly longer than that of chemotherapy alone. It can also be speculated that with the increase in PD-L1 expression, the survival advantage of combination therapy over chemotherapy alone may become more apparent.
The present study has some limitations. First, there was heterogeneity in the research in some of the indicators in this study; due to the small number of included studies, it was not possible to identify the source of heterogeneity. Second, due to the lack of relevant clinical trials, some of the results can only be systematically reviewed and not meta-analyzed to obtain more objective evidence-based medical evidence. Third, the lack of clinical trials makes it impossible to assess the publication bias of this study. Future studies need to supplement the assessment of publication bias based on the inclusion of more clinical trials.
In conclusion, single agent of PD-1/PD-L1 inhibitor alone or in combination with chemotherapy significantly prolonged the survival of patients compared with chemotherapy alone with fewer adverse effects. However, the degree of CPS may affect efficacy, but further investigation is needed to verify this.
Supplementary Material
Supporting Data
Acknowledgements
Not applicable.
Funding
This study was supported by the Joint Funds for the innovation of Science and Technology, Fujian province (grant no. 2019QH1120).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SQS wrote the manuscript and analyzed the data. SQS confirms the authenticity of the raw data and has read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
GC/GEJC |
gastric or gastro-esophageal junction cancer patients |
|
RCT |
randomized controlled trial |
|
ICI |
immune checkpoint inhibitor |
|
PD-1 |
programmed cell death 1 |
|
PD-L1 |
programmed cell death ligand 1 |
|
CPS |
combined positive score |
|
OS |
overall survival |
|
PFS |
progression free-survival |
|
ORR |
objective response rate |
|
SD |
stable disease |
|
PD |
progressive disease |
|
CI |
confidence interval |
|
RR |
risk ratio |
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