Nasopharyngeal carcinoma (NPC) is a common type of head and neck cancer with a skewed geographical, ethnic, and sex distribution. It is particularly prevalent in east and southeast Asia, where the highest age-standardized rates occur (1). According to GLOBOCAN 2020 data, approximately 133,354 new cases and 80,008 deaths from NPC were reported worldwide, of which 62,444 cases (46.8%) and 34,810 deaths (43.5%) were registered in China (2).

In the past decade, the global incidence and mortality rates of NPC have gradually declined (3), which could be attributable to lifestyle and environmental changes, the use of intensity-modulated radiation therapy, and the increasing application of adjuvant chemotherapy (4, 5). However, approximately 15%–30% of patients who develop recurrent or metastatic (R/M) NPC have a median overall survival (OS) of less than 2 years (6). The main challenges in treating these patients are overcoming chemo-resistance and reducing the risk of adverse events (7). Currently, immunotherapies, especially immune checkpoint inhibitors (ICIs), represent a promising strategy to resolve these problems and effectively treat R/M NPC patients.

ICIs, particularly anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies, which activate CD8-positive T cells and induce cancer cell mortality, have revolutionized the treatment of advanced cancers. The tumor microenvironment of NPCs, characterized by massive inflammatory and immune cell infiltration, allows NPC patients to fully benefit from ICI therapy. ICIs have emerged as effective treatment options for patients with refractory R/M NPC. More recently, the Food and Drug Administration (FDA) approved toripalimab as a treatment for R/M NPC to be used in combination with first-line chemotherapies or subsequent-line monotherapies (8). The National Comprehensive Cancer Network (NCCN) Guidelines version 2.2024 refer to cisplatin/gemcitabine combined with ICIs as the first-line treatment in the management of R/M NPC (9). However, only about 50% of patients respond to treatment, indicating the major challenge of identifying patients who are suitable for immunotherapy (6).

The level of PD-L1 expression is one of the most commonly explored predictive biomarkers for the success of ICIs. Previous studies have shown that higher PD-L1 expression levels are associated with a higher response rate and better survival in patients with advanced stage melanoma treated with ICIs (10–13). However, the predictive value of PD-L1 expression in NPC patients receiving ICIs remains controversial (14–16). Currently, there is no report of studies exploring the optimal cutoff value of PD-L1 expression to guide the clinical use of ICIs.

In this systematic review (SR), we comprehensively evaluated whether the expression level of PD-L1 influences the efficacy of anti-PD-1/PD-L1 monotherapy or combined therapy in NPC patients. Furthermore, subgroup analyzes were performed to assess and quantify the best cutoff value for PD-L1-positive tumors to guide future clinical practice.

The study was reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyzes (PRISMA) (17). The protocol for this SR and meta-analysis was registered in PROSPERO (no.: 495841).

To the best of our understanding, this is the first in-depth analysis of the predictive value of PD-1/PD-L1 status in clinical trials of immunotherapy and combined therapy for patients with advanced metastatic NPC. We comprehensively evaluated the correlation between different expression levels of PD-L1 and the ORR, PFS, and OS of R/M NPC patients, with data retrieved from 14 studies that included 1,434 patients in total. We aimed to determine the predictive value of PD-L1 and to identify an optimal PD-L1 cutoff value for the selection of patients likely to respond effectively to anti-PD-1/PD-L1 treatment.

The NCCN guidelines only recommend to use i) cisplatin/gemcitabine alone, or ii) cisplatin/gemcitabine plus toripalimab, or iii) cisplatin/gemcitabine plus the other PD-1 inhibitors (pembrolizumab or nivolumab) as first-line therapies for R/M NPC (9). In our analysis of the two included studies in the first-line setting, the use of ICIs could significantly improve PFS, regardless of the PD-L1 expression levels. Various ICI monotherapies (toripalimab, pembrolizumab or nivolumab) are recommended as subsequent-line therapy based on the PD-L1 expression levels in NCCN guidelines (9). The availability of ample subsequent-line treatment data gave us the opportunity to draw more precise and accurate conclusions. The most compelling finding in our study was that patients with PD‐L1 ≥ 1% who received ICI in the subsequent-line setting had significantly higher ORR than in those with PD-L1 < 1%. Our pooled results showed no significant difference between subgroups in analysis of PFS and ORR for PD-L1 cutoff value of ≥ 10%, and ≥ 25%. However, higher the PD-L1 expression, the higher the probability that the patient was able to achieve clinical benefit from ICIs in the subsequent-line setting.

ICIs, which reactivate immune response in the tumor by preventing immunosuppressive factors from binding to their ligands, have fewer side effects compared to chemotherapy (37). Side effects of ICIs are usually mild. The most common side effects include fatigue, itchy rash, and diarrhea (38). In addition, as ICIs may also activate autoreactive T cells, they increase the risk of immune-related adverse events (irAEs). In our included studies, irAEs such as hypothyroidism, aspartate aminotransferase(AST) level increased, and rash, were also frequently reported. The detail information is shown in Table 1 .

PD-L1, the most common immunosuppressive ligand, expressed on the tumor cell membrane combines with the PD-1 of tumor-infiltrating lymphocytes (TIL), contributing to tumor cell evasion from host immune system surveillance (39). In previous studies, high expression of PD-L1 appeared to adversely affect the survival outcomes of NPC patients. A meta-analysis involving 13 studies showed that PD-L1 over-expression in NPC was associated with a poor OS (hazard ratio = 1.48, 95% CI: 1.00–2.18, P = 0.049) (40). Another study discovered a significant correlation between high PD-L1 expression and a short PFS/OS (41). In contrast to previous studies that examined the prognostic value of PD-L1 in patients with NPC, our study evaluated the predictive value of PD-L1 expression for ICI therapy. The results provide evidence that PD-L1-positive patients received more benefit than PD-L1-negative patients at a PD-L1 cutoff value of 1%, which sets a preliminary framework for the R/M NPC patient population suitable for ICI treatment. However, as the cutoff values varied across articles, coupled with the fact that 1% was the most widely used expression-level cutoff for PD-L1 detection, more comprehensive studies on PD-L1 expression levels and ICI treatment efficacy are warranted to accurately validate these results.

Moreover, the PD-L1 expression on ICIs effect shows differences between first-line treatment and subsequent-line treatment, which may be caused by many factors. First, it is known that tumor progression is influenced by the tumor immune microenvironment, one of the important mechanisms is escape from immune surveillance with the selection of poorly immunogenic cells (42, 43). When the disease becomes refractory, the tumor microenvironment (TME) becomes more immune-suppressive. As a result, in the first-line setting when TME is still favorable, the immunotherapy-chemotherapy combination would improve survival regardless of PD-L1 expression. However, in subsequent line settings when TME becomes more immunosuppressive, only those with higher PD-L1 expression derived benefit from checkpoint inhibitors.

Second, all first-line trials evaluate the immunotherapy-chemotherapy combination while most later-line studies are using immunotherapy-alone (44). Chemotherapy could activate the T-cell priming and recruitment and works synergistically with immunotherapy, therefore patients who accept first-line treatment of immunotherapy-chemotherapy combination would respond to the treatment regardless of PD-L1 expression.

Though PD-L1 is the most widely studied biomarker for immunotherapy, additional biomarkers have been evaluated in several studies. For instance, a meta-analysis showed that patients with lower baseline plasma Epstein-Barr virus (EBV) DNA levels had a higher ORR and longer median PFS than those with higher EBV DNA levels, but tumor mutational burden (TMB) was not significantly correlated with clinical prognosis in NPC patients treated with ICIs (16). Furthermore, a statistical difference in PFS was observed between patients with tumors showing loss of HLA-A and/or HLA-B expression, and patients with tumors expressing both HLA-A and HLA-B in trial NCI-9742 (26). A single-arm phase II clinical trial indicated that, in R/M NPC patients, a strong suppression of TGFβ1 levels was associated with worse ORR and PFS (30).

With the development of bioinformatics and biotechnologies, novel forms of biomarkers, such as mutations/chromosomal abnormalities, have been made available that provide new perspectives on precision medicine. A recent clinical trial revealed that 11q13.3 focal amplification and high MRGPRF expression are predictive of poor outcomes following gemcitabine plus apatinib and toripalimab therapy, but in another study (POLARIS-02), the genomic alternations had no statistically significant associations with clinical efficacy (28, 33). However, our study of the PD-L1 biomarker has particular clinical relevance. PD-L1 status is readily used in clinical settings, as the technology is well established and inexpensive.

Our meta-analysis has several limitations. First, there was significant variability in the literature with regards to the prevalence and prognostic significance of PD-L1 expression in NPC patients, probably because of differences in the assays and scoring methods used across studies. However, in a cross-correlation study performed using different PD-L1 immunohistochemical assays, the JS311 antibody had similar PD-L1 staining patterns and scores to the antibodies 22C3, 28–8, and SP263 (45). The predictive utility of PD-L1 expression may also depend on its differential expression in immune cells versus tumor cells. Second, there was a lack of sufficient clinical trials of first-line treatments reporting OS and ORR in patients with different PD-L1 expression levels that could be included in our analysis. Despite the encouraging outcomes, the limited number of articles means we are skeptical of the conclusions, and more clinical trials focusing on ICI treatments are needed for further validation. Third, only three and two studies were included in the analysis of the PFS and OS, respectively, for the PD-L1 10% level. More clinical trials are needed to further enrich and validate our conclusions and better guide the use of clinical PD-L1 levels to maximize the benefits and reduce the side effects of ICIs. Lastly, most of the studies included were conducted in Asian populations, and the regional characteristics of NPC may limit the generalizability of our findings.

Our meta-analysis suggested that first-line immunotherapy could significantly improve PFS in R/M NPC patients, regardless of the PD-L1 expression levels. Nonetheless, positive PD-L1 expression (≥ 1%) might be a potential predictive biomarker for a better response to immunotherapy in R/M NPC patients in subsequent-line setting. The higher the PD-L1 expression, the higher the probability that the patient was able to achieve clinical benefit from subsequent-line treatment.

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

RX: Data curation, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing. CW: Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Writing – review & editing. KC: Investigation, Methodology, Validation, Writing – review & editing. CC: Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review & editing.