Gastric cancer (GC) is the fifth most common cancer worldwide, with an estimated 1.1 million new cases and 769,000 deaths in 2020 (Sung et al., 2021). For decades, fluoropyrimidine and platinum-based doublet chemotherapy has been the most frequently used first-line treatment for patients with HER-2-negative advanced GC (Alsina et al., 2023). During this timeframe, the median overall survival (OS) was unsatisfactory, with a median OS less than 12 months (Wagner et al., 2017). Recently, the advent of immune checkpoint inhibitors has significantly transformed the treatment for advanced GC (Zhang et al., 2022; Wang et al., 2023). The ATTRACTION-02 study found that the Programmed Cell Death Protein-1 (PD-1) inhibitor nivolumab resulted in prolonged OS in patients with advanced GC refractory to standard treatment (Kang et al., 2017). In the first-line setting, the CheckMate 649 study has demonstrated that the addition of chemotherapy significantly improved OS and progression-free survival (PFS) in patients with treatment-naïve advanced GC, leading to the US Food and Drug Administration (FDA)’s approval of nivolumab plus chemotherapy for the first-line treatment of advanced GC (Janjigian et al., 2021; FDA, 2025). Additionally, several randomized clinical trials (RCTs) have shown the superior efficacy of anti-PD-1 therapy plus chemotherapy versus chemotherapy alone in patients with treatment-naïve advanced GC (Kang et al., 2022; Moehler et al., 2023; Rha et al., 2023; Xu et al., 2021).

Despite the partial success of anti-PD-1–chemotherapy combinations in first-line advanced GC, 40%–50% of patients still do not respond and median OS improvements remain modest (about 2–3 months), highlighting the urgent need for effective biomarkers to guide patient selection, with PD-L1 CPS being more predictive than TPS. (Janjigian et al., 2021; Kang et al., 2022; Rha et al., 2023; Havel et al., 2019; Wang and Xu, 2023; Martin and Märkl, 2019; Kulangara et al., 2019). Although the CheckMate 649 trial revealed that patients with high PD-L1 expression (CPS≥5) benefitted better from the addition of nivolumab to chemotherapy than those with low PD-L1 expression (CPS<5) (FDA, 2025). However, the FDA’s approval of nivolumab plus chemotherapy for first-line advanced gastric cancer did not mandate PD-L1 testing (FDA, 2025), meaning many patients with low PD-L1 expression (CPS<5) may receive a treatment not specifically suited for them. Given the strong correlation between PD-1 blockade efficacy and PD-L1 expression levels shown in CheckMate 649 and other studies, identifying patients most likely to benefit from this combination therapy is crucial. Moreover, most clinical trials have not reported detailed outcomes or Kaplan-Meier (KM) survival curves for the PD-L1-low subgroup. This data gap makes it difficult to draw clear conclusions about the potential benefits or lack thereof for patients with low PD-L1 expression. Without reliable evidence for this subgroup, clinicians face significant uncertainties in decision-making, especially regarding whether to use PD-1 blockade plus chemotherapy for patients with CPS<5. This missing data also hampers the development of more personalized treatment strategies and may lead to unnecessary treatment-related toxicities and costs for patients unlikely to benefit.

To address this issue, we first searched for and collected published RCTs studying PD-1 blockade plus chemotherapy versus chemotherapy alone in treatment-naïve advanced GC, reconstructed individual patient-level data (IPD) from the previously reported KM curves of the all-randomized population and the PD-L1-high subgroup, and further derived the IPD of the PD-L1-low subgroup based on the reconstructed IPD. We then performed a pooled analysis of these data and assessed whether the treatment effect of PD-1 blockade plus chemotherapy versus chemotherapy alone differed between PD-L1-high and PD-L1-low subgroups. The pipeline of analyses performed in this study is shown in Figure 1.

Recently, multiple RCTs have shown that PD-1 blockade plus chemotherapy outperforms chemotherapy alone as a first-line therapy for patients with advanced GC, especially for those with high PD-L1 expression levels (Janjigian et al., 2021; Kang et al., 2022; Moehler et al., 2023; Rha et al., 2023; Xu et al., 2021; Shitara et al., 2020). However, most RCTs did not report survival data or KM curves for patients with low PD-L1 expression; therefore, it remains unclear whether the treatment effect in the all-randomized population is largely driven by that in the CPS≥5 subgroup (Yoon et al., 2022). Therefore, we reconstructed the IPD of the CPS≥5 and CPS<5 subgroups from two large-scale RCTs: CheckMate 649 and ORIENT-16. The reconstructed data revealed that, compared to the CPS≥5 subgroup, the treatment effect in the CPS<5 subgroup was significantly less pronounced in terms of overall survival (OS) and progression-free survival (PFS).

These findings provide robust evidence for the utility of the PD-L1 CPS as a biomarker for predicting the efficacy of PD-1 blockade plus chemotherapy in patients with treatment-naïve advanced GC. Therefore, it is recommended that the PD-L1 CPS be routinely tested prior to first-line therapy for patients with advanced GC. For patients with CPS≥5, PD-1 blockade in combination with chemotherapy should be considered the standard first-line treatment. In contrast, for those with a CPS<5, the lack of efficacy of adding PD-1 blockade to chemotherapy should be part of the informed discussion of treatment options with patients, Decisions regarding the use of anti-PD-1 therapy should be made on a case-by-case basis, taking into account each patient’s specific circumstances, such as socioeconomic status, alternative therapeutic options, and predisposition to immune-related adverse events.

In the subgroup analyses of CheckMate 649 and KEYNOTE-859, PD-1 blockade plus chemotherapy did not improve OS compared to chemotherapy alone in patients with CPS<1 (HR = 0.95 and 0.92, respectively) (Janjigian et al., 2021; Rha et al., 2023). Therefore, determining whether patients with CPS 1–4 still benefit from PD-1 blockade plus chemotherapy is of interest. In a recent study, Zhao et al. reconstructed IPD from CheckMate 649 and found that the addition of nivolumab to chemotherapy did not improve OS and PFS in patients with CPS 1–4 (HR = 0.95 and 0.96, respectively) (Zhao et al., 2022b), further suggesting that neither the CPS<1 nor CPS 1–4 subgroups benefit from this combination treatment. Subgroup analysis of CheckMate 649 showed that high microsatellite instability and high tumor mutational burdens were associated with greater survival benefits from PD-1 blockade plus chemotherapy versus chemotherapy alone (Janjigian et al., 2021; Lei et al., 2022); and whether the incorporation of these features with PD-L1 expression can further improve patient selection is worthy of further investigation (Chen et al., 2023). These results have important implications for clinical practice, suggesting that for patients with CPS<5, PD-1 blockade plus chemotherapy may not be the optimal choice. Clinical decisions should take into account individual patient characteristics, such as certain tumor biology features, including microsatellite instability status and tumor mutational burden levels, as well as features of the immune microenvironment, to more precisely select appropriate treatment strategies.

Our findings highlight the urgent need to need to develop efficacious therapeutics to improve the survival of patients with PD-L1-low advanced GC. Some combination regimens have shown promising preliminary results. For instance, a recent phase 2 study investigated the efficacy of regorafenib, a potent inhibitor of angiogenic and oncogenic kinases, in combination with the PD-1 inhibitor camrelizumab and chemotherapy in patients with treatment-naïve advanced GC, which revealed a favorable objective response rate of 61.5% in the CPS<1 subgroup (Peng et al., 2021). The upregulation of DKK1 impairs CD8⁺ T cell functions and promotes MDSC-mediated immunosuppression (Shi et al., 2022). In a recent phase 2 study, the combination of a DKK1 inhibitor with the PD-1 inhibitor tislelizumab and first-line chemotherapy yielded a remarkable objective response rate of 100% in patients with DKK1-high and PD-L1-low GC (Klempner et al., 2022). These regimens warrant further confirmatory investigation, and future research should explore the role of these biomarkers in patient selection and develop more personalized treatment options for patients with PD-L1-low expression.

This study has some limitations. First, we analyzed the reconstructed IPD rather than the original IPD. However, the method used for IPD reconstruction has been validated in previous studies with excellent accuracy and reproducibility (Wang et al., 2021). Second, PD-L1 CPS was not a prespecified stratification factor in either CheckMate 649 or ORIENT-16; therefore, there may be confounding factors between the treatment arms in both trials. However, the findings regarding the treatment effect in the CPS<5 subgroup were consistent with those of the CheckMate 649 and ORIENT-16. Moreover, different IHC assays (28–8 and Dako 22C3) were used to assess PD-L1 expression in CheckMate 649 and ORIENT-16, which may have led to between-heterogeneity and posed challenges to the pooled analysis. However, good concordance in identifying PD-L1-high and PD-L1-low cases between the 28-8 and Dako 22C3 assays was reported in a previous GC study (Ahn and Kim, 2021), suggesting the potential interchangeability of these two PD-L1 assays (Wang et al., 2022).

In summary, this pooled analysis of two large-scale RCTs in treatment-naïve advanced GC, CheckMate 649 and ORIENT-16, demonstrated that the efficacy of PD-1 blockade plus chemotherapy versus chemotherapy alone significantly attenuated in the CPS<5 subgroup than in the CPS≥5 subgroup. Since the added value of anti-PD-1 therapy to first-line chemotherapy is minimal in patients with a CPS<5, the use of PD-1 inhibitors should be individualized for this patient subset. In addition, major efforts should be made to develop highly efficacious therapeutics beyond the anti-PD-1-chemotherapy combination to improve the survival outcomes of these patients.