晚期胃癌一线免疫检查点抑制剂联合化疗预后因素及对二线化疗的影响

  目的  探索免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）联合化疗一线治疗晚期胃癌中肝转移状态、中性粒细胞与淋巴细胞比值（neutrophil-to-lymphocyte ratio，NLR）、体质量指数（body mass index，BMI）等因素与患者预后的关系，以及一线应用ICIs对二线化疗疗效的影响。  方法  收集解放军总医院2018年1月至2022年4月收治的胃癌患者临床资料，通过随访获得生存数据。采用Kaplan-Meier法进行生存分析，Log-rank检验比较胃癌一线程序性细胞死亡受体1（programmed cell death receptor- 1，PD-1）/程序性细胞死亡配体1（programmed cell death-ligand 1，PD-L1）抑制剂联合化疗中不同NLR、BMI和肝转移状态对预后的影响，以及一线应用PD-1/PD-L1抑制剂对二线化疗的影响。应用Cox回归模型确定影响患者生存的预后因素。  结果  共纳入晚期胃癌患者268例，在一线PD-1/PD-L1抑制剂联合化疗组中，总体客观缓解率（objective response rate，ORR）为46.5%，疾病控制率（disease control rate，DCR）为87.7%，中位无进展生存期1（median progression-free survival 1，mPFS1）为6.9（95%CI:6.0～7.8）个月。各亚组中，仅NLR<3组与NLR≥3组的中位PFS1有显著性差异（7.4 vs. 6.7个月，P=0.044）。多因素分析显示，基线NLR<3的患者在PD-1/PD-L1抑制剂联合化疗中能够获得更长的无进展生存期（HR=0.57，95%CI:0.36～0.90；P=0.015），而BMI、肝转移状态与患者预后无明显相关（均P＞0.05）。二线治疗中，一线PD-1/PD-L1抑制剂联合化疗进展后仅接受化疗患者的ORR（34.6% vs. 14.6%，P=0.025）和mPFS2（4.4 vs. 2.9个月，HR=0.54，95%CI:0.35～0.82；P=0.004）优于一、二线均仅应用化疗的患者，而DCR及中位总生存期（median overall survival，mOS）比较差异无统计学意义（均P>0.05）。  结论  在一线接受PD-1/PD-L1抑制剂联合化疗的晚期胃癌中，基线NLR<3的患者更易从免疫治疗中获益，而肝转移状态、BMI与患者的预后无明显相关。另外，一线应用含免疫治疗的方案可提高胃癌患者二线化疗的疗效，使其获得更长的无进展生存期。 

The prognostic factors of first-line immune checkpoint inhibitors combined with chemotherapy for advanced gastric cancer and its effect on second-line chemotherapy

  Objective  To determine the relationship between the presence of liver metastasis, neutrophil-to-lymphocyte ratio (NLR), body mass index (BMI), and the prognosis of patients with advanced gastric cancer treated with first-line immune checkpoint inhibitors (ICIs) and chemotherapy. It also evaluated the effectiveness of ICIs as first-line therapy for patients on second-line chemotherapy.   Methods  The clinical data of patients with gastric cancer admitted to Chinese PLA General Hospital from January 2018 to April 2022 were retrieved, and the survival data were obtained through follow-up. The Kaplan–Meier method was used to conduct the survival analysis, and a Log-rank test was performed to compare the effect of the different NLR, BMI, and liver metastasis statuses on the prognosis of patients with gastric cancer treated with first-line programmed cell death receptor-1 (PD-1)/programmed cell death-ligand1 (PD-L1) inhibitors and chemotherapy. The effect of administering first-line PD-1/PD-L1 inhibitors to patients on second-line chemotherapy was also evaluated. A Cox regression model was used to determine the prognostic factors affecting patient survival.   Results  A total of 268 patients with advanced gastric cancer were enrolled. In the first-line PD-1/PD-L1 inhibitors combined with chemotherapy group, the overall objective response rate (ORR) and disease control rate (DCR) were 46.5% and 87.7%, respectively, while the median progression-free survival 1 (mPFS1) was 6.9 months (95%CI: 6.0–7.8). In the subgroup analysis, there was a statistical difference in median PFS1 between the NLR<3 and NLR≥3 groups (7.4 vs. 6.7 months, P=0.044). On multivariate analysis, patients with a baseline NLR<3 achieved a longer PFS after therapy with PD-1/PD-L1 inhibitors and chemotherapy than those with NLR ≥3(HR=0.57, 95%CI: 0.36–0.90; P=0.015). Meanwhile, the BMI and liver metastasis status were not significantly associated with prognosis (P>0.05). Patients who received chemotherapy alone after a failed treatment with first-line PD-1/PD-L1 inhibitors and chemotherapy had a better ORR (34.6% vs. 14.6%, P=0.025) and mPFS2 (4.4 vs. 2.9 months, HR=0.54, 95%CI:0.35–0.82; P=0.004) than those who received chemotherapy only as first-line and second-line treatments. However, there were no significant differences in DCR and median overall survival (mOS) between the two groups (P>0.05).   Conclusions  Among advanced patients with gastric cancer who received first-line PD-1/PD-L1 inhibitors and chemotherapy, those with a baseline NLR<3 were more likely to benefit from immunotherapy. Meanwhile, liver metastasis status and BMI were not significantly associated with prognosis. Additionally, first-line treatment containing ICIs improved the efficacy of second-line chemotherapy in patients with gastric cancer, resulting in longer PFS.