Efficacy, Safety And Biomarker Analysis Of First-Line Immune Checkpoint Inhibitors Plus Chemotherapy Versus Chemotherapy Alone For Advanced Gastric Cancer: A Real-World Retrospective Study

Background:Gastric cancer is a common malignant digestive tract tumor,showing the characteristics of three "high" and three "low",which means high incidence,metastasis rate and mortality,low early diagnosis rate,R0 resection rate and five-year survival rate.The median overall survival(OS)of advanced gastric or gastroesophageal junction(GEJ)adenocarcinoma patients with first-line chemotherapy is less than 1 year,which is unsatisfactory.Recently,the introduction of immune-checkpoint inhibitors(ICIs)in clinical practice revamped the therapeutic strategies of many solid tumors,including gastric cancer.Although large randomized controlled trials(RCTs)have explored the efficacy and safety of first-line ICIs combined with chemotherapy versus chemotherapy for advanced gastric cancer,restricted extrapolation still exists due to inconsistent conclusions and strict inclusion criteria of RCTs,and RCTs also failed to address all the clinical issues such as biomarkers of efficacy prediction.Therefore,it is of great significance to conduct the real-world studies to compare the efficacy and safety of first-line ICIs combined with chemotherapy and chemotherapy alone for advanced gastric cancer.Objective:To evaluate the efficacy and safety of first-line ICIs combined with chemotherapy compared with chemotherapy alone in the real world patients with advanced gastric or gastroesophageal junction(GEJ)adenocarcinoma,and to explore related biomarkers affecting the efficacy of ICIs.Method:Patients with advanced gastric or GEJ adenocarcinoma who received first-line systemic treatment from multiple hospitals in Shandong Province from January 1,2018 to July 15,2022 were included and followed up until December 31,2022.The primary endpoint was progression-free survival(PFS),and the secondary study endpoint was OS,objective response rate(ORR),adverse events(AEs).An exploratory analysis of biomarkers associated with ICIs was conducted.Median PFS and OS were estimated using Kaplan-Meier methods,and the corresponding two-sided 95%confidence intervals were calculated using the Logrank method.We calculated hazard ratio(HR)and 95%confidence interval(CI)using univariable and multivariable Cox proportional hazards regression model to assess the differences between treatment groups in OS and PFS.Confounding factors were balanced by Inverse Probability of Treatment Weighting(IPTW).We investigated the genomic determinants of ICIs benefits using LASSO-COX regression method and developed a multi-gene score containing the most decisive prognosis-related genes to better predict the clinical outcomes of ICIs.Result:573 patients assessed for eligibility,including 523 patients with negative and unknown HER-2 expression.242 patients received chemotherapy alone and 281 received ICIs combined with chemotherapy.After balancing confounding factors by IPTW,ICIs combined with chemotherapy resulted in significant improvements in median OS[(18.30 vs.11.50 months,HR=0.44(95%CI:0.35～0.56)]and median PFS[9.57 vs.5.17 months,HR=0.42(95%CI:0.31-0.58)]versus chemotherapy alone in patients with HER-2 negative expression.Furthermore,ICIs combined with chemotherapy showed higher ORR than chemotherapy in total population(44.4%vs.34.7%,P=0.020).The incidence of grade 3-4 AEs was acceptable.In the subgroups with Programmed cell death-ligand 1(PD-L1)combined positive score(CPS)≥ 5,OS(HR=0.23,95%CI:0.06～0.96)and PFS(HR=0.09,95%CI:0.02～0.41)were significantly prolonged in the ICIs group.And ICIs combined with chemotherapy showed a significant improvement in OS in patients with PD-L1 CPS 1～4(HR=0.26,95%CI:0.08～0.84).Additional results showed significant improvement in OS(HR=0.37,95%CI:0.24～0.59),along with PFS(HR=0.40,95%CI:0.30～0.55)benefit,in patients with unknown CPS.An X-genes score was established based on the currently available DNA sequencing results of patients receiving ICIs combined with chemotherapy,of which the patients with high X-genes score accounted for 28%.Compared with the patients with low X-genes scores,PFS(HR=0.04,95%CI:0.01～0.30)was significantly longer in patients with high X-genes scores.Conclusions:In summary,ICIs in combination with chemotherapy showed a superior survival benefit and a tolerable safety profile,versus chemotherapy alone in previously untreated patients with advanced gastric or GEJ adenocarcinoma.In the ICIs combined with chemotherapy group,the PFS and OS were significantly prolonged in patients with PD-L1 CPS≥5 and unknown CPS,while the OS of patients with PD-L1 CPS 1-4 was significantly prolonged compared with chemotherapy alone.Multi-gene score is valuable for predicting the efficacy and prognosis of ICIs.