Pembrolizumab plus chemotherapy improves ORR and OS in HER2-negative advanced gastric or gastroesophageal junction cancerPembrolizumab Plus Chemotherapy Improves Outcomes for Advanced Gastric Cancer

IntroductionPembrolizumab, an immune checkpoint inhibitor (ICI) targeting programmed cell death protein 1 (PD-1), has demonstrated significant clinical value in the treatment of human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (GC) and gastroesophageal junction cancer (GEJC). However, due to the relatively short duration of existing studies, inconsistent survival benefits among patients, and the lack of a standardized risk assessment system, its efficacy and safety still remain controversial.Materials and methodsBy systematically querying the following English-language databases, including PubMed, Embase, Web of Science, Scopus, Ovid, Cochrane Library, and CINAHL, along with the clinical trial registry ClinicalTrials.gov, studies reporting clinical efficacy and safety outcomes of pembrolizumab in patients with HER2-negative advanced GC or GEJC were identified. A meta analysis was subsequently conducted to pool objective response rate (ORR), duration of response (DoR), overall survival (OS), progression free survival (PFS), 12/24-month overall survival rate (OS-12/24), 12/24-month progression-free survival rate (PFS-12/24), as well as treatment related adverse events (TRAEs) and immune related adverse events (irAEs). Comprehensive subgroup analyses were further performed based on PD-L1 combined positive score (CPS), age, region, chemo backbone, and median follow-up.ResultsNine studies encompassing 3406 patients with HER2-negative advanced GC or GEJC were included. In randomized controlled trials (RCTs), pembrolizumab plus chemotherapy significantly improved ORR (OR 1.57, 95%CI:1.35-1.81) and OS (HR 0.82, 95%CI:0.75-0.89) compared with chemotherapy alone. Pooled median PFS from RCTs in the pembrolizumab arm was 6.77 months (95%CI:6.19-7.36) and from single-arm studies was 6.53 months (95%CI:4.59-9.31). Combination chemotherapy regimens showed numerically longer median OS (RCT combination subgroup median OS (mOS) 12.74 months vs monotherapy subgroup 10.60 months; single-arm combination cohort mOS 16.96 months). The most common TRAEs was decreased neutrophil count with an incidence of 24.9%, which was also the most common grade 3 or higher event. The most common irAEs was hypothyroidism (pooled incidence 21.4% in RCTs). Overall toxicity was manageable and safety outcomes were consistent across studies.ConclusionPembrolizumab in conjunction with chemotherapy confers substantial clinical advantage in the management of HER2-negative advanced GC or GEJC, as evidenced by improvements in ORR, OS, and PFS. In contrast, the therapeutic efficacy of pembrolizumab monotherapy appears constrained. Vigilant surveillance for heightened hematologic and gastrointestinal toxicities is warranted within routine clinical practice.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261298020.