Immune checkpoint inhibitor plus chemotherapy versus chemotherapy alone in HER2-negative advanced gastric or gastroesophageal junction cancer: A systematic review and meta-analysis of randomized controlled trials.

person João Pedro Oliveira Federal Univerity of Rio de Janeiro, Rio De Janeiro, Brazil info_outline João Pedro Oliveira, Isadora Mamede Mendes da Silva, Caio Dabbous de Liz, Melissa Maia, Audrey Cabral Ferreira de Oliveira, Ana Caroline Fonseca Alves

Authors person João Pedro Oliveira Federal Univerity of Rio de Janeiro, Rio De Janeiro, Brazil info_outline João Pedro Oliveira, Isadora Mamede Mendes da Silva, Caio Dabbous de Liz, Melissa Maia, Audrey Cabral Ferreira de Oliveira, Ana Caroline Fonseca Alves Organizations Federal Univerity of Rio de Janeiro, Rio De Janeiro, Brazil, Federal University of São João Del-rei, Divinópolis, Brazil, DASA Oncologia, São Paulo, Brazil, Federal University of Ceará, Fortaleza, Brazil, Clion Clínica de Oncologia, Salvador, Brazil, Hospital São Domingos, São Luís, Brazil Abstract Disclosures Research Funding No funding sources reported Background: Synergistic effects of immune checkpoint inhibitors (ICI) and chemotherapy (CTX) have been documented, demonstrating promising efficacy across diverse cancer types. This report presents a meta-analysis aimed at assessing the effectiveness and safety profile of ICI plus CTX in patients diagnosed with Human Epidermal Growth Factor Receptor type 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) cancers. Methods: PubMed, EMBASE, Cochrane Central, and ASCO Abstracts databases were systematically searched for randomized controlled trials comparing PD-1 or PD-L1 inhibitors plus CTX with CTX alone in patients diagnosed with HER2-negative gastric or GEJ cancers. The assessed outcomes included Progression-Free Survival (PFS) and Overall Survival (OS), stratified by PD-L1 Combinated Positive Score (CPS) in tumors, as well as any Adverse Events (AE) and Treatment-Related Adverse Events (TRAE) graded as ≥ 3. Statistical analysis employed a random effects model in R version 4.3.2, with heterogeneity assessed using the I 2 statistic. Results: We conducted a meta-analysis comprising 6 RCTs involving 5,520 patients, among whom 2,766 received PD-1 or PD-L1 inhibitors in combination with chemotherapy. This combined regimen demonstrated significant improvements in both general PFS (HR 0.73; 95% CI [0.68; 0.78]; p < 0.01) and OS (HR 0.77; 95% CI [0.71; 0.84]; p < 0.01). Specifically, the combination of ICI with CTX exhibited enhanced PFS across various subgroups, including CPS ≥ 5 (HR 0.66; 95% CI [0.59; 0.75]; p < 0.01), CPS ≥ 10 (HR 0.75; 95% CI [0.65; 0.87]; p < 0.01), and CPS ≤ 1 (HR 0.75; 95% CI [0.69; 0.82]; p < 0.01). Median OS similarly reflected this improvement in CPS ≥ 5 (HR 0.71; 95% CI [0.63; 0.81]; p < 0.01) and CPS ≥ 10 (HR 0.66; 95% CI [0.57; 0.75]; p < 0.01) subgroups, albeit not in the CPS ≤ 1 subgroup (HR 0.91; 95% CI [0.77; 1.08]; p = 0.29). Furthermore, no significant differences were observed in the incidence of adverse events (AE) (RR 1.01; 95% CI [0.99; 1.04]; p = 0.221), while grade 3 or more treatment-related adverse events (TRAE) were slightly higher in the ICI plus CTX group (RR 1.15; 95% CI [1.01; 1.32]; p = 0.038). Conclusions: These findings indicate that the combination of ICI with CTX demonstrates superior efficacy compared to CTX alone in HER2-negative gastric or GEJ cancer. However, this efficacy trend is not maintained in patients with PD-L1 CPS ≤ 1 tumors. Moreover, the absence of differences in AE and the slight increase in TRAE in the ICI plus CTX group still further supports the safety profile of this combination therapy.