Comparison of Alpha-fetoprotein-positive and AFP-negative patients with advanced gastroesophageal junction or gastric cancer receiving immunotherapy: an analysis stratified by HER2 status.

[BACKGROUND] Immunotherapy-based regimens are standard first-line treatment for advanced gastroesophageal junction or gastric cancer (GEJ/GC), but their efficacy in alpha-fetoprotein-producing gastric cancer (AFPGC) remains unclear. We investigated the positivity of AFP influenced immunotherapy outcomes in advanced GEJ/GC, and examined whether this role is influenced by the patient's HER2 status. Secondly, we aim to assess the efficacy of anti-angiogenic agents within advanced AFP-positive GEJ/GC (AFP-GEJ/GC).

[METHODS] This retrospective study analyzed patients with advanced GEJ/GC receiving first-line immunotherapy, stratified by HER2 status. AFP-positive GEJ/GC was defined as a pretreatment serum AFP level ≥ 20 ng/mL or positive immunohistochemistry.

[RESULTS] In the overall population, the AFP-GEJ/GC group (n = 79) showed similar median progression-free survival (mPFS; 7.30 vs. 8.53 months; P = 0.42) and median overall survival (mOS; 21.80 vs. 19.70 months; P = 0.38) compared with the AFP-negative group (n = 478). In the HER2-negative cohort, 246 patients receiving standard two-drug chemotherapy combined with PD-1 inhibitors, the AFP-GEJ/GC group (n = 16) exhibited shorter mPFS (5.40 vs. 7.0 months; P = 0.02) and numerically worse mOS (11.40 vs. 16.80 months; P = 0.24) compared with the AFP-negative group (n = 230), despite similar objective response rates (ORRs 50.0% vs. 45.2%; P = 0.80) and disease control rates (DCRs 93.8% vs. 90.4%; P > 0.99). In the HER2-positive cohort, 107 patients receiving standard chemotherapy-based regimens, AFP-GEJ/GC (n = 14) showed numerically shorter mPFS (7.67 vs. 12.20 months; P = 0.60) but similar mOS (32.40 vs. 28.30 months; P = 0.38) versus AFP-negative group (n = 93). Notably, anti-angiogenic combination therapy did not statistically improve mPFS and mOS in AFP-GEJ/GC (n = 79). However, in the HER2-negative AFP-GEJ/GC group (n = 47), anti-angiogenic combination therapy (n = 31) was associated with a modestly longer mPFS (6.33 vs. 5.40 months; P = 0.02) and a numerical improved mOS (15.70 vs. 11.40 months; P = 0.15) compared with chemo-immunotherapy (n = 16).

[CONCLUSION] AFP positivity may indicate inferior efficacy of first-line chemo-immunotherapy in HER2-negative advanced GEJ/GC, and anti-angiogenic therapy warrants further evaluation as a potential strategy to improve outcomes.