Plasma PlGF as a Potential Biomarker in Ramucirumab-Based Second-Line Therapy for Advanced Gastroesophageal Adenocarcinoma: Exploratory Biomarker Analysis from the Phase II Part of the RAMIRIS Trial.

Antiangiogenic treatment with ramucirumab (RAM) is a standard second-line option in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. However, reliable biomarkers are lacking. The phase II RAMIRIS trial compared RAM plus paclitaxel with RAM plus FOLFIRI (5-fluororuracil, leucovorin and irinotecan) in this setting. We present the exploratory biomarker analysis evaluating placental growth factor (PlGF), carbonic anhydrase IX (CAIX), and tryptase. Plasma samples from 99 patients enrolled in RAMIRIS were collected at predefined timepoints (baseline, Cycle 2 Day 1, and Cycle 4 Day 1). PlGF, CAIX, and tryptase were quantified by ELISA. Associations with progression-free survival (PFS) and overall survival (OS) were analyzed using dichotomized biomarker levels and Cox regression models. PlGF levels increased substantially under treatment, whereas CAIX showed a transient rise, followed by a slight decline, and tryptase remained stable. Elevated PlGF levels at baseline and early-treatment (c2d1) were associated with shorter OS in univariate analysis (baseline HRu = 1.75; p = 0.020; c2d1 HRu = 1.69; p = 0.054). After multivariate adjustment, the association remained directionally consistent; although statistical support was retained only for c2d1 (baseline HRm = 1.41, p = 0.198; c2d1 HRm = 1.85, p = 0.030). CAIX and tryptase showed no consistent associations with survival. Elevated PlGF-particularly its early increase during RAM-based therapy-was associated with shortened survival and may represent a dynamic marker of unfavorable prognosis in advanced gastric/GEJ adenocarcinoma. Given the exploratory nature of this analysis, these findings should be considered hypothesis-generating and require validation in independent biomarker-driven studies.