The Vascular Endothelial Growth Factor-A121/Vascular Endothelial Growth Factor-A165 Ratio as a Predictor of the Therapeutic Response to Immune Checkpoint Inhibitors in Gastric Cancer

Background/objectives: The response rate to immune checkpoint inhibitor (ICI) therapy is limited. Further, there is a need to discover biomarkers to predict therapeutic efficacy. The vascular endothelial growth factor (VEGF) is strongly associated with intra-tumoral immunity; however, its utility as a marker remains unknown. Therefore, our objectives were to examine the isoforms of VEGF and determine whether VEGF levels predict ICI efficacy.

Methods: Levels of VEGF isoforms VEGF-A121 and VEGF-A165 were measured in stored serum samples obtained from 30 patients with advanced or recurrent gastric cancer who received nivolumab monotherapy at Kagoshima University Hospital, and the association with prognosis and treatment efficacy was retrospectively analyzed.

Results: The serum levels of the total VEGF, VEGF-A121, and VEGF-A165 were not significantly associated with prognosis. However, the ratio of VEGF-A121/VEGF-A165 (VEGF-A121/165) exhibited a statistically significant (p = 0.0088) difference in progression-free survival (PFS) with the low-ratio group having a 67-day prolonged median PFS time. Under univariable analysis, only VEGF-A121/165 values exhibited reduced progression-free survival with statistical significance. When comparing treatment responses in the low (n = 15) and high (n = 15) serum VEGF-A-121/165 groups, RECIST evaluation was 3 to 0 for complete response (CR), 2 to 0 for partial response (PR), 3 to 2 for stable disease (SD), and 3 to 10 for progressive disease (PD). Patients with clinically unsettled PR or SD were classified as non-CR/non-PD (4 vs. 3), with a disease control rate of 80% vs. 33%.

Conclusions: The serum VEGF-A121/165 ratio may represent a new, easily measured biomarker for predicting the therapeutic response to ICIs.