Exploring potential biomarkers for FOLFIRI plus aflibercept as second-line treatment in patients with metastatic colorectal cancer.

Abstract

e15563 Background: FOLFIRI plus aflibercept (AFL) or bevacizumab (BEV) are significant therapeutic options for patients with metastatic colorectal cancer (mCRC) who have failed prior oxaliplatin-based chemotherapy. While accumulating evidence suggests an association between the tumor microenvironment, inflammation, and the prognosis of mCRC, biomarkers predictive of response to these chemotherapy regimens remain unknown. Studies have demonstrated that AFL exerts biological effects on macrophages within the tumor microenvironment. Methods: We conducted a multi-institutional retrospective biomarker study to analyze the relationship between CD68, CD163 (M2 macrophage), iNOS (M1 macrophage), and S100A4 expression in biopsy or surgical colon samples and the efficacy of FOLFIRI plus AFL (cohort A) or plus BEV (cohort B) in Japanese patients with mCRC who failed prior treatment with 5-fluorouracil + oxaliplatin + anti-EGFR agent. The primary outcome was overall response rate (ORR), and the secondary outcome was progression-free survival (PFS) according to the biomarker status. The expression of biomarkers was evaluated independently using immunohistochemical staining scores (IHCSS) by three investigators, including a board-certified pathologist. Statistical analyses were performed using the chi-square test and log-rank test. Results: Forty patients were enrolled in the study, including 19 in cohort A and 21 in cohort B. The median age was 67.5 years (range, 36-79), and 25 patients (62.5%) were male. The ORR was 26.3% in cohort A and 19.0% in cohort B, while median PFS was 11.1 months and 7.1 months, respectively. The percentage of cases that were positive for CD68, CD163, iNOS, and S100A4 were 78.9%, 26.3%, 57.9%, and 89.5% in cohort A, 42.9%, 38.1%, 81.0%, and 81.0% in cohort B. Among these biomarkers, none demonstrated a statistically significant association with outcomes, although the Kaplan-Meier plot and PFS at 6 and 12 months indicated a potential trend suggesting that patients with iNOS-negative tumors may exhibit improved PFS, particularly in cohort A (Table). Conclusions: In our biomarker study of patients with mCRC treated with FOLFIRI plus AFL or BEV, none of the analyzed biomarkers associated with macrophages in the tumor microenvironment demonstrated significant correlations with treatment outcomes. The observed trend towards improved PFS in iNOS-negative tumors treated with AFL merits further investigation, and larger prospective studies are necessary to elucidate this potential relationship. Progression-free survival at 6 and 12 months. Progression-free survival 6 months 12 months All iNOS pos (n=28 ) 46.4 % (13) 21.4 % (6) iNOS neg (n= 12) 83.3 % (10) 50.0 % (6) Cohort A iNOS pos (n= 11) 45.5 % (5) 18.2 % (2) iNOS neg (n= 8) 87.5 % (7) 50.0 % (4) Cohort B iNOS pos (n= 17) 47.1 % (8) 23.5 % (4) iNOS neg (n= 4) 75.0 % (3) 50.0 % (2)