Plasma Biomarkers Associated with Clinical Outcomes of FOLFIRI Plus Ramucirumab in RAS Wild-Type Metastatic Colorectal Cancer: The JACCRO CC-16AR Trial.

BACKGROUND

Second-line FOLFIRI plus ramucirumab (RAM) is one of standard treatments for metastatic colorectal cancer (mCRC) following progression on anti-EGFR therapy in RAS wild-type tumors. However, biomarkers for RAM efficacy remain unclear.

OBJECTIVE

We conducted a translational analysis to evaluate the association of plasma biomarkers, including angiogenesis-related factors (AFs) and RAS mutations in circulating tumor DNA (ctDNA), with clinical outcomes.

METHODS

This biomarker study was embedded within the JACCRO CC-16 trial, which enrolled patients with mCRC with RAS wild-type tumors receiving FOLFIRI plus RAM after anti-EGFR therapy. Plasma samples were collected at baseline, day 15, and post-treatment. RAS status in ctDNA was analyzed using BEAMing digital PCR; AFs were assessed using Luminex multiplex assay. Associations with progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were analyzed.

RESULTS

Among 41 evaluable patients with RAS wild-type tumors, RAS mutations were detected in ctDNA at pretreatment in 44%. Patients without RAS mutations had significantly longer OS (28.1 versus 14.8 months; HR 0.30, p = 0.0008) and higher ORR (14.3% versus 5.6%). Elevated baseline interleukin-8 (IL-8) was associated with poorer OS (16.5 versus 32.2 months; HR 1.99, p = 0.049). IL-8 levels were significantly higher in patients with RAS mutations.

CONCLUSION

RAS mutations in ctDNA and elevated IL-8 levels prior to second-line FOLFIRI plus RAM were associated with worse prognosis in mCRC. Moreover, our study demonstrated a significant association between RAS mutations and high IL-8 levels in this setting, suggesting a potential molecular-inflammatory interplay that contributes to resistance to VEGFR2 blockade.