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Background <p>Second-line FOLFIRI plus ramucirumab (RAM) is one of standard treatments for metastatic colorectal cancer (mCRC) following progression on anti-EGFR therapy in <i>RAS</i> wild-type tumors. However, biomarkers for RAM efficacy remain unclear.</p> Objective <p>We conducted a translational analysis to evaluate the association of plasma biomarkers, including angiogenesis-related factors (AFs) and <i>RAS</i> mutations in circulating tumor DNA (ctDNA), with clinical outcomes.</p> Methods <p>This biomarker study was embedded within the JACCRO CC-16 trial, which enrolled patients with mCRC with <i>RAS</i> wild-type tumors receiving FOLFIRI plus RAM after anti-EGFR therapy. Plasma samples were collected at baseline, day 15, and post-treatment. <i>RAS</i> 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.</p> Results <p>Among 41 evaluable patients with <i>RAS</i> wild-type tumors, <i>RAS</i> mutations were detected in ctDNA at pretreatment in 44%. Patients without <i>RAS</i> mutations had significantly longer OS (28.1 versus 14.8 months; HR 0.30, <i>p</i> = 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, <i>p</i> = 0.049). IL-8 levels were significantly higher in patients with <i>RAS</i> mutations.</p> Conclusion <p><i>RAS</i> 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 <i>RAS</i> mutations and high IL-8 levels in this setting, suggesting a potential molecular–inflammatory interplay that contributes to resistance to VEGFR2 blockade.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月20日

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  • Yu Sunakawa,
  • Hisateru Yasui,
  • Manabu Shiozawa,
  • Hiroyuki Takeda,
  • Naoya Akazawa,
  • Tamotsu Sagawa,
  • Kazuhiro Shiraishi,
  • Takahisa Kyogoku,
  • Takashi Mine,
  • Yasuhiro Yuasa,
  • Takanori Watanabe,
  • Tatsuya Kinjo,
  • Yoshihiro Okita,
  • Hiroyuki Okuyama,
  • Satoshi Yuki,
  • Koki Miyakawa,
  • Ayana Kobara,
  • Shoko Yanaka,
  • Yukiko Abe,
  • Wataru Ichikawa,
  • Masashi Fujii,
  • Akihito Tsuji

摘要

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.