KEY TAKEAWAYS
- The FIRE-3 phase 3 trial aimed to investigate the enhanced patient selection for first-line RAS-WT mCRC treatment by assessing combined clinical biomarkers impact.
- Researchers concluded combining clinical biomarkers may enhance optimal patient selection for targeted first-line treatment in RAS-WT mCRC. Further validation is needed.
Julian Walter Holch and her team aimed to address optimal patient selection for first-line treatment in RAS-WT metastatic colorectal cancer (mCRC), emphasizing the role of primary tumor sidedness (PTS). Anti-EGFR is favored for left-sided mCRC (LC), while right-sided mCRCs (RC) are treated in combination with bevacizumab targeting vascular endothelial growth factor (VEGF). The research seeks to enhance patient selection by integrating clinical biomarkers beyond PTS, using the randomized phase III trial FIRE-3.
Researchers performed an inclusive analysis in the FIRE-3 trial, comparing first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) vs FOLFIRI plus bevacizumab (FOLFIRI/Bev) in RAS-WT mCRC patients. Beyond primary tumor sidedness (PTS), additional clinical biomarkers were assessed, including age, sex, liver-limited disease status (LLD), and baseline carcinoembryonic antigen serum level (CEA). Pairwise combinations of these biomarkers were analyzed using Cox regression models and model-based recursive partitioning with Weibull models to predict overall survival (OS) benefit for each treatment arm. Adjustments for multiple testing were made using Holm-Bonferroni correction, selecting the model with the best test statistics and P-value for further evaluations.
About 400 patients with RAS-WT mCRC were included in the study, where a predictive model combining primary tumor sidedness (PTS) and LLD status demonstrated the best accuracy in forecasting treatment outcomes for either FOLFIRI plus cetuximab (FOLFIRI/Cet) or FOLFIRI plus bevacizumab (FOLFIRI/Bev) arms (c-index = 0.603, P=0.005).
In patients with LC and non-liver-limited disease (non-LLD), FOLFIRI/Cet exhibited a significant survival benefit over FOLFIRI/Bev (HR 0.62, P=0.02). However, in LC patients with LLD, the difference in OS between FOLFIRI/Cet and FOLFIRI/Bev was not statistically significant (HR 0.83, P=0.40).
For patients with right-sided mCRC (RC), FOLFIRI/Bev demonstrated a significantly increased OS compared to FOLFIRI/Cet when patients suffered from non-LLD (HR 2.09, P=0.010). Conversely, in RC patients with LLD, FOLFIRI/Cet provided a survival benefit over FOLFIRI/Bev, although the difference was not statistically significant (HR 0.59, P=0.218).
The study concluded that integrating clinical biomarkers PTS and LLD status could enhance optimal patient selection for targeted first-line treatment in RAS-WT mCRC. Further validation in additional datasets is deemed necessary to validate these findings.
The study is sponsored by PD Dr. med. Volker Heinemann
Source: https://meetings.asco.org/abstracts-presentations/229437
Clinical Trial: https://clinicaltrials.gov/study/NCT00433927
Holch J W, Ohnmacht A, Stintzing S, et al. (2024). “Refining first-line treatment decision in RAS wildtype (RAS‑WT) metastatic colorectal cancer (mCRC) by combining clinical biomarkers: Results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).” Presented at ASCO-GI 2024 (Abstract 13).
