PuSH - Publication Server of Helmholtz Zentrum München: FOLFIRI with cetuximab or bevacizumab in RAS wild-type metastatic colorectal cancer: Refining first-line treatment selection by combining clinical parameters: A post hoc analysis of the randomized open-label phase III trial FIRE-3/AIO KRK0306.

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Holch, J.W.* ; Ohnmacht, A. ; Stintzing, S.* ; Heinrich, K.* ; Weiss, L.* ; Probst, V.* ; Stahler, A.* ; Fischer von Weikersthal, L.* ; Decker, T.* ; Kiani, A.* ; Kaiser, F.* ; Heintges, T.* ; Kahl, C.* ; Kullmann, F.* ; Link, H.* ; Höffkes, H.G.* ; Moehler, M.* ; Modest, D.P.* ; Menden, M.P. ; Heinemann, V.*

FOLFIRI with cetuximab or bevacizumab in RAS wild-type metastatic colorectal cancer: Refining first-line treatment selection by combining clinical parameters: A post hoc analysis of the randomized open-label phase III trial FIRE-3/AIO KRK0306.

Eur. J. Cancer 220:115388 (2025)

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BACKGROUND: Primary tumor sidedness (PTS) with discrimination of left-sided (LC) and right-sided tumors (RC) guides patient selection for targeted first-line therapy in RAS wild-type (RAS-WT) metastatic colorectal cancer (mCRC). This study assessed the hypothesis whether considering PTS with additional clinical parameters better predicts the treatment benefit of targeted first-line treatment. METHODS: In FIRE-3, first-line treatment with folinic acid, fluorouracil and irinotecan (FOLFIRI) plus cetuximab (FOLFIRI/Cet) was compared to FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC and unresectable metastasis. We evaluated whether combining PTS with number of metastatic sites (NOM), liver-limited disease status (LLD), age, sex, or carcinoembryonic antigen level (CEA) better predicts treatment benefit regarding overall survival (OS). Here, Cox regression models with second-order interactions were applied. Further, the results were validated by policy learning and Lasso regression analysis. FINDINGS: Among 400 RAS-WT mCRC patients, combining PTS with LLD status in a Cox regression model outperformed PTS alone for predicted treatment benefit (P = 0·005; c‑index=0·603). Significant OS benefit from FOLFIRI/Cet over FOLFIRI/Bev was observed in LC/non-LLD patients (HR=0·62; 95 %-confidence interval [CI]=0·46-0·82; P = 0·002), but mitigated in LC/LLD patients (HR=0·83; 95 %-CI=0·53-1·29; P = 0·400). In RC/non-LLD patients, FOLFIRI/Bev demonstrated a significant OS advantage over FOLFIRI/Cet (HR=2·09; 95 %‑CI=1·20-3·63; P = 0·010). However, RC/LLD patients showed potential benefit from FOLFIRI/Cet, though not statistically significant (HR=0·59; 95 %-CI=0·25-1·39; P = 0·218). INTERPRETATION: Incorporating PTS and LLD status might improve selection of targeted first-line treatment in RAS-WT mCRC patients. FOLFIRI/Cet appears to be particularly beneficial for LC/non-LLD patients with mitigated benefit in patients with LC/LLD. In contrast, FOLFIRI/Bev is significantly favoured over FOLFIRI/Cet in patients with RC/non-LLD. Notably, RC/LLD patients may still benefit from anti-EGFR therapy despite right-sided primary tumor. These results are hypothesis-generating and warrant further validation.

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