Samaille, Thomas, Raeisi, Morteza, Cohen, Romain, Shi, Qian, Yoshino, Takayuki, Zalcberg, John R., Adams, Richard  ORCID: https://orcid.org/0000-0003-3915-7243, Cremolini, Chiara, Grothey, Axel, Mayer, Robert J., Chibaudel, Benoist, de Gramont, Aimery and Andre, Thierry
2026.
Prognostic value of liver metastases and KRAS mutations in patients with metastatic colorectal cancer: A pooled analysis of third-line placebo-controlled trials from the ARCAD CRC database.
Clinical Colorectal Cancer
10.1016/j.clcc.2026.05.007
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Abstract
Background: KRAS mutations in metastatic colorectal cancer (mCRC) are a factor of poor prognosis, partly because of associated resistance to anti-EGFR therapies. Liver metastases (LM) were also described as a factor of poor prognosis. This study aims to compare the outcomes of patients treated in third-line setting with placebo or Trifluridine/Tipiracil or regorafenib (TToR) and to assess the impact of LM and KRAS mutations on prognosis. Methods: Data were pooled from five placebo-controlled randomized trials of the ARCAD CRC database (CORRECT, RECOURSE, CONCUR, TERRA, and J003). Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier estimates and adjusted Cox models. Interaction tests were conducted to evaluate the combined effects of LM and KRAS mutations. Results: The study included 2,207 patients: 1,464 treated with TToR and 743 with placebo. 73% had LM and 51% had KRAS mutations. Patients with LM had significantly lower OS and PFS compared to those without LM in both TToR (HR=0.48 for OS; HR=0.55 for PFS) and placebo groups (HR=0.49 for OS; HR=0.58 for PFS). Patients with KRAS mutations had worse OS compared to wild-type KRAS in TToR-treated patients (HR=1.18), but not in placebo-treated patients (HR=1.03). Interaction tests were not significant between LM and KRAS status in both TToR and placebo groups. Conclusions: In patients with refractory mCRC, LM are a major poor prognosis factor, while KRAS mutations have no clinically relevant additive impact. These results underline the importance to stratify clinical trials on liver metastases rather than on RAS status in latter lines. Micro Abstract: In this pooled analysis of five placebo-controlled third-line mCRC trials, patients receiving trifluridine/tipiracil or regorafenib (n = 1,464) and those on placebo (n = 743) were evaluated for the prognostic impact of liver metastases (LM) and KRAS mutation status. LM were strongly associated with worse overall and progression-free survivals in both groups, while KRAS mutations had only a modest impact in trifluridine/tipiracil group and no significant interaction with LM. These results identify LM as a key prognostic factor in refractory mCRC and support stratifying future clinical trials by liver metastasis status rather than by RAS status.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | In Press |
| Schools: | Schools > Medicine Research Institutes & Centres > Centre for Trials Research (CNTRR) |
| Additional Information: | License information from Publisher: LICENSE 1: Title: This article is under embargo with an end date yet to be finalised. |
| Publisher: | Elsevier |
| ISSN: | 1533-0028 |
| Date of Acceptance: | 21 May 2026 |
| Last Modified: | 02 Jun 2026 11:15 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/187370 |
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