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. 2025 Nov 13:232:116105.
doi: 10.1016/j.ejca.2025.116105. Online ahead of print.

First-line treatment efficacy of anti-EGFR versus anti-VEGF antibodies in BRAFV600E-mutated metastatic colorectal cancer according to primary tumor sidedness: A pooled analysis of seven clinical trials performed in the first-line treatment of mCRC (German AIO Study Group)

Lena Weiss  1 , Sebastian Stintzing  2 , Dominik Paul Modest  3 , Arndt Stahler  3 , Ludwig Fischer von Weikersthal  4 , Anke Reinacher-Schick  5 , Thomas Decker  6 , Victoria Probst  7 , Kathrin Heinrich  7 , Ingo Schwaner  8 , Florian Kaiser  9 , Rudolf Pihusch  10 , Martin Fuchs  11 , Swantje Held  12 , Annabel Alig  3 , Birgit Gruenberger  13 , Gerald Werner Prager  14 , David Tougeron  15 , Julien Taieb  16 , Volker Heinemann  7
Affiliations

First-line treatment efficacy of anti-EGFR versus anti-VEGF antibodies in BRAFV600E-mutated metastatic colorectal cancer according to primary tumor sidedness: A pooled analysis of seven clinical trials performed in the first-line treatment of mCRC (German AIO Study Group)

Lena Weiss et al. Eur J Cancer. .

Abstract

Background: Both BRAFV600E-mutation and right-sided primary tumor location (PTL), have been associated with poor prognosis in metastatic colorectal cancer (mCRC). The present pooled analysis of individual patient data evaluates the efficacy of first-line chemotherapy combined with anti-EGFR- or anti-VEGF-directed therapy in BRAFV600E-mut mCRC together with PTL.

Methods: We conducted a pooled analysis of seven first-line AIO-studies (FIRE-3, FIRE-4, FIRE-4.5, CIOX, XELAVIRI, PANAMA, VOLFI) including patients with BRAFV600E-mut and RAS-wild-type mCRC.

Results: Among 209 evaluable patients, left-sided primary tumors (LSPT) were observed in 98 (46.9 %) compared to 111 (53.1 %) patients with right-sided primary tumors (RSPT). In the overall cohort, ORR was comparable (OR 0.85; 95 % CI 0.47-1.52), while median PFS was significantly shorter in patients receiving anti-EGFR-based therapy (HR 1.42; 95 % CI 1.05-1.91; P = 0.022), no major difference was observed with regard to OS (HR 0.96; 95 % CI 0.70-1.32; P = 0.80). Patients with LSPT showed comparable PFS (HR 0.98; 95 % CI 0.63-1.51), but a numerical OS benefit (HR 0.71; 95 % CI, 0.45-1.14) with anti-EGFR- compared to anti-VEGF-based therapy. This effect was observed independent of sex. In contrast, patients with RSPT showed both, inferior PFS (HR 2.09; 95 % CI 1.35-3.22; P < 0.001) and OS (HR 1.31; 95 % CI, 0.84-2.05). These effects were observed in male and female patients.

Conclusions: The present analysis of BRAFV600E-mut mCRC suggests a survival benefit from anti-EGFR- or anti-VEGF-directed antibodies in patients with LSPT. This effect was not observed in RSPT, where patients showed a clearly greater benefit from bevacizumab.

Keywords: Anti-EGFR monoclonal antibody; BRAFV600E-mutation; Bevacizumab; Cetuximab; Metastatic colorectal cancer; Panitumumab.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lena Weiss: Sebastian Stintzing Dominik Paul Modest Arndt Stahler Anke Reinacher-Schick Thomas Decker Consulting or Advisory Role - AstraZeneca/Daiichi Sankyo; Lilly; Novartis Victoria Probst Travel, Accommodations, Expenses - Nordic Bioscience Kathrin Heinrich Ingo Schwaner Travel, Accommodations, Expenses - Abbvie; BeiGene; Janssen Florian Kaiser Consulting or Advisory Role - Abbvie; Astellas Pharma; Elsevier; Gilead Sciences; GlaxoSmithKline; Janssen; MSD; Novartis; Pierre Fabre; Sanofi; Sanofi; Servier Annabel Alig Birgit Gruenberger Gerald Werner Prager Consulting or Advisory Role - Amgen; Arcus Biosciences; Astellas Pharma; AstraZeneca; Bayer; BMSi; Merck Serono; MSD; Pierre Fabre; Roche/Genentech; SERVIER; Taiho Oncology; Takeda David Tougeron Julien Taieb Volker Heinemann All remaining authors declare no conflict of interest.

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