Neo-adjuvant FOLFOX with and without panitumumab for patients with KRAS-wt locally advanced colon cancer: results following an extended biomarker panel on the FOxTROT Trial embedded phase II population

J F Seligmann; D Morton; F Elliott; K Handley; R Gray; M Seymour; B Glimelius; L Magill; C J M Williams; P Quirke; D Bottomley; H M Wood; K Murakami; A D Beggs; N P West; FOxTROT Collaborative Group

doi:10.1016/j.annonc.2024.12.013

Neo-adjuvant FOLFOX with and without panitumumab for patients with KRAS-wt locally advanced colon cancer: results following an extended biomarker panel on the FOxTROT Trial embedded phase II population

Ann Oncol. 2025 Jan 11:S0923-7534(25)00002-X. doi: 10.1016/j.annonc.2024.12.013. Online ahead of print.

Authors

J F Seligmann¹, D Morton², F Elliott³, K Handley⁴, R Gray⁵, M Seymour³, B Glimelius⁶, L Magill⁴, C J M Williams³, P Quirke⁷, D Bottomley⁷, H M Wood⁷, K Murakami⁸, A D Beggs⁹, N P West⁷; FOxTROT Collaborative Group

Affiliations

¹ Division of Oncology, Leeds Institute of Medical Research, University of Leeds, UK. Electronic address: j.seligmann@leeds.ac.uk.
² University Hospital Birmingham, Birmingham, UK.
³ Division of Oncology, Leeds Institute of Medical Research, University of Leeds, UK.
⁴ University of Birmingham Clinical Trials Unit, Birmingham, UK.
⁵ Clinical Trials Service Unit, University of Oxford, Oxford, UK.
⁶ Uppsala University, Uppsala, Sweden.
⁷ Division of Pathology & Data Analytics, Leeds Institute of Medical Research, University of Leeds, UK.
⁸ Department of Pathology, Tohoku University, Sendai, Japan.
⁹ Institute of Cancer & Genomic Sciences, University of Birmingham, UK.

PMID: 39805350
DOI: 10.1016/j.annonc.2024.12.013

Abstract

Background: The FOxTROT trial has reported advantages of neoadjuvant chemotherapy (NAC) in locally advanced colon cancer (LACC). Here we present results of the embedded randomized phase II trial testing the addition of panitumumab to neoadjuvant FOLFOX compared with FOLFOX alone in RAS and BRAF-wild-type patients and with biomarker hyperselction.

Patients and methods: Patients had operable, CT-predicted stage T3-4, N0-2, M0 colon adenocarcinoma. KRAS-wt pts allocated to NAC could optionally be sub-randomized 1:1 to FOLFOX ± panitumumab during the pre-operative phase. RAS/BRAF were tested by NGS; EREG/AREG by RNAseq. Primary endpoint is time to recurrence (TTR) in RAS/BRAF-wt patients; secondary endpoints include safety, histological downstaging, disease-free survival (DFS), colon cancer-specific survival (CCSS), overall survival (OS), and impact of primary tumor location and EREG/AREG.

Results: In total 269 KRAS-wt patients were enrolled into the embedded phase II trial. Extended RAS/BRAF data were available for 232 (83%) patients; 22/232(9.5%) were RAS-mutant; 41/210(20%) were BRAF-mutant. Median follow up was 42 months. In 169 RAS/BRAF-wt patients there was a trend towards reduced recurrences with FOLFOX plus panitumumab compared with FOLFOX (12% vs 21%, HR=0.51, p=0.09); significant improvements were seen for DFS, CCSS and OS. Within the hyperselected EREG/AREG high group, there was significant reduction in recurrences with panitumumab. Panitumumab was not associated with increased pathological regression of the primary tumor (TRG 1-3 16% vs 22%,p=0.27). FOLFOX plus panitumumab was associated with higher rates of grade 3 diarrhoea (8% vs 3%,) and rash (22% vs 2%).

Conclusion: This exploratory analysis from a randomized phase II study shows a non-significant improvement in TTR from the addition of neoadjuvant panitumumab to peri-operative FOLFOX in RAS/BRAF-wt LACC. Hyperselection with EREG/AREG status was associated with increased efficacy. A dedicated prospective trial within a biomarker selected population is under development.

Clinical trials registration: ISRCTN87163246.

Keywords: Colon; amphiregulin; epiregulin; hyperselection; neoadjuvant; panitumumab.