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

Abstract

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

Patients and methods: Patients had operable, computed tomography-predicted stage T3-4, N0-2, M0 colon adenocarcinoma. KRAS-wt patients allocated to NAC could optionally be sub-randomised 1 : 1 to FOLFOX ± panitumumab during the preoperative phase. RAS/BRAF were tested by next-generation sequencing; and epiregulin (EREG)/amphiregulin (AREG) by RNAseq. The primary endpoint was time to recurrence (TTR) in RAS/BRAF-wt patients; secondary endpoints included safety, histological down-staging, disease-free survival (DFS), colon cancer-specific survival (CCSS), overall survival (OS) and impact of primary tumour 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% versus 21%, hazard ratio = 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 tumour (tumour regression grade 1-3 16% versus 22%, P = 0.27). FOLFOX plus panitumumab was associated with higher rates of grade 3 diarrhoea (8% versus 3%) and rash (22% versus 2%).

Conclusion: This exploratory analysis from a randomised phase II study shows a non-significant improvement in TTR from the addition of neoadjuvant panitumumab to perioperative 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.

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