FOxTROT: Predictive effects of ERBB2 and ERBB3 on neoadjuvant panitumumab benefit in RAS/BRAF wild-type (-wt) locally advanced colon cancer (LACC).

Abstract

17Background: The FOxTROT trial reported advantages of neoadjuvant chemotherapy in LACC. An embedded phase II trial tested neoadjuvant FOLFOX+panitumumab vs FOLFOX and reported a trend towards a TTR benefit and a significant DFS and OS benefit from panitumumab (pan) in RAS/BRAF-wt patients (pts). ERBB2 and ERBB3 overexpression have putative negative and positive predictive effects on pan efficacy, respectively. Here we examined whether ERBB2/3 could improve patient selection for neoadjuvant pan. The additional impact of AREG/EREG expression (EGFR ligands) on pan efficacy was tested. Method(s): In FOxTROT, 279 pts with cT3-4 N0-2 M0, KRAS-wt LACC were randomized 1:1 to neoadjuvant FOLFOX+/-pan (6 weeks). All pts received FOLFOX post-op. 169 (61%) were confirmed RAS/BRAF-wt by NGS. ERBB2/3 and AREG/EREG were tested by RNAseq. Endpoints in this exploratory analysis were TTR, DFS, CCSS and OS. Result(s): 157 (93%) pts had available ERBB2/3 data. Median follow-up was 49 months. There were no associations between ERBB2/3 and stage, primary tumor location or MMR status. ERBB2 and ERBB3 were dichotomized using internally derived cut-points at the 50th and 40th percentiles respectively. Trends were consistent across all endpoints but strongest for DFS and OS, presented here. ERBB2 expression had no association with pan efficacy: trends towards benefit from FOLFOX+pan vs FOLFOX were similar in ERBB2-high (DFS: HR 0.45 [95% CI 0.17-1.19], P= 0.11; OS: 0.40 [0.12-1.38], P= 0.15) and -low pts (DFS: 0.60 [0.23-1.59], P= 0.30; OS: 0.24 [0.05-1.18], P= 0.08). ERBB3 enabled improved patient selection for neoadjuvant pan: ERBB3-high pts had significant benefit from FOLFOX+pan vs FOLFOX (DFS: 0.37 [0.14-0.97], P=0.04; OS: 0.16 [0.04-0.75], P=0.02), whereas ERBB3-low pts did not (DFS: 0.80 [0.29-2.22], P=0.67; OS: 0.71 [0.18-2.84], P=0.63). Tests for interaction did not reach significance in this subgroup analysis (DFS: Pinteraction=0.28; OS: Pinteraction=0.14). We have previously reported the ability of AREG/EREG to predict pan benefit in this dataset. ERBB3 strengthened the predictive effect of AREG/EREG: AREG, EREG and/or ERBB3-high pts had significant benefit from FOLFOX+pan vs FOLFOX (DFS: 0.38 [0.17-0.82], P=0.01; OS: 0.22 [0.07-0.67], P=0.008), while there was a trend towards disbenefit from pan in AREG, EREG and ERBB3-low pts (DFS: 2.58 [0.50-13.31], P=0.26; OS: 3.05 [0.32-29.35], P=0.33). Biomarker-treatment interactions were significant (DFS: Pinteraction=0.03; OS: Pinteraction=0.045). AREG/EREG and ERBB3 were not correlated, suggesting differing underlying biology. Conclusion(s): High ERBB3 expression predicted benefit from neoadjuvant FOLFOX+pan. ERBB3 augmented the known predictive effect of the EGFR ligands, AREG/EREG. Validation in a biomarker-enriched trial is warranted. There was no association between ERBB2 expression and pan efficacy. Clinical trial information: NCT00647530.