Seligmann J F, Morton D, Elliott F, Handley K, Gray R, Seymour M, Glimelius B, Magill L, Williams C J M, Quirke P, Bottomley D, Wood H M, Murakami K, Beggs A D, West N P
Division of Oncology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.
University Hospital Birmingham, Birmingham, UK.
Ann Oncol. 2025 May;36(5):520-528. doi: 10.1016/j.annonc.2024.12.013. Epub 2025 Jan 11.
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 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.
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%).
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.
FOxTROT试验报告了新辅助化疗（NAC）在局部晚期结肠癌（LACC）中的优势。在本文中，我们展示了一项嵌入式随机II期试验的结果，该试验在RAS和BRAF野生型（wt）患者中测试了在新辅助FOLFOX方案基础上加用帕尼单抗与单纯FOLFOX方案相比的疗效，并进行了生物标志物超选择。
患者患有可手术切除的、计算机断层扫描预测为T3 - 4期、N0 - 2期、M0期的结肠腺癌。分配接受NAC的KRAS野生型患者在术前阶段可选择按1:1随机分入FOLFOX ± 帕尼单抗组。通过下一代测序检测RAS/BRAF；通过RNAseq检测表皮调节素（EREG）/双调蛋白（AREG）。主要终点是RAS/BRAF野生型患者的复发时间（TTR）；次要终点包括安全性、组织学降期、无病生存期（DFS）、结肠癌特异性生存期（CCSS）、总生存期（OS）以及原发肿瘤位置和EREG/AREG的影响。
共有269例KRAS野生型患者入组了嵌入式II期试验。232例（83%）患者有扩展的RAS/BRAF数据；22/232例（9.5%）为RAS突变型；41/210例（20%）为BRAF突变型。中位随访时间为42个月。在169例RAS/BRAF野生型患者中，与FOLFOX相比，FOLFOX加帕尼单抗组有复发减少的趋势（12%对21%，风险比 = 0.51，P = 0.09）；DFS、CCSS和OS有显著改善。在超选择的EREG/AREG高表达组中，帕尼单抗使复发显著减少。帕尼单抗与原发肿瘤的病理退缩增加无关（肿瘤退缩分级1 - 3级：16%对22%，P = 0.27）。FOLFOX加帕尼单抗与3级腹泻（8%对3%）和皮疹（22%对2%）的发生率较高相关。
这项来自随机II期研究的探索性分析表明 RAS/BRAF野生型LACC患者在围手术期FOLFOX方案基础上加用新辅助帕尼单抗，TTR虽未显著改善，但EREG/AREG状态的超选择与疗效增加相关。一项在生物标志物选择人群中开展的专门前瞻性试验正在进行中。
