RAS 野生型转移性结直肠癌患者中，基线循环肿瘤细胞<3 的情况下，BRAF 和 PIK3CA 突变对 FOLFIRI 联合贝伐珠单抗或西妥昔单抗一线治疗疗效的影响：随机 II 期 VISNÚ-2 研究。
Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study.
机构信息
Medical Oncology, Hospital Clínico San Carlos, Instituto de Investigación Hospital Clínico San Carlos (IdISSC), CIBERONC, Madrid, Spain.
Medical Oncology, Hospital Universitario Gregorio Marañón, Madrid, Spain.
出版信息
ESMO Open. 2021 Apr;6(2):100062. doi: 10.1016/j.esmoop.2021.100062. Epub 2021 Mar 10.
BACKGROUND
We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC).
PATIENTS AND METHODS
VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m then 250 mg/m weekly) plus FOLFIRI [irinotecan 180 mg/m, leucovorin 400 mg/m, 5-fluorouracil 400 mg/m (bolus) then 2400 mg/m (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory.
RESULTS
Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups.
CONCLUSIONS
BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.
背景
我们研究了 BRAF 和 PIK3CA 突变状态对贝伐珠单抗或西妥昔单抗联合 5-氟尿嘧啶/亚叶酸钙和伊立替康（FOLFIRI）作为 RAS 野生型转移性结直肠癌（mCRC）一线治疗的疗效的影响。
方法
VISNÚ-2 是一项多中心、随机、二期研究。根据 BRAF/PIK3CA 状态（野生型与突变型）和受累器官数量（1 个与 >1 个），将 RAS 野生型 mCRC 且<3 个循环肿瘤细胞/7.5 ml 血液的患者分层，并分配至贝伐珠单抗（5 mg/kg，每 2 周）或西妥昔单抗（400 mg/m，然后每周 250 mg/m）联合 FOLFIRI[伊立替康 180 mg/m、亚叶酸钙 400 mg/m、5-氟尿嘧啶 400 mg/m（推注），然后 2400 mg/m（46 小时持续输注），每 2 周]。主要终点是无进展生存期（PFS）。所有分析均为探索性分析。
结果
共有 240 名 BRAF/PIK3CA 野生型（n=196）或 BRAF 和/或 PIK3CA 突变型肿瘤患者（n=44）入组。BRAF/PIK3CA 野生型和 BRAF/PIK3CA 突变型肿瘤患者的中位 PFS 分别为 12.7 和 8.8 个月[风险比（HR）1.22；95%置信区间（CI）0.80-1.85；P=0.3602]。在 BRAF 和/或 PIK3CA 突变型肿瘤患者中，BRAF/PI3KCA 突变型（n=8）、BRAF 突变型/PI3KCA 野生型（n=16）和 BRAF 野生型/PI3KCA 突变型（n=20）肿瘤患者的中位 PFS 分别为 2.8、8.8 和 15.0 个月（P=0.0002）。在 BRAF/PIK3CA 野生型和 BRAF/PIK3CA 突变型肿瘤患者中，贝伐珠单抗联合 FOLFIRI 与西妥昔单抗联合 FOLFIRI 的 PFS 相似[HR 0.99；95%CI 0.67-1.45；P=0.9486]和 HR 1.11；95%CI 0.53-2.35；P=0.7820]。两组最常见的 3/4 级治疗相关不良事件为中性粒细胞减少症、腹泻和乏力。
结论
BRAF/PIK3CA 状态影响 RAS 野生型 mCRC 患者的预后，但似乎不能帮助选择一线靶向治疗。
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