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.
ESMO Open. 2021 Apr;6(2):100062. doi: 10.1016/j.esmoop.2021.100062. Epub 2021 Mar 10.
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).
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.
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.
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.
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。
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。
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。
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。
