Tryfonidis Konstantinos, Basaran Gul, Bogaerts Jan, Debled Marc, Dirix Luc, Thery Jean-Christophe, Tjan-Heijnen Vivianne C G, Van den Weyngaert Danielle, Cufer Tanja, Piccart Martine, Cameron David
EORTC-Headquarters, Medical Department, Brussels, Belgium.
Acıbadem Üniversitesi İç Hastalıkları/Tıbbi Onkoloji, Turkey.
Eur J Cancer. 2016 Jan;53:144-54. doi: 10.1016/j.ejca.2015.10.012. Epub 2015 Dec 24.
Preclinical data suggest that epidermal growth factor receptor (EGFR) inhibitors (e.g. gefitinib) can delay endocrine resistance in breast cancer. A double-blind, placebo-controlled, phase II trial investigated whether adding gefitinib (G) to anastrozole (A) would improve outcome in advanced breast cancer (ABC).
Postmenopausal pre-treated hormone receptor-positive ABC patients (locally recurrent or metastatic) were 1:1 randomized to A (1 mg/d) plus G 250 mg/d or plus placebo (P). Patients who had prior treatment with an aromatase inhibitor in metastatic setting or with trastuzumab, anti-EGFR or anti-VEGF agents were excluded. Treatment was given until disease progression, unacceptable toxicity or patient withdrawal. Progression-free survival (PFS) rate at 1 year was assessed according to Response Evaluation Criteria in Solid Tumours, version 1.0.
Of 108 planned patients, 71 were recruited (36 in A/G and 35 in A/P). The trial closed prematurely due to slow recruitment; 31 patients had prior chemotherapy and 53 prior endocrine therapy (all except one received tamoxifen); 60% in adjuvant and 16% in metastatic setting received tamoxifen; 59 patients had visceral disease. Median follow-up was 18 months. PFS rate at 1 year was 35% for A/G and 32% for A/P arm. Objective responses were six (22%) in the A/G and nine (28%) in the A/P arm. Median duration of response was 13.8 and 18.6 months in the A/G and A/P arms, respectively. Fatigue (35%), diarrhoea (31%), rash (32%), dry skin (27%), and arthralgia/myalgia (27%) were the commonest adverse events in the A/G arm.
This phase II study, although prematurely closed, did not show a signal that adding G to A improves PFS at 1 year and its use is not supported. Gastrointestinal and skin toxicities were more pronounced with G resulting in premature therapy interruption in almost 1 in 3 patients (ClinicalTrials.gov number, NCT00066378).
临床前数据表明，表皮生长因子受体（EGFR）抑制剂（如吉非替尼）可延缓乳腺癌的内分泌耐药。一项双盲、安慰剂对照的II期试验研究了在阿那曲唑（A）基础上加用吉非替尼（G）是否能改善晚期乳腺癌（ABC）的预后。
绝经后接受过治疗的激素受体阳性ABC患者（局部复发或转移）按1:1随机分为A（1毫克/天）加G 250毫克/天组或加安慰剂（P）组。排除既往在转移情况下接受过芳香化酶抑制剂治疗或接受过曲妥珠单抗、抗EGFR或抗VEGF药物治疗的患者。治疗持续至疾病进展、出现不可接受的毒性或患者退出。根据实体瘤疗效评价标准1.0版评估1年时的无进展生存率（PFS）。
计划入组108例患者，共招募了71例（A/G组36例，A/P组35例）。由于入组缓慢，试验提前结束；31例患者曾接受过化疗，53例曾接受过内分泌治疗（除1例接受他莫昔芬外，其余均接受他莫昔芬治疗）；辅助治疗中60%接受他莫昔芬治疗，转移情况下16%接受他莫昔芬治疗；59例患者有内脏疾病。中位随访时间为18个月。A/G组1年时的PFS率为35%，A/P组为32%。A/G组有6例（22%）出现客观缓解，A/P组有9例（28%）。A/G组和A/P组的中位缓解持续时间分别为13.8个月和18.6个月。疲劳（35%）、腹泻（31%）、皮疹（32%）、皮肤干燥（27%）和关节痛/肌痛（27%）是A/G组最常见的不良事件。
这项II期研究虽提前结束，但未显示出在A基础上加用G可提高1年PFS的信号，不支持其使用。G导致的胃肠道和皮肤毒性更明显，近三分之一的患者因此提前中断治疗（ClinicalTrials.gov编号，NCT00066378）。
