Schilder Russell J, Sill Michael W, Chen Xiaowei, Darcy Kathleen M, Decesare Steven L, Lewandowski George, Lee Roger B, Arciero Cletus A, Wu Hong, Godwin Andrew K
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Clin Cancer Res. 2005 Aug 1;11(15):5539-48. doi: 10.1158/1078-0432.CCR-05-0462.
This phase II trial assessed the activity and tolerability of a daily oral dose of 500 mg gefitinib (ZD1839, Iressa) in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma, and explored the clinical value of determining the status of the epidermal growth factor receptor (EGFR).
Primary measure of efficacy was progression-free survival at 6 months. Mutations in exons 18 to 21 of EGFR and/or immunohistochemical expression of EGFR were evaluated in tumor specimens from patients enrolled in this trial as well as from patients not treated with gefitinib.
Twenty-seven of 30 (90%) patients were eligible and evaluable for analysis of gefitinib efficacy and toxicity. Of these, four survived progression-free >6 months with one objective response (4%). The most commonly observed grade 3 toxicities were dermatologic (15%, 4 of 27) and diarrhea (30%, 8 of 27). Specimens from 26 of 26 or 25 of 26 patients were evaluable for immunohistochemical or mutation analysis, respectively. The response rate for patients with EGFR-positive tumors was 9% (1 of 11). EGFR expression was associated with longer progression-free survival (P = 0.008) and possibly longer survival (P = 0.082). The patient with the only objective response had a mutation in the catalytic domain of the tumor's EGFR (P = 0.04). Among 32 invasive tumors from patients not treated with gefitinib, one exhibited a catalytic domain mutation.
Gefitinib was well tolerated but had minimal activity in unscreened patients with recurrent ovarian or primary peritoneal carcinoma. Prescreening patients for activating mutations in EGFR may improve response rate to gefitinib. This report is the first to document activating mutations in catalytic domain of EGFR in 3.5% (2 of 57) of ovarian cancers.
本II期试验评估了每日口服500毫克吉非替尼（ZD1839，易瑞沙）对复发性或持续性上皮性卵巢癌或原发性腹膜癌患者的活性和耐受性，并探讨了确定表皮生长因子受体（EGFR）状态的临床价值。
疗效的主要衡量指标是6个月时的无进展生存期。在参与本试验的患者以及未接受吉非替尼治疗的患者的肿瘤标本中，评估了EGFR第18至21外显子的突变和/或EGFR的免疫组化表达。
30例患者中有27例（90%）符合条件并可评估吉非替尼的疗效和毒性。其中，4例患者无进展生存期>6个月，有1例客观缓解（4%）。最常见的3级毒性是皮肤病（15%，27例中的4例）和腹泻（30%，27例中的8例）。分别有26例或25例患者的标本可用于免疫组化或突变分析。EGFR阳性肿瘤患者的缓解率为9%（11例中的1例）。EGFR表达与更长的无进展生存期相关（P = 0.008），可能与更长的生存期相关（P = 0.082）。唯一有客观缓解的患者肿瘤的EGFR催化结构域存在突变（P = 0.04）。在未接受吉非替尼治疗的患者的32例浸润性肿瘤中，有1例表现出催化结构域突变。
吉非替尼耐受性良好，但对未经筛选的复发性卵巢癌或原发性腹膜癌患者活性极小。对患者进行EGFR激活突变的预筛选可能会提高对吉非替尼的反应率。本报告首次记录了3.5%（57例中的2例）卵巢癌中EGFR催化结构域的激活突变。
