Agulnik Mark, Cohen Ezra W E, Cohen Roger B, Chen Eric X, Vokes Everett E, Hotte Sebastien J, Winquist Eric, Laurie Scott, Hayes D Neil, Dancey Janet E, Brown Shirley, Pond Gregory R, Lorimer Ian, Daneshmand Manijeh, Ho James, Tsao Ming-Sound, Siu Lillian L
Princess Margaret Hospital Phase II Consortium, Toronto, Ontario, Canada.
J Clin Oncol. 2007 Sep 1;25(25):3978-84. doi: 10.1200/JCO.2007.11.8612.
Expression of erbB2 and/or epidermal growth factor receptor (EGFR) is associated with biologic aggressiveness and poor prognosis in malignant salivary gland tumors (MSGTs). This phase II study was conducted to determine the antitumor activity of lapatinib, a dual inhibitor of EGFR and erbB2 tyrosine kinase activity, in MSGTs.
Patients with progressive, recurrent, or metastatic adenoid cystic carcinoma (ACC) immunohistochemically expressing at least 1+ EGFR and/or 2+ erbB2 were treated with lapatinib 1,500 mg daily, in a two-stage cohort. Patients with non-ACC MSGTs were treated as a separate single-stage cohort.
Of 62 patients screened, 29 of 33 (88%) ACC and 28 of 29 (97%) non-ACC patients expressed EGFR and/or erbB2. Forty patients with progressive disease were enrolled onto the study. Among 19 assessable ACC patients, there were no objective responses, 15 patients (79%) had stable disease (SD), nine patients (47%) had SD > or = 6 months, and four patients (21%) had progressive disease (PD). For 17 assessable non-ACC patients, there were no objective responses, eight patients (47%) had SD, four patients (24%) had SD > or = 6 months, and nine patients (53%) had PD. The most frequent adverse events were grade 1 to 2 diarrhea, fatigue, and rash. Eight paired tumor biopsies for correlative studies were procured; results did not correlate with clinical outcome.
Although no responses were observed, lapatinib was well tolerated, with prolonged tumor stabilization of > or = 6 months in 36% (95% CI, 21% to 54%) of assessable patients. The antitumor effects of lapatinib in MGSTs appear mainly cytostatic, hence evaluation of other molecular targeted agents, or combinations with lapatinib, may be considered. Continued efforts should be made to gain better understanding into the biology of this heterogeneous group of malignancies.
erbB2和/或表皮生长因子受体（EGFR）的表达与恶性涎腺肿瘤（MSGT）的生物学侵袭性及不良预后相关。本II期研究旨在确定EGFR和erbB2酪氨酸激酶活性双重抑制剂拉帕替尼对MSGT的抗肿瘤活性。
免疫组化显示至少表达1+EGFR和/或2+erbB2的进行性、复发性或转移性腺样囊性癌（ACC）患者，分两个阶段队列接受每日1500mg拉帕替尼治疗。非ACC的MSGT患者作为单独的单阶段队列进行治疗。
在62例筛查患者中，33例ACC患者中的29例（88%）以及29例非ACC患者中的28例（97%）表达EGFR和/或erbB2。40例疾病进展患者入组本研究。在19例可评估的ACC患者中，无客观缓解，15例患者（79%）疾病稳定（SD），9例患者（47%）SD≥6个月，4例患者（21%）疾病进展（PD）。对于17例可评估的非ACC患者，无客观缓解，8例患者（47%）SD，4例患者（24%）SD≥6个月，9例患者（53%）PD。最常见的不良事件为1至2级腹泻、疲劳和皮疹。获取了8份用于相关性研究的配对肿瘤活检标本；结果与临床结局无相关性。
尽管未观察到缓解，但拉帕替尼耐受性良好，36%（95%CI，21%至54%）的可评估患者肿瘤稳定期延长≥6个月。拉帕替尼对MGST的抗肿瘤作用似乎主要是细胞抑制性的，因此可考虑评估其他分子靶向药物或与拉帕替尼联合使用。应继续努力更好地了解这类异质性恶性肿瘤的生物学特性。
