CHICAGO (EGMN) – The investigational compound BIBW 2992 is the first tyrosine kinase inhibitor that appears to be at least as effective as cetuximab in metastatic or recurrent head and neck cancer.
In addition, the response rate for BIBW 2992 is twice that of the best results reported with other tyrosine kinase inhibitors (TKIs), according to Dr. Tanguy Seiwert who presented preliminary findings of an ongoing phase II trial at the annual meeting of the American Society of Clinical Oncology.
BIBW 2992 is a small molecule that irreversibly binds to and inhibits the epidermal growth factor receptor (EGFR/HER1) and human epidermal receptor 2 (HER2) tyrosine kinases.
The trial evenly randomized 120 patients with metastatic or recurrent platinum-refractory head and neck cancer to receive 50 mg of oral BIBW 2992 daily or weekly IV cetuximab at a loading dose of 400 mg/m2 and 250 mg/m2 thereafter, both until disease progression or undue side effects. Patients could cross over to the opposite treatment upon progression, but data from that stage were limited.
The objective response rate in the first stage was 21.7% for BIBW 2992 and 13.3% for cetuximab, said Dr. Seiwert of the University of Chicago Medical Center. No patient had a complete response. Tumor shrinkage, measured as partial response by RECIST, was reported in 13 patients treated with BIBW 2992 and in 8 patients treated with cetuximab.
By comparison, the response rate for cetuximab was also 13% in an earlier trial in patients with recurrent and/or metastatic head and neck cancer failing platinum therapy (J. Clin. Oncol. 2007;25:2171-7), while the observed response rate for BIBW 2992 surpasses those reported for the first-generation tyrosine kinase inhibitors (TKIs) erlotinib (4.3%), gefitinib (10.6%), and lapatinib (0%) in this setting, Dr. Seiwert noted.
The disease control rate was similar at 56.7% for BIBW 2992 vs. 61.7% for cetuximab.
“This is the first time that a small molecule is challenging the old cetuximab in head and neck cancer, said invited discussant Dr. Lisa F. Licitra of the Istituto Nazionale Tumori, Milan. “The way to go could be a long way; how and which way to take is under discussion.”
She said the mechanism of BIBW 2992 is good, as three strategies identified to minimize the risk of resistance to EGFR inhibitors include irreversible inhibition, multiple EGFR inhibition and simultaneous inhibition of EGFR and other oncogenic pathways.
Dr. Licitra and members of the audience noted that factors known to positively affect response favored the BIBW 2992 arm over the cetuximab arm, including a baseline ECOG performance status of 0 (37% v. 18%) and having oropharynx cancer (32% vs. 25%), an imbalance that might explain the benefit of the drug.
Patients in the trial were predominantly male (85%-90%), three-fourths had prior surgery, more than 90% had radiotherapy with a curative intent, and one-third had no prior chemotherapy for recurrent/metastatic disease.
Although several patients remain on study and are still censored, preliminary progression-free survival is comparable between the two drugs, Dr. Seiwert said. The median was 16 weeks with BIBW 2992 vs. 10 weeks with cetuximab.
Results from stage II are limited to less than one-third of patients. So far there has been one BIBW 2992 response after cetuximab failure and one cetuximab response after BIBW 2992 failure, suggesting that all EGFR agents “are likely not alike,” Dr. Seiwert said.
The side effect profile of BIBW 2992, however, was similar to other EGFR inhibitors, with diarrhea and skin disorders the most clinically significant adverse events. The rate of grade 3/4 diarrhea was increased with BIBW 2992 at 23.4% vs. 6.7% with cetuximab. All but one event was grade 3, but the data still suggest that appropriate measures with antidiarrheal agents and dose reductions may be necessary, he said.
BIBW 2992 is Boehringer Ingelheim’s lead investigational oncology compound and is being study extensively in non–small cell lung cancer under the LUX-Lung clinical trial program. It also will be evaluated in a recently initiated phase III trial (LUX-Breast 1) in advanced breast cancer, according to information on the company’s Web site.
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芝加哥(EGMN)——对于转移性或复发性头颈癌，在研化合物BIBW 2992是首个至少与西妥昔单抗(cetuximab)等效的酪氨酸激酶抑制剂。
而且，BIBW 2992的有效率是其他酪氨酸激酶抑制剂(TKI)所报告的最佳结果的2倍。在美国临床肿瘤学会2010年年会上，Tanguy Seiwert博士报告了一项正在进行的II期试验的初步结果。
BIBW 2992是一种会不可逆地结合并抑制表皮生长因子受体(EGFR/HER1)和人表皮受体2(HER2) 酪氨酸激酶的小分子。
该试验将120例转移性或复发性铂难治性头颈癌患者随机、均衡分配至接受口服BIBW 2992 50 mg，每日1次；或静脉输注西妥昔单抗，每周1次，负荷剂量为400 mg/m2，之后减至250 mg/m2，直至疾病进展或出现不可接受的不良反应。疾病一旦进展，患者可交叉接受另一种治疗，但来自这一阶段的数据很有限。
美国芝加哥大学医学中心的Seiwert 博士说，BIBW 2992组在I期试验中的客观有效率为21.7%，而西妥昔单抗组仅为13.3%。无1例患者完全有效。依照实体瘤疗效评价标准(RECIST)，将肿瘤体积缩小视为部分有效，BIBW 2992组和西妥昔单抗组分别有13例和8例患者部分有效。
Seiwert 博士指出，相比而言，先前在经铂类药物治疗失败的复发性和(或)转移性头颈癌患者中开展的另一项试验显示，西妥昔单抗的有效率也只有13% (J. Clin. Oncol. 2007;25:2171-7)。而观察到的BIBW 2992的有效率高于第一代酪氨酸激酶抑制剂(TKI) 厄洛替尼(erlotinib，4.3%)、吉非替尼(gefitinib，10.6%)和拉帕替尼(lapatinib，0)所报告的用于这类患者的结果。
BIBW 2992组和西妥昔单抗组的疾病控制率相似，分别为56.7%和61.7%。
作为特邀评论员，意大利米兰国家肿瘤研究所的Lisa F. Licitra博士说：“对于头颈癌的治疗，这是小分子药物首次向老药西妥昔单抗发出挑战。未来的道路可能还会很长；应该如何走，走哪条路，目前都尚在讨论中。”
Licitra博士说，BIBW 2992的作用机制很好，目前已发现其可以通过3种策略来尽可能地降低患者对EGFR抑制剂的耐药风险，这3种策略包括：不可逆地抑制、多种EGFR抑制以及同时抑制EGFR和其他致癌途径。
Licitra博士以及与会者指出，已知正面影响了BIBW 2992组的有效率高于西妥昔单抗组的因素包括：基线ECOG(美国东部肿瘤协作组)行为状态评分为0 (37%对18%)以及伴有口咽癌(32%对25%)，这种不平衡性可以用于解释药物BIBW 2992的优势。
在该试验中，患者以男性为主(85%~90%)，其中3/4既往都曾接受过手术治疗，超过90%都曾接受过放疗以期治愈，1/3之前没有因疾病复发/转移而接受过化疗。
Seiwert博士说，虽然还有几名患者尚未完成试验，仍在接受评估，但两组患者初步的无进展生存期是相似的。BIBW 2992组和西妥昔单抗组的中位无进展生存期分别为16周和10周。
Seiwert博士说，II期结果仅限于不足1/3的患者。到目前为止，只有1例患者经西妥昔单抗治疗失败后获得了BIBW 2992应答，1例患者经BIBW 2992治疗失败后获得了西妥昔单抗应答，这提示各种EGFR药物“很可能并不相似”。
Seiwert博士说，而BIBW 2992的不良反应特征与其他EGFR抑制剂相似，最常见的有临床意义的不良事件是腹泻和皮肤病。BIBW 2992组3/4级腹泻的发生率高于西妥昔单抗组，分别为23.4%和6.7%。除1例4级腹泻外，其余均为3级；但数据仍表明，可能需要采用止泻药以及减量等恰当的处理措施。
BIBW 2992是勃林格殷格翰公司主要的在研肿瘤药之一。根据该公司官网上的信息，目前正在开展LUX- Lung临床试验项目，对BIBW 2992用于非小细胞肺癌进行广泛的研究。此外，最近刚刚启动的一项III期试验(LUX-Breast 1)也将对其用于晚期乳腺癌的效果进行评价。
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