根据2012年6月6日《新英格兰医学杂志》发表的两项小型早期研究结果，vismodegib可有效治疗基底细胞痣综合征和进展期基底细胞癌(BCC)。
基底细胞恶性肿瘤在美国是最常见的非黑色素瘤皮肤癌之一，在210万例患者中占80%以上。这是一种严重破坏容貌的癌症，但较少危及生命。几乎所有的BCC都由hedgehog信号传导通路的改变所致。美国食品药品管理局(FDA)今年1月份批准了Vismodegib用于治疗局部进展期和转移性BCC。Vismodegib(基因泰克公司生产)是一种小分子抑制剂，参与hedgehog通路的修复。
第一项研究：局部进展期和转移性BCC
在vismodegib获准用于治疗局部进展期和转移性BCC之前，梅奥医院的Aleksandar Sekulic博士及其同事开展了这项II期多中心、非随机、双队列试验。33例转移性BCC患者和63例局部进展期BCC患者使用了Vismodegib，两个队列的均无法或不适宜接受手术。
所有患者的用药剂量均为150 mg/d口服。患者的中位年龄为62岁，均为白人。当出现疾病进展、不再能耐受副作用、或研究结束时，即停止治疗。如果无法耐受副作用，患者可在1个月内停药。
设计这项研究时，在评估局部进展期BCC治疗应答方面还没有标准的终点，研究者采用的定义为外观或影像学肿瘤大小减少≥30%，或溃疡完全愈合。进展性疾病定义为外观或影像学尺寸增加≥20%，或新发溃疡，或出现新病灶。
结果显示，转移性BCC组的治疗应答率为30%，均为部分应答(定义为活检标本中未发现残余BCC)。局部进展期BCC组的治疗应答率为43%，63例患者中有13例获得完全应答。应答的中位持续时间为7.6个月(N. Engl. J. Med. 2012;366:2171-9)。
半数患者早期停药，18%的转移性BCC患者由于疾病进展而中止治疗。25%的局部进展期患者自行决定停药，原因不详。几乎所有患者均有不良事件，主要为肌肉痉挛、体重下降、疲乏和食欲不振。1/4的患者报告称发生严重不良事件。7例患者死亡，但目前还不清楚是否与vismodegib有关。“试验点的研究者考虑与vismodegib无关。”
基因泰克资助了这项试验并部分参与了试验设计，Sekulic. A majority博士及其同事报告称是该公司的员工和(或)获得其提供的资金。
乔治城大学医学中心的Ali Hendi博士在接受采访时指出，他感觉研究者对局部进展期肿瘤的定义过于主观。“这类肿瘤虽然是侵袭性的，但未必不能手术。”此外，不理想的依从率加之过高的毒性和治疗费用，使得这种治疗对很多患者而言缺乏价值。“我觉得，由于手术疗效理想，Vismodegib对局部进展期BCC用处有限，而基底细胞痣综合征和转移性BCC缺乏治疗选择，vismodegib可能更有价值。” Hendi博士称无利益冲突。
第二项研究：基底细胞痣综合征
斯坦福大学的Jean Y. Tang博士及其同事开展的这项随机、双盲、安慰剂对照试验纳入了41例基底细胞痣综合征患者，结果显示vismodegib可使BCC肿瘤缩小，并阻止新发BCC。
基底细胞痣综合征是一种罕见病，然而一旦患病就会出现成百上千的癌症病灶。目前该病还没有治疗手段，患者往往需要反复接受手术以切除肿瘤。该病患者有1个肿瘤抑制基因(PTCH1)的缺陷拷贝，后者会抑制hedgehog信号传导通路。
该研究计划在2009年9月~2011年1月期间招募患者，但由于研究结果显示vismodegib 优势巨大，2010年12月数据安全监测委员会决定终止安慰剂治疗。入组患者随机分组，接受安慰剂或vismodegib 150 mg治疗，计划治疗18个月。平均随访8个月。
结果显示，vismodegib组新发可手术BBC病灶的患者数远远低于安慰剂组：2例 vs. 29例。Vismodegib组患者的既有癌症病灶缩小65%，而安慰剂组仅为11%。Vismodegib组患者也较少接受手术：0.31次/例 vs. 4.4次/例。治疗1个月时，hedgehog目标基因表达水平下降90%。在从被判定为临床逆转的病灶提取的活检标本中，83%无残余癌细胞(N. Engl. J. Med. 2012;366:2180-8)。
54%的受试者应不良事件而停止治疗。接受vismodegib治疗的患者更多发生1或2级dysgeusia、肌肉痉挛、脱发和体重下降，也更易发生3或4级不良事件。作者称，这些不良反应与vismodegib 1期和2期试验、其他抑制hedgehog通路治疗的研究报告的不良反应相似。
作者总结称，vismodegib可降低肿瘤负担和阻止新肿瘤生长，但无法排除临床逆转性肿瘤仍含有残余癌细胞的可能性，这或许可以解释为何停止治疗后可出现肿瘤再生。“不过，上述发现证明了hedgehog通路在BCC中的关键作用。”
曼彻斯特大学的John T. Lear博士在随刊述评中指出，这两项研究显示vismodegib非常有效，对于BCC患者及其家属和医生而言都具有里程碑意义。患者的应答率令人印象深刻，尤其是基底细胞痣综合征患者。“但副作用也较频繁、较明显，使得停药率较高，而且在临床实践中停药率可能更高。”
上述研究带来的另一个问题是，抑制hedgehog通路是否的确能清除BCC，或是仍会留下残余癌细胞而可能引起复发。要想回答这一问题需要开展随访研究(N. Engl. J. Med. 2012;366:2225-6)。
间歇性给药或许能使更多患者从预防新发病灶中获益，这对于BCC nevus综合征患者尤其重要。对于病灶大、有症状的患者，“不要低估局部控制对于改善生活质量的意义” 。(生物谷Bioon.com)
DOI: 10.1056/NEJMoa1113713
PMC:
PMID:
Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma
Aleksandar Sekulic, M.D., Ph.D., Michael R. Migden, M.D., Anthony E. Oro, M.D., Ph.D., Luc Dirix, M.D., Ph.D., Karl D. Lewis, M.D., John D. Hainsworth, M.D., James A. Solomon, M.D., Ph.D., Simon Yoo, M.D., Sarah T. Arron, M.D., Ph.D., Philip A. Friedlander, M.D., Ph.D., Ellen Marmur, M.D., Charles M. Rudin, M.D., Ph.D., Anne Lynn S. Chang, M.D., Jennifer A. Low, M.D., Ph.D., Howard M. Mackey, Ph.D., Robert L. Yauch, Ph.D., Richard A. Graham, Ph.D., Josina C. Reddy, M.D., Ph.D., and Axel Hauschild, M.D.
BACKGROUND Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma. METHODS In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma. RESULTS In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted. CONCLUSIONS Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma.
DOI: 10.1056/NEJMoa1113538
PMC:
PMID:
Inhibiting the Hedgehog Pathway in Patients with the Basal-Cell Nevus Syndrome
Jean Y. Tang, M.D., Ph.D., Julian M. Mackay-Wiggan, M.D., Michelle Aszterbaum, M.D., Robert L. Yauch, Ph.D., Joselyn Lindgren, M.S., Kris Chang, B.A., Carol Coppola, R.N., Anita M. Chanana, B.A., Jackleen Marji, M.D., Ph.D., David R. Bickers, M.D., and Ervin H. Epstein, Jr., M.D..
BACKGROUND Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas. METHODS We tested the anti–basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas. RESULTS In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (−65% vs. −11%, P=0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas. CONCLUSIONS Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients.
DOI: 10.1056/NEJMe1202170
PMC:
PMID:
Oral Hedgehog-Pathway Inhibitors for Basal-Cell Carcinoma
John T. Lear, M.D.
Basal-cell carcinoma of the skin is the most common cancer worldwide, and its prevalence is increasing, accounting for 80% of nonmelanoma skin cancers.1 In 2006, more than 2.1 million new cases of nonmelanoma skin cancer were treated in the United States.2 Basal-cell carcinoma has many clinical subtypes and can progress to an advanced state in which surgery or radiation therapy is not considered to be helpful (locally advanced basal-cell carcinoma). Such lesions arise either from earlier lesions that have not been treated or from a recurrence of aggressive basal-cell carcinoma. Metastatic basal-cell carcinoma is rare.1
