Dummer R, Ascierto P A, Basset-Seguin N, Dréno B, Garbe C, Gutzmer R, Hauschild A, Krattinger R, Lear J T, Malvehy J, Schadendorf D, Grob J J
Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy.
J Eur Acad Dermatol Venereol. 2020 Sep;34(9):1944-1956. doi: 10.1111/jdv.16230. Epub 2020 Mar 4.
Sonidegib and vismodegib are hedgehog pathway inhibitors (HhIs) approved for the treatment of advanced basal cell carcinoma (BCC). Until recently, vismodegib was the only targeted treatment available for patients with locally advanced BCC (laBCC) in cases where surgery and radiotherapy are inappropriate. Sonidegib has recently been approved and now presents an alternative treatment option. The clinical differences between the two HhIs in patients with laBCC are unclear, as no head-to-head randomized controlled trials are or will be initiated. Moreover, there were important differences in the designs of their pivotal studies, BOLT (sonidegib) and ERIVANCE (vismodegib), and these differences complicate evidence-based analysis of their relative efficacy and safety profiles. In this paper, a group of clinical experts in the management of laBCC summarizes the clinical and pharmacological profiles of sonidegib and vismodegib based on published data and their own clinical experience. One key difference between the two pivotal studies was the criteria used to assess BCC severity. ERIVANCE (a single-arm phase II trial) used the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while the more recent double-blind randomized BOLT trial used the stringent modified RECIST. A preplanned analysis adjusted the outcomes from BOLT with RECIST-like criteria, and this enabled the experts to discuss relative efficacy outcomes for the two treatments. Centrally reviewed objective response rate (ORR) for vismodegib was 47.6% (95% CI: 35.5-60.6) at 21-month follow-up using RECIST. After adjusting with RECIST-like criteria, the ORR for sonidegib according to central review at 18-month follow-up was 60.6% (95% CI: 47.8-72.4). Both treatments were associated with similar patterns of adverse events. Sonidegib and vismodegib share the same efficacy and tolerability profiles, but their pharmacokinetic profiles show several differences, such as volume of distribution and half-life. Further studies are needed to understand how these differences may impact clinical practice.
索尼德吉和维莫德吉是已获批用于治疗晚期基底细胞癌（BCC）的刺猬通路抑制剂（HhIs）。直到最近，维莫德吉还是局部晚期基底细胞癌（laBCC）患者在手术和放疗不适用情况下唯一可用的靶向治疗药物。索尼德吉最近已获批，现在提供了另一种治疗选择。由于尚未开展且不会开展头对头随机对照试验，两种HhIs在laBCC患者中的临床差异尚不清楚。此外，它们的关键研究BOLT（索尼德吉）和ERIVANCE（维莫德吉）在设计上存在重要差异，这些差异使基于证据对它们的相对疗效和安全性进行分析变得复杂。在本文中，一组laBCC管理方面的临床专家根据已发表的数据和他们自己的临床经验，总结了索尼德吉和维莫德吉的临床和药理学特征。两项关键研究之间的一个关键差异是评估BCC严重程度所使用的标准。ERIVANCE（一项单臂II期试验）使用了传统的实体瘤疗效评价标准（RECIST），而更近的双盲随机BOLT试验使用了更严格的改良RECIST。一项预先计划的分析用类似RECIST的标准调整了BOLT的结果，这使得专家们能够讨论两种治疗的相对疗效结果。使用RECIST在21个月随访时，维莫德吉经中心审查的客观缓解率（ORR）为47.6%（95%CI：35.5 - 60.6）。用类似RECIST的标准进行调整后，索尼德吉在18个月随访时经中心审查的ORR为60.6%（95%CI：47.8 - 72.4）。两种治疗的不良事件模式相似。索尼德吉和维莫德吉具有相同的疗效和耐受性特征，但它们的药代动力学特征存在一些差异，如分布容积和半衰期。需要进一步研究以了解这些差异如何可能影响临床实践。
