2015年8月20日，Odomzo继7月底获得美国FDA批准之后，瑞士制药巨头诺华（Novartis）开发的抗癌药Odomzo（sonidegib，200mg）近日再获欧盟批准，用于不适合手术治疗或放射治疗的局部晚期基底细胞癌（laBCC）成人患者的治疗。此前，Odomzo已获得澳大利亚和瑞士批准，并于今年6月25日获得欧盟CHMP建议批准的积极意见。 基底细胞癌（BCC）是一种最常见的皮肤癌，约占非黑色素瘤皮肤癌的80%以上，该病常发于头颈部，鼻子是最常见部位。局部晚期是指BCC从最初部位扩散至附近组织，可导致高度毁容，从身体和精神双方面对患者带来严重影响。晚期BCC约占BCC病例的1-10%。尽管BCC通常可在早期阶段确诊并治疗，但约3%的患者在治疗5年后病情复发。由于人口老龄化、紫外线暴露增加等因素，BCC的发病率每年上升10%左右，该病在全球范围内的发病率预计在0.003%-0.55%。 尽管BCC很少发展为晚期，但一旦进展到这一阶段几乎没有治疗选择。Odomzo将为局部晚期BCC群体提供一种新的非侵入性治疗方案，为这类患者带来新的生活希望。 Odomzo的获批，是基于一项国际多中心随机双盲II期BOLT研究中所取得的可持续的客观缓解率（ORR）数据。该研究在不适合局部治疗的局部晚期基底细胞癌（laBCC）或转移性基底细胞癌（mBCC）成人患者中开展，评估了Odomzo 200mg和800mg剂量的疗效和安全性。经中心审查委员会评定的数据显示，200mg剂量组客观缓解率（ORR）为56%，其中完全缓解率（CR）为5%，部分缓解率（PR）为52%；经研究人员评定的数据显示ORR为71%，其中CR占9%，PR占62%。目前，中位缓解持续时间尚未达到。中心审查委员会评定的中位无进展生存期为22个月，研究人员评定的无进展生存期为19个月。此外，无证据表明800mg剂量组ORR数据好于200mg剂量组。 Odomzo（sonidegib，原名LDE225）是一种口服选择性Smoothened（SMO）抑制剂 SMO是一种7次跨膜蛋白，调控Hedgehog（Hh）信号通路，该通路在干细胞维持、组织修复、晚期基底细胞癌中发挥关键作用。目前，诺华正在调查sonidegib用于多种疾病的治疗，包括骨髓纤维化、白血病及实体瘤（如胰腺癌、乳腺癌和非小细胞肺癌）。 Sonidegib (Odomzo) Approved for Basal Cell Carcinoma in EU The European Commission has approved sonidegib (Odomzo, Novartis) for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) who are not amenable to curative surgery or radiation therapy. The approval follows a positive opinion issued in June. The drug was recently approved in the United States, in July, for a similar indication. Sonidegib inhibits the Hedgehog signaling pathway, which in turn could stop or reduce the growth of the cancerous lesions. This is the second such drug approved for the treatment of basal cell carcinoma. The first — vismodegib (Erivedge, Genentech/Roche), another Hedgehog pathway inhibitor — was approved in 2012 in the United States. This drug was hailed as the "greatest advance in therapy for BCC" at that time. Basal cell carcinoma (BCC) is the most common type of skin cancer, accounting for more than 80% of nonmelanoma skin cancers. It consists of abnormal uncontrolled growths or lesions that arise in the skin's basal cells, which line the deepest layer of the epidermis. Although BCC rarely becomes advanced (in about 1% - 10% of cases), there have been few treatment options at this stage of the disease, according to the manufacturer. "I have seen first-hand the devastating impact advanced basal cell carcinoma can have on those living with the disease. As the lesions are usually highly visible and located predominantly on the face, they can impact patients both physically and emotionally," Reinhard Dummer, MD, professor of dermatology at the University of Zurich, commented in a company press release. "The approval of sonidegib brings new hope in the form of a noninvasive option to help treat this disfiguring and potentially life-threatening disease," he said. The approval was based on data from the phase 2 Basal Cell Carcinoma Outcomes in LDE225 (later named sonidegib) Trial (BOLT). The study was conducted in patients with laBCC not amenable to local therapy or with metastatic BCC, and investigated two doses of the drug: 200 mg and 800 mg. The higher dose was no more beneficial, and the approval was based on data for the lower dose of sonidegib 200 mg in 66 patients with laBCC, who were followed for at least 18 months unless they discontinued early. In this cohort of 66 patients, the objective response rate (ORR) was 56% per central review (comprised of three complete responses [CR] and 34 partial responses [PR]) and was 71% per investigator review (comprising six CR and 41 PR). The ORR was the primary end point, and evaluation of tumor response was based on a composite assessment of modified Response Evaluation Criteria in Solid Tumors (mRECIST) that integrated tumor measurements obtained by radiographic assessments of target lesions (per RECIST 1.1), digital clinical photography (World Health Organization–adapted criteria), and histopathology assessments (via punch biopsies). All modalities used must have demonstrated absence of tumor to achieve a composite assessment of CR. These criteria were more stringent than those used in the pivotal study of vismodegib, a researcher who was involved in both studies told Medscape Medical News earlier this year when the BOLT study was published. In addition, the vismodegib study included patients with metastatic BCC, so the two studies cannot be compared directly, said Michael R. Migden, MD, from the Mohs Surgery Center, Department of Dermatology, University of Texas M.D. Anderson Cancer Center, Houston. The median progression-free survival was 22 months per central review and 19 months per investigator review. The most frequent grade 3 and 4 adverse reactions occurring in at least 2% of patients treated with sonidegib 200 mg were fatigue, decreased weight, and muscle spasms. Adverse reactions occurring in more than 10% of patients treated with sonidegib 200 mg were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus The manufacturer notes that musculoskeletal adverse reactions, which may be accompanied by serum creatine kinase elevations, appear to be a class effect as they may also occur with other drugs that inhibit the Hedgehog pathway. The incidence of musculoskeletal adverse reactions in patients with laBCC treated with sonidegib 200 mg was 54%, with 8% reported as grade 3 or 4.