Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial.
Cemislimab治疗局部晚期皮肤鳞状细胞癌: 一项开放标签、 2 期、单组试验的结果。
- 作者列表："Migden MR","Khushalani NI","Chang ALS","Lewis KD","Schmults CD","Hernandez-Aya L","Meier F","Schadendorf D","Guminski A","Hauschild A","Wong DJ","Daniels GA","Berking C","Jankovic V","Stankevich E","Booth J","Li S","Weinreich DM","Yancopoulos GD","Lowy I","Fury MG","Rischin D
BACKGROUND:Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma. METHODS:This pivotal open-label, phase 2, single-arm trial was done across 25 outpatient clinics, primarily at academic medical centres, in Australia, Germany, and the USA. Eligible patients (aged ≥18 years with histologically confirmed locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0-1) received cemiplimab 3 mg/kg intravenously over 30 min every 2 weeks for up to 96 weeks. Tumour measurements were done every 8 weeks. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response, according to independent central review as per Response Evaluation Criteria in Solid Tumors version 1.1 for radiological scans and WHO criteria for medical photography. Data cutoff was Oct 10, 2018, when the fully enrolled cohort reached the prespecified timepoint for the primary analysis. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. This study is registered with ClinicalTrials.gov, number NCT02760498. FINDINGS:Between June 14, 2016, and April 25, 2018, 78 patients were enrolled and treated with cemiplimab. The median duration of study follow-up was 9·3 months (IQR 5·1-15·7) at the time of data cutoff. An objective response was observed in 34 (44%; 95% CI 32-55) of 78 patients. The best overall response was ten (13%) patients with a complete response and 24 (31%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 34 (44%) of 78 patients; the most common were hypertension in six (8%) patients and pneumonia in four (5%). Serious treatment-emergent adverse events occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia. INTERPRETATION:Cemiplimab showed antitumour activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma for whom there was no widely accepted standard of care. FUNDING:Regeneron Pharmaceuticals and Sanofi.
背景: cemisimab在转移性皮肤鳞状细胞癌患者中显示出实质性的抗肿瘤活性。局部晚期皮肤鳞状细胞癌患者常规全身治疗预后差。我们对cemitlimab在局部晚期皮肤鳞状细胞癌患者中的安全性和抗肿瘤活性进行了初步分析。 方法: 这项关键的开放标签、 2 期、单组试验在澳大利亚、德国和美国的 2 5 个门诊诊所进行，主要是学术医疗中心。符合条件的患者 (年龄 ≥ 1 8 岁，组织学证实为局部晚期皮肤鳞状细胞癌，东部肿瘤协作组表现状态为 0-1) 每 2 周静脉注射塞米单抗 3 mg/kg，持续 3 0 min，持续 96 周。每 8 周进行一次肿瘤测量。主要终点是客观缓解，定义为完全或部分缓解的患者比例，根据独立中央审查，按照实体瘤 1.1 版放射扫描的反应评价标准和WHO医学摄影标准。数据截止日期为 2018 年 10 月 10 日，当时完全入组的队列达到了初步分析的预定时间点。根据意向治疗原则进行分析。安全性分析包括至少接受一剂cemisimab的所有患者。本研究在ClinicalTrials.gov注册，编号nct02760498。 结果: 在 2016 年 6 月 14 日至 20 18 年 4 月 25 日期间，78 例患者入组并接受cemisimab治疗。研究随访的中位持续时间为 9 · 3 个月 (IQR 5 · 1-1 5 · 7)，数据截止时。78 例患者中 34 例 (44%; 95% CI 32-55) 观察到客观缓解。最佳总体缓解为 10 例 (13%) 完全缓解患者和 24 例 (31%) 部分缓解患者。3-4 级治疗-在 78 例患者中发生不良事件 3 4 例 (4 4%); 最常见的是 6 例 (8%) 的高血压患者和肺炎 4 例 (5%)。78 例患者中有 23 例 (29%) 发生严重的治疗紧急不良事件。报告了 1 例发生于吸入肺炎后的治疗相关性死亡。 解读: cemislimab在没有广泛接受的治疗标准的局部晚期皮肤鳞状细胞癌患者中显示出抗肿瘤活性和可接受的安全性。 资助: Regeneron制药和赛诺菲。
METHODS::Blue rubber bleb naevus syndrome (BRBNS) is an extremely rare venous malformation that often manifests as multiple haemangioma-like lesions in the skin and gastrointestinal tract. The drug sirolimus plays a key role in the signalling pathway of angiogenesis and subsequent development of BRBNS and its use has been described in several case reports. We present a case series of four patients with BRBNS who exhibited good treatment response to sirolimus. All four patients were administered oral sirolimus at doses of 1.0-1.5 mg/m2 /day with a target drug level of 5-10 ng/mL and median treatment duration of 20 months. All patients had a reduction in the size of the lesions and a normalization of coagulopathy with tolerable drug adverse reactions at follow-up. Sirolimus may be effective and safe in paediatric patients with BRBNS. Further prospective studies are suggested to evaluate the long-term effectiveness of this drug.
METHODS:BACKGROUND:Human papillomavirus (HPV) infections are associated with common dermatologic and nondermatologic diseases. Although HPV vaccines are well established as preventive measures for genital warts and cervical neoplasia, their use as therapeutic agents deserves greater attention. OBJECTIVE:To evaluate the use of HPV vaccine(s) as a treatment modality for cutaneous and/or mucosal disease. METHODS:A primary literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in January 2019 by using the PubMed and Cochrane databases. RESULTS:A total of 63 articles with 4439 patients were included. The majority of patients with cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas were successfully treated with HPV vaccination. Preliminary data on patients with pre-existing anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia is promising. LIMITATIONS:This review was limited by the lack of controls, patients' previous HPV vaccination status, and publication bias. CONCLUSION:The commercially available three-dose, quadrivalent HPV vaccine is a potential therapeutic option for the treatment of cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas. Noncommercially available HPV vaccines demonstrate therapeutic response for treating anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia. The vaccine's efficacy as an adjunct therapy for HPV-associated cutaneous and/or mucosal disease warrants further exploration.
METHODS::Our understanding of melanoma precursors and progression to melanoma has developed as a result of advances in the field of molecular diagnostics. We now better understand the potential for genetic heterogeneity within a single lesion. Combined tumors can pose a diagnostic challenge when deciding the line between benign and malignant, which in turn has direct implications for patient management. Primary cilia (PC) are ubiquitous sensory organelles that have essential functions in cellular proliferation, differentiation, and development. The ciliation index (percentage of ciliated melanocytes) has been shown to reliably differentiate melanoma, which fail to ciliate, from melanocytic nevi, which retain PC. We therefore analyzed the potential for using the ciliation index to differentiate benign and malignant components in combined melanocytic lesions. We collected patient samples (n = 10) of unequivocal combined lesions with both melanoma and associated nevus components. Melanocytes were highlighted with SOX10 and costained with gamma-Tubulin and acetylated alpha-Tubulin to highlight the basal body and cilium, respectively. The number of melanocytes retaining cilia under high-power microscopy was examined. The melanoma component had average of 4% ciliation (SD: 7%), whereas the associated nevus component was significantly higher with 59% ciliation (SD: 17%). These data show that PC may be a reliable means of distinguishing benign from malignant components within a single tumor. The ciliation index may be a helpful tool in distinguishing challenging cases of combined lesions of melanoma in situ with a dermal nevus component from invasive melanoma, thus promoting improved staging and clinical management.