Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial.
辅助dabrafenib联合trametinib与安慰剂治疗切除的BRAFV600-mutant III期黑色素瘤 (COMBI-AD) 患者: 一项随机、 3 期试验的探索性生物标志物分析。
- 作者列表："Dummer R","Brase JC","Garrett J","Campbell CD","Gasal E","Squires M","Gusenleitner D","Santinami M","Atkinson V","Mandalà M","Chiarion-Sileni V","Flaherty K","Larkin J","Robert C","Kefford R","Kirkwood JM","Hauschild A","Schadendorf D","Long GV
BACKGROUND:Adjuvant dabrafenib plus trametinib reduced the risk of relapse versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma in the phase 3 COMBI-AD trial. This prespecified exploratory biomarker analysis aimed to evaluate potential prognostic or predictive factors and mechanisms of resistance to adjuvant targeted therapy. METHODS:COMBI-AD is a randomised, double-blind, placebo-controlled, phase 3 trial comparing dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily versus two matched placebos. Study participants were at least 18 years of age and underwent complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma, per American Joint Committee on Cancer 7th edition criteria, with a BRAFV600E or BRAFV600K mutation. Patients were randomly assigned (1:1) to the two treatment groups by an interactive voice response system, stratified by mutation type and disease stage. Patients, physicians, and the investigators who analysed data were masked to treatment allocation. The primary outcome was relapse-free survival, defined as the time from randomisation to disease recurrence or death from any cause. Biomarker assessment was a prespecified exploratory outcome of the trial. We assessed intrinsic tumour genomic features by use of next-generation DNA sequencing and characteristics of the tumour microenvironment by use of a NanoString RNA assay, which might provide prognostic and predictive information. This trial is registered with ClinicalTrials.gov, number NCT01682083, and is ongoing but no longer recruiting participants. FINDINGS:Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled in the trial. Median follow-up at data cutoff (April 30, 2018) was 44 months (IQR 38-49) in the dabrafenib plus trametinib group and 42 months (21-49) in the placebo group. Intrinsic tumour genomic features were assessed in 368 patients (DNA sequencing set) and tumour microenvironment characteristics were assessed in 507 patients (NanoString biomarker set). MAPK pathway genomic alterations at baseline did not affect treatment benefit or clinical outcome. An IFNγ gene expression signature higher than the median was prognostic for prolonged relapse-free survival in both treatment groups. Tumour mutational burden was independently prognostic for relapse-free survival in the placebo group (high TMB, top third; hazard ratio [HR] 0·56, 95% CI 0·37-0·85, p=0·0056), but not in the dabrafenib plus trametinib group (0·83, 95% CI 0·53-1·32, p=0·44). Patients with tumour mutational burden in the lower two terciles seem to derive a substantial long-term relapse-free survival benefit from targeted therapy (HR [versus placebo] 0·49, 95% CI 0·35-0·68, p<0·0001). However, patients with high tumour mutational burden seem to have a less pronounced benefit with targeted therapy (HR [versus placebo] 0·75, 95% CI 0·44-1·26, p=0·27), especially if they had an IFNγ signature lower than the median (HR 0·88 [95% CI 0·40-1·93], p=0·74). INTERPRETATION:Tumour mutational burden alone or in combination with IFNγ gene expression signature or other markers for an adaptive immune response might be of relevance for identifying patients with stage III melanoma who might derive clinical benefit from targeted therapy. Further validation in prospective clinical trials is warranted. FUNDING:Novartis Pharmaceuticals.
背景: 在 3 期COMBI-AD试验中，与安慰剂相比，辅助dabrafenib联合trametinib降低了切除的BRAFV600-mutant III期黑色素瘤患者的复发风险。这项预先设定的探索性生物标志物分析旨在评估潜在的预后或预测因素以及对辅助靶向治疗耐药的机制。 方法: COMBI-AD是一项随机、双盲、安慰剂对照、 3 期试验，比较了dabrafenib 150 mg口服，每日两次加曲美替尼 2 mg口服，每日一次与 2 个匹配的安慰剂。研究参与者至少 18 岁，接受了IIIA期 (淋巴结转移> 1毫米) 、IIIB或IIIC皮肤黑色素瘤的完全切除，根据美国癌症联合委员会第 7 版标准，BRAFV600E或BRAFV600K突变。通过交互式语音应答系统将患者随机分配 (1:1) 到两个治疗组，按突变类型和疾病分期分层。患者、医生和分析数据的研究者被掩盖到治疗分配。主要结局是无复发生存期，定义为从随机分组到疾病复发或任何原因死亡的时间。生物标志物评估是试验预先设定的探索性结果。我们通过使用下一代DNA测序评估了固有的肿瘤基因组特征，并通过使用NanoString RNA检测评估了肿瘤微环境的特征，这可能提供预后和预测信息。该试验在ClinicalTrials.gov注册，编号为NCT01682083，正在进行，但不再招募参与者。 研究结果: 在 2013 年 1 月 31 日至 20 14 年 12 月 11 日之间，870 例患者入选试验。Dabrafenib加trametinib组截止数据 (2018 年 4 月 30 日) 的中位随访时间为 44 个月 (IQR 38-49)，42 个月 (21-49) 在安慰剂组。在 368 例患者 (DNA测序集) 中评估了内在肿瘤基因组特征，在 507 例患者 (NanoString生物标志物集) 中评估了肿瘤微环境特征。基线时MAPK通路基因组改变不影响治疗获益或临床结局。两个治疗组中ifn γ 基因表达标记高于中位数是延长无复发生存期的预后。肿瘤突变负荷是安慰剂组无复发生存期的独立预后因素 (高TMB，前三分之一; 风险比 [HR] 0 · 56，95% CI 0 · 37-0 · 85，p = 0 · 0056)，但在达拉非尼联合曲美替尼组中不存在 (0 · 83，95% CI 0 · 53-1 · 32，p = 0 · 44)。肿瘤突变负荷较低的患者似乎从靶向治疗中获得了可观的长期无复发生存获益 (HR [vs.安慰剂] 0 · 49，95% CI 0 · 35-0 · 68，p<0 · 0001)。然而，肿瘤突变负荷高的患者靶向治疗的获益似乎不太明显 (HR [vs.安慰剂] 0 · 75，95% CI 0 · 44-1 · 26，p = 0 · 27)，特别是如果他们的ifn γ 标记低于中位数 (HR 0 · 88 [95% CI 0 · 40-1 · 93]，p = 0 · 74)。 解释: 肿瘤突变负荷单独或与ifn γ 基因表达标记或其他适应性免疫应答标志物联合可能与识别可能从靶向治疗中获得临床获益的III期黑色素瘤患者相关。需要在前瞻性临床试验中进一步验证。 资助: 诺华制药。
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.