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Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib monotherapy: Analysis from phase 2 and 3 clinical trials.

接受dabrafenib单药治疗的BRAF V600-mutant转移性黑色素瘤患者的长期预后: 来自 2 期和 3 期临床试验的分析。

  • 影响因子:6.15
  • DOI:10.1016/j.ejca.2019.10.033
  • 作者列表:"Hauschild A","Ascierto PA","Schadendorf D","Grob JJ","Ribas A","Kiecker F","Dutriaux C","Demidov LV","Lebbé C","Rutkowski P","Blank CU","Gutzmer R","Millward M","Kefford R","Haas T","D'Amelio A Jr","Gasal E","Mookerjee B","Chapman PB
  • 发表时间:2020-01-01

BACKGROUND:Previous analyses of BREAK-2 and BREAK-3 showed that durable outcomes lasting ≥3 years are achievable with dabrafenib in some patients with BRAF V600-mutant metastatic melanoma (MM); however, additional follow-up is needed to fully characterise the long-term impact of dabrafenib in these patients. METHODS:BREAK-2 was a single-arm phase 2 study evaluating dabrafenib in treatment-naive or previously treated BRAF V600E/K-mutant MM. BREAK-3, a randomised (3:1) phase 3 study, assessed dabrafenib versus dacarbazine in previously untreated unresectable or metastatic BRAF V600E-mutant melanoma. Five-year analyses were performed. RESULTS:All BREAK-2 patients (N = 92 [V600E, n = 76; V600K, n = 16]) discontinued treatment by the data cutoff. Median follow-up was 13.0 months. In BRAF V600E patients, 5-year progression-free survival (PFS) and overall survival (OS) were 11% and 20%, respectively. Subsequent immunotherapy was received by 22% of patients. In BREAK-3, median follow-up was 17.0 and 12.0 months in the dabrafenib (n = 187) and dacarbazine (n = 63) arms, respectively. Thirty-seven patients (59%) receiving dacarbazine crossed over to dabrafenib following disease progression as per protocol. Five-year PFS was 12% in the dabrafenib arm; all dacarbazine-arm patients progressed or were censored by 5 years. Dabrafenib improved PFS versus dacarbazine, regardless of baseline lactate dehydrogenase levels. Five-year OS rates were 24% and 22% in the dabrafenib and dacarbazine arms, respectively. Subsequent therapy in each arm included anti-CTLA-4 (dabrafenib [24%] and dacarbazine [24%]) and/or anti-PD-1 (8% and 2%) treatment. No new safety signals were observed. CONCLUSIONS AND RELEVANCE:These data, representing extended follow-up for dabrafenib monotherapy, demonstrate that durable benefit lasting ≥5 years is achievable in a subset of patients. TRIAL REGISTRATION:ClinicalTrials.gov (BREAK-2, NCT01153763; BREAK-3, NCT01227889).


背景: 既往对BREAK-2 和BREAK-3 的分析表明,在一些BRAF V600-mutant转移性黑色素瘤 (MM) 患者中,dabrafenib可实现持续 ≥ 3 年的持久结局; 然而,需要额外的随访以充分表征dabrafenib对这些患者的长期影响。 方法: BREAK-2 是一项单臂 2 期研究,评价dabrafenib治疗初治或既往治疗的BRAF V600E/K-突变MM。BREAK-3,一项随机 (3:1) 3 期研究,评估了dabrafenib与达卡巴嗪在既往未经治疗的不可切除或转移性BRAF V600E-mutant黑色素瘤中的疗效。进行了五年分析。 结果: 所有BREAK-2 患者 (N = 92 [V600E,n = 76; V600K,n = 16]) 按数据截止停止治疗。中位随访时间为 13.0 个月。在BRAF V600E患者中,5 年无进展生存期 (PFS) 和总生存期 (OS) 分别为 11% 和 20%。22% 的患者接受了随后的免疫治疗。在BREAK-3 中,达拉非尼 (n = 17.0) 和达卡巴嗪 (n = 63) 组的中位随访时间分别为 12.0 和 187 个月。根据方案,37 例接受达卡巴嗪的患者 (59%) 在疾病进展后交叉至dabrafenib。Dabrafenib组的 5 年PFS为 12%; 所有达卡巴嗪-arm患者均进展或经过 5 年审查。与达卡巴嗪相比,Dabrafenib改善了PFS,而不管基线乳酸脱氢酶水平如何。达达非尼和达卡巴嗪组的 5 年OS率分别为 24% 和 22%。每个组的后续治疗包括anti-CTLA-4 (达拉非尼 [24%] 和达卡巴嗪 [24%]) 和/或anti-PD-1 (8% 和 2%) 治疗。未观察到新的安全信号。 结论和相关性: 这些数据代表了dabrafenib单药治疗的延长随访,证明持续 ≥ 5 年的持久获益在一部分患者中是可以实现的。 试用注册: ClinicalTrials.gov (BREAK-2,NCT01153763; BREAK-3,NCT01227889)。



作者列表:["Zhang B","Li L","Zhang N","Zhao M","Liu Y","Wei L","Ma L","Xu Z"]

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.

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作者列表:["Pham CT","Juhasz M","Sung CT","Mesinkovska NA"]

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.

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作者列表:["Lang UE","Love NR","Cheung C","McCalmont TH","Kim J"]

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.

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