Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study.
Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study.
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DOI：
10.1001/jamaoncol.2017.5029
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发表时间：
2018-03-01
期刊：
影响因子：
28.4
通讯作者：
Hyman DM
中科院分区：
文献类型：
--
作者：
Diamond EL;Subbiah V;Lockhart AC;Blay JY;Puzanov I;Chau I;Raje NS;Wolf J;Erinjeri JP;Torrisi J;Lacouture M;Elez E;Martínez-Valle F;Durham B;Arcila ME;Ulaner G;Abdel-Wahab O;Pitcher B;Makrutzki M;Riehl T;Baselga J;Hyman DM
组织细胞肿瘤埃尔德海姆-切斯特病（ECD）和朗格汉斯细胞组织细胞增多症（LCH）是BRAF V600突变的高度富集，并且先前已显示对BRAF V600激酶抑制剂vemurafenib治疗有反应。然而，这些患者长期使用vemurafenib的长期疗效和安全性尚未确定。在这里，我们分析了vemurafenib在纳入VE-BASKET研究的ECD和LCH患者中的最终疗效和安全性数据。确定vemurafenib在纳入VE-BASKET研究的成人ECD或LCH患者中的有效性和安全性。VE-BASKET研究是一项开放标签、非随机、多队列研究，针对携带BRAF V600突变的非黑色素瘤癌症患者。BRAF v600突变ECD或LCH患者被纳入VE-BASKET研究的“其他实体肿瘤”队列，他们被纳入本研究。患者接受vemurafenib， 960mg，连续每日两次，直到疾病进展、研究退出或出现无法忍受的不良反应。主要终点是根据实体肿瘤反应评价标准（RECIST, version 1.1）确定的客观缓解率（ORR）。次要终点包括无进展生存期（PFS）、总生存期（OS）、改进的正电子发射断层扫描（PET）代谢反应。使用18f -氟脱氧葡萄糖(FDG)-PET/计算机断层扫描（CT）的实体瘤反应标准（PERCIST）和安全性。本研究共纳入了来自VE-BASKET试验的26例患者（22例患有ECD， 4例患有LCH）（14例女性，12例男性，中位年龄61岁，年龄范围51-74岁）。确诊的ORR在整个队列中为61.5%(95%CI, 40.6%-79.8%)，在ECD患者中为54.5%（95%CI, 32.2%-75.6%）。所有可评估的患者均达到病情稳定或更好。尽管中位随访时间为28.8个月，但在研究结束时，整个队列的中位PFS和OS尚未达到；2年PFS为86%(95%CI, 72%-100%)， 2年OS为96%（95%CI, 87%-100%）。FDG-PET/CT评估的15例患者均达到代谢缓解，其中12例（80%）达到完全代谢缓解。整个队列中最常见的不良事件（ae）包括关节痛、斑疹、疲劳、脱发、QT间期延长、皮肤乳头状瘤和角化过度。高血压和皮肤病ae的发生率高于转移性黑色素瘤。在这项研究中，vemurafenib对BRAF v600突变ECD和LCH患者的疗效延长，值得考虑作为这些患者的新护理标准。
The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously shown to be responsive to treatment with vemurafenib, an inhibitor of the BRAF V600 kinase. However, the long-term efficacy and safety of prolonged vemurafenib use in these patients are not defined. Here we analyze the final efficacy and safety data for vemurafenib in patients with ECD and LCH enrolled in the VE-BASKET study. To determine the efficacy and safety of vemurafenib in adults with ECD or LCH enrolled in the VE-BASKET study. The VE-BASKET study was an open-label, nonrandomized, multicohort study for patients with nonmelanoma cancers harboring the BRAF V600 mutation. Patients with BRAF V600–mutant ECD or LCH were enrolled in an “other solid tumor” cohort of the VE-BASKET study, and they were enrolled in the present study. Patients received vemurafenib, 960mg, twice daily continuously until disease progression, study withdrawal, or occurrence of intolerable adverse effects. The primary end point was confirmed objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Secondary end points included progression-free survival (PFS), overall survival (OS), metabolic response by modified positron-emission tomography (PET) Response Criteria in Solid Tumors (PERCIST) using 18F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT), and safety. A total of 26 patients from the VE-BASKET trial (22 with ECD, 4 with LCH) were included in the present study (14 women and 12 men; median age, 61 years; age range, 51–74 years). The confirmed ORR was 61.5%(95%CI, 40.6%–79.8%) in the overall cohort and 54.5%(95%CI, 32.2%–75.6%) in patients with ECD. All evaluable patients achieved stable disease or better. The median PFS and OS had not been reached in the overall cohort at study closure despite a median follow-up of 28.8 months; 2-year PFS was 86%(95%CI, 72%–100%), and 2-year OS was 96%(95%CI, 87%–100%). All 15 patients evaluated by FDG-PET/CT achieved ametabolic response, including 12 patients (80%) with a complete metabolic response. The most common adverse events (AEs) in the overall cohort included arthralgia, maculopapular rash, fatigue, alopecia, prolonged QT interval, skin papilloma, and hyperkeratosis. Hypertension and dermatologic AEs occurred at higher rates than those reported in metastatic melanoma. In this study, vemurafenib had prolonged efficacy in patients with BRAF V600–mutant ECD and LCH and warrants consideration as a new standard of care for these patients.
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DOI：
10.1056/nejmoa1502309
发表时间：
2015-08-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hyman DM;Puzanov I;Subbiah V;Faris JE;Chau I;Blay JY;Wolf J;Raje NS;Diamond EL;Hollebecque A;Gervais R;Elez-Fernandez ME;Italiano A;Hofheinz RD;Hidalgo M;Chan E;Schuler M;Lasserre SF;Makrutzki M;Sirzen F;Veronese ML;Tabernero J;Baselga J
通讯作者：
Baselga J
影响因子：
20.3
作者：
Badalian-Very, Gayane;Vergilio, Jo-Anne;Rollins, Barrett J.
通讯作者：
Rollins, Barrett J.
影响因子：
45.3
作者：
Haroche, Julien;Cohen-Aubart, Fleur;Amoura, Zahir
通讯作者：
Amoura, Zahir
影响因子：
51.1
作者：
Larkin, James;Del Vecchio, Michele;Blank, Christian U.
通讯作者：
Blank, Christian U.
影响因子：
1.9
作者：
Lin, Y;Shih, WJ
通讯作者：
Shih, WJ