Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.
Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.
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DOI：
10.1056/nejmoa1502309
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发表时间：
2015-08-20
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影响因子：
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通讯作者：
Baselga J
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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
BRAF V600突变发生在各种非黑色素瘤癌症中。我们在BRAF V600突变阳性的非黑色素瘤癌症中进行了一项独立于组织学的维莫拉非尼的2期“篮子”研究。我们将患者纳入六个预先指定的癌症队列；所有其他肿瘤类型的患者被纳入第七个队列。共有122名BRAF V600突变阳性癌症患者接受治疗，其中包括27名接受维莫拉非尼和西妥昔单抗治疗的结直肠癌患者。主要终点是应答率；次要终点包括无进展和总存活率。在非小细胞肺癌的队列中，有效率为42%(95%可信区间为20~67)，中位无进展生存期为7.3个月(95%可信区间为3.5~10.8)。在Erdheim-Chester病或朗格汉斯细胞组织细胞增生症的队列中，有效率为43%(95%CI，18~71)；中位治疗时间为5.9个月(0.6~18.6)，治疗期间无患者病情进展。在多形性黄色星形细胞瘤、间变性甲状腺癌、胆管癌、涎管癌、卵巢癌和透明细胞肉瘤以及接受维莫拉非尼和西妥昔单抗治疗的结直肠癌患者中，有轶事般的反应。安全性与之前关于维莫拉非尼治疗黑色素瘤的研究相似。BRAF V600似乎是某些(但不是全部)非黑色素瘤癌症的靶向癌基因。初步观察到维莫拉非尼在非小细胞肺癌、埃尔德海姆-切斯特病和朗格汉斯细胞组织细胞增生症中的活性。在BRAF V600突变的癌症中，组织学背景是一个重要的决定因素。(由F.Hoffmann-La Roche/Genentech提供资金；ClinicalTrials.gov编号，NCT01524978。)
BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 “basket” study of vemurafenib in BRAF V600 mutation–positive nonmelanoma cancers. We enrolled patients in six prespecified cancer cohorts; patients with all other tumor types were enrolled in a seventh cohort. A total of 122 patients with BRAF V600 mutation–positive cancer were treated, including 27 patients with colorectal cancer who received vemurafenib and cetuximab. The primary end point was the response rate; secondary end points included progression-free and overall survival. In the cohort with non–small-cell lung cancer, the response rate was 42% (95% confidence interval [CI], 20 to 67) and median progression-free survival was 7.3 months (95% CI, 3.5 to 10.8). In the cohort with Erdheim–Chester disease or Langerhans’-cell histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients had disease progression during therapy. There were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab. Safety was similar to that in prior studies of vemurafenib for melanoma. BRAF V600 appears to be a targetable oncogene in some, but not all, nonmelanoma cancers. Preliminary vemurafenib activity was observed in non–small-cell lung cancer and in Erdheim–Chester disease and Langerhans’-cell histiocytosis. The histologic context is an important determinant of response in BRAF V600–mutated cancers. (Funded by F. Hoffmann–La Roche/Genentech; ClinicalTrials.gov number, NCT01524978.)