Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene.
Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene.
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Olaparib在恶性间皮瘤中的2阶段研究以及BAP1基因中种系或体细胞突变的功效相关性。
DOI：
10.1016/j.jtocrr.2021.100231
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发表时间：
2021-10
影响因子：
--
通讯作者：
Hassan R
中科院分区：
文献类型：
--
作者：
Ghafoor A;Mian I;Wagner C;Mallory Y;Agra MG;Morrow B;Wei JS;Khan J;Thomas A;Sengupta M;Steinberg SM;Hassan R
PARP抑制可能通过诱导合成致死性增强BAP 1相关间皮瘤的抗肿瘤反应。进行了一项单中心、非随机、2期试验，其中难治性间皮瘤患者在21天周期内接受olaparib 300 mg每日两次给药，直至疾病进展或出现不可耐受的毒性。主要目的是根据DNA修复基因的体细胞或种系突变状态确定客观缓解率。次要目的是评估安全性和耐受性，并确定无进展生存期（PFS）和总生存期（OS）。对血液和肿瘤进行全外显子组测序。共23例既往接受过治疗的胸膜和腹膜间皮瘤患者入组并接受治疗（种系BAP 1，n = 4;种系MRE 11 A，n = 1;体细胞BAP 1，n = 8突变）。有1例（4%）部分缓解，18例（78%）在6周时病情稳定，4例（17%）病情进展。中位总体PFS和OS分别为3.6个月（95%置信区间[CI]：2.7-4.2个月）和8.7个月（95% CI：4.7个月-无法估计）。生殖系BAP 1突变体（n = 4）的中位PFS为2.3个月（95% CI：1.3-3.6个月），野生型为4.1个月（95% CI：2.7-5.5个月）（n = 19; p = 0.019）。生殖系BAP 1突变的中位OS为4.6个月（95% CI：3.1-4.9个月），而无生殖系突变的中位OS为9.6个月（95% CI：5.5个月-无法估计）（p = 0.0040）。奥拉帕尼是安全的，没有新的安全性问题。奥拉帕尼在既往接受过治疗的间皮瘤（包括BAP 1突变患者）中的活性有限。生殖系BAP 1突变与PFS和OS降低相关。
PARP inhibition may enhance antitumor responses in BAP1-associated mesothelioma by inducing synthetic lethality. A single-center, nonrandomized, phase 2 trial was conducted, in which patients with refractory mesothelioma were given olaparib 300 mg twice daily in a 21-day cycle until disease progression or intolerable toxicity. The primary objective was to determine the objective response rate on the basis of somatic or germline mutation status of DNA repair genes. The secondary objectives were to assess safety and tolerability and to determine progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing was performed on blood and tumor. A total of 23 previously treated patients with pleural and peritoneal mesothelioma were enrolled and treated (germline BAP1, n = 4; germline MRE11A, n = 1; somatic BAP1, n = 8 mutations). There was one (4%) partial response, 18 (78%) with stable disease at 6 weeks, and four (17%) with progressive disease. The median overall PFS and OS were 3.6 months (95% confidence interval [CI]: 2.7–4.2 mo) and 8.7 months (95% CI: 4.7 mo–not estimable), respectively. The median PFS of germline BAP1 mutants (n = 4) was 2.3 months (95% CI: 1.3–3.6 mo) versus 4.1 months (95% CI: 2.7–5.5 mo) for wild-type (n = 19; p = 0.019). The median OS was 4.6 months (95% CI: 3.1–4.9 mo) for germline BAP1 mutation versus 9.6 months (95% CI: 5.5 mo–not estimable) in no germline mutation (p = 0.0040). Olaparib was safe with no new safety concerns. Olaparib has limited activity in previously treated mesothelioma including patients with BAP1 mutations. Germline BAP1 mutations were associated with decreased PFS and OS.
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影响因子：
8.4
作者：
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通讯作者：
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