An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery-the BUMPER study.
An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery-the BUMPER study.
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DOI：
10.1093/noajnl/vdaa140
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发表时间：
2020-01
期刊：
影响因子：
--
通讯作者：
Meier F
中科院分区：
文献类型：
--
作者：
Amaral T;Niessner H;Sinnberg T;Thomas I;Meiwes A;Garbe C;Garzarolli M;Rauschenberg R;Eigentler T;Meier F
黑色素瘤脑转移（MBM）患者的预后仍然很差。源自异种移植模型的临床前数据表明，buparlisib 疗法对于初治 MBM 非常有效。在这项开放标签的 II 期试验中，我们研究了 PI3K 抑制剂 buparlisib 单药治疗对于不适合局部治疗的无症状 MBM 患者的安全性和有效性。如果 BRAF 野生型，这些患者也在免疫治疗下取得进展；如果携带 BRAFV600E/K 突变，则在 BRAF/MEK 抑制剂靶向治疗下取得进展。主要终点是研究人员评估的颅内疾病控制率。次要终点是布帕利西的总体缓解率、颅内疾病缓解持续时间（DOR）、总体缓解、无进展生存期（PFS）、总体生存期（OS）、安全性和耐受性。总共筛选了 20 名患者，其中 17 名患者接受了 Buparlisib 治疗。 12 名患者在超过 2 种全身治疗方案下病情出现进展，17 名患者之前接受过至少 1 次局部治疗。没有颅内反应。 3名患者颅内病情稳定；中位 DOR 为 117 天。中位 PFS 为 42 天（95% 置信区间 [CI]：23-61 天），中位 OS 为 5.0 个月（95% CI：2.24-7.76 个月）。没有观察到新的安全迹象。 Buparlisib 耐受性良好，但未观察到颅内反应。这些结果的部分解释可能是因为仅纳入了经过大量预处理的患者。然而，临床前数据强烈支持在 PI3K-AKT 通路过度激活的 MBM 患者中探索基于 PI3K 抑制剂的联合治疗的基本原理。
Patients with melanoma brain metastasis (MBM) still carry a dismal prognosis. Preclinical data originated in xenograft models showed that buparlisib therapy was highly effective in therapy-naïve MBM. In this open-label, phase II trial, we investigate the safety and efficacy of monotherapy with buparlisib, a PI3K inhibitor, in patients with asymptomatic MBM who were not candidates for local therapy. These patients had also progressed under immunotherapy if BRAF wild-type or under targeted therapy with BRAF/MEK inhibitors if carrying a BRAFV600E/K mutation. The primary endpoint was the intracranial disease control rate assessed by the investigators. The secondary endpoints were overall response rate, duration of response (DOR) of intracranial disease, overall response, progression-free survival (PFS), overall survival (OS), safety, and tolerability of buparlisib. A total of 20 patients were screened and 17 patients were treated with buparlisib. Twelve patients had progressed under more than 2 systemic therapy lines and 17 had received at least 1 previous local therapy. There were no intracranial responses. Three patients achieved intracranial stable disease; the median DOR was 117 days. The median PFS was 42 days (95% confidence interval [CI]: 23–61 days) and the median OS was 5.0 months (95% CI: 2.24–7.76 months). No new safety signs were observed. Buparlisib was well tolerated but no intracranial responses were observed. These results might be explained in part by the inclusion of only heavily pretreated patients. However, preclinical data strongly support the rationale to explore PI3K inhibitor-based combinations in patients with MBM displaying hyperactivation of the PI3K–AKT pathway.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
通过荧光共振能量转移成像，PI3K/MTOR和MEK抑制（SAR245409和Pimasertib）组合的协同抗肿瘤作用（SAR245409和Pimasertib）在粘液卵巢癌细胞中。
影响因子：
--
作者：
Inaba K;Oda K;Aoki K;Sone K;Ikeda Y;Miyasaka A;Kashiyama T;Fukuda T;Makii C;Arimoto T;Wada-Hiraike O;Kawana K;Yano T;Osuga Y;Fujii T
通讯作者：
Fujii T
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
5.2
作者：
Amaral, Teresa;Seeber, Olivia;Garbe, Claus
通讯作者：
Garbe, Claus
影响因子：
11.5
作者：
Niessner, Heike;Schmitz, Jennifer;Meier, Friedegund
通讯作者：
Meier, Friedegund