Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Internal Medicine II (Oncology Center), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Lancet Oncol. 2022 Jan;23(1):53-64. doi: 10.1016/S1470-2045(21)00578-7. Epub 2021 Nov 24.
Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAF mutation-positive high-grade glioma and low-grade glioma.
This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAF mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110.
Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).
Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAF mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAF testing could potentially be adopted in clinical practice for patients with glioma.
Novartis.
需要有效的治疗方法来改善高级别和低级别胶质瘤患者的预后。在 27 个国家的 13 个社区和学术癌症中心进行的一项正在进行的开放标签、单臂、2 期罕见肿瘤学泛癌种研究（ROAR）篮子试验中，评估了 dabrafenib 联合 trametinib 用于复发性或进展性 BRAF 突变阳性高级别胶质瘤和低级别胶质瘤患者的疗效和安全性。
该研究是一项正在进行的开放标签、单臂、2 期罕见肿瘤学泛癌种研究（ROAR）篮子试验的一部分，该试验在 27 个国家的 13 个社区和学术癌症中心（奥地利、比利时、加拿大、法国、德国、意大利、日本、荷兰、挪威、韩国、西班牙、瑞典和美国）进行。研究纳入了年龄在 18 岁及以上、东部肿瘤协作组体力状态为 0、1 或 2 的患者。BRAF 突变阳性高级别胶质瘤和低级别胶质瘤患者接受 dabrafenib 150mg 每日 2 次联合 trametinib 2mg 每日 1 次口服治疗，直至出现无法耐受的毒性、疾病进展或死亡。在高级别胶质瘤队列中，患者需要在基线时使用神经肿瘤学反应评估标准（Response Assessment in Neuro-Oncology，RANO）的高级别胶质瘤反应标准测量有可测量的疾病，并且之前接受过放疗和一线化疗或同步放化疗。低级别胶质瘤患者需要在基线时使用神经肿瘤学反应评估标准（Response Assessment in Neuro-Oncology，RANO）测量有可测量的非增强性疾病（除毛细胞星形细胞瘤外）。主要终点是在可评估的意向治疗人群中，研究者评估的客观缓解率（高级别胶质瘤为完全缓解加部分缓解，低级别胶质瘤为完全缓解加部分缓解加轻微缓解）。该试验正在进行中，但已关闭入组，NCT02034110。
在 2014 年 4 月 17 日至 2018 年 7 月 25 日期间，共有 45 名患者（31 名患有胶质母细胞瘤）入组高级别胶质瘤队列，13 名患者入组低级别胶质瘤队列。这里报告的结果基于中期分析 16（数据截止日期为 2020 年 9 月 14 日）。在高级别胶质瘤队列中，中位随访时间为 12.7 个月（IQR 5.4-32.3），15 名（33%；95%CI 20-49）患者的研究者评估有客观缓解，包括 3 例完全缓解和 12 例部分缓解。在低级别胶质瘤队列中，中位随访时间为 32.2 个月（IQR 25.1-47.8）。9 名（69%；95%CI 39-91）患者的研究者评估有客观缓解，包括 1 例完全缓解、6 例部分缓解和 2 例轻微缓解。31 名（53%）患者发生了 3 级或更高级别的不良事件，最常见的不良事件为疲劳（5 例[9%]）、中性粒细胞计数减少（5 例[9%]）、头痛（3 例[5%]）和中性粒细胞减少（3 例[5%]）。
dabrafenib 联合 trametinib 对 BRAF 突变阳性复发性或难治性高级别胶质瘤和低级别胶质瘤患者具有显著的临床疗效，安全性与其他适应证一致。BRAF 检测可能会在胶质瘤患者的临床实践中得到采用。
诺华公司。
