This pilot clinical trial plans to carry out dabrafenib adjuvant therapy combined with lesion curettage after fenestrated decompressive surgery for BRAF mutation-positive multicystic ameloblastoma to explore the effectiveness of this therapy in preventing tumor recurrence, reducing or even avoiding postoperative deformity and dysfunction. effect. Based on this, we plan to launch a prospective clinical study of dabrafenib in the treatment of BRAF V600E ameloblastoma, verify the feasibility of drug treatment or drug-assisted treatment of ameloblastoma, and provide patients with a safer Effective new treatment options will benefit more patients.

开始日期2024-03-01

申办/合作机构

山东大学

NCT06262919 / RecruitingN/A

Observational Study to Assess Safety and Effectiveness of Dabrafenib and Trametinib in Patients With BRAF V600E Mutation-positive Unresectable Advanced or Recurrent Solid Tumor

This is a prospective, multicenter, single-arm, non-interventional and observational J-PMS conducted by the central registration system and operated in Electronic data capture.

开始日期2024-02-09

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT06054191 / Not yet recruiting临床2期IIT

A Phase II, Two Parallel Group Study of Neoadjuvant and Adjuvant Targeted Treatment in NSCLC With BRAF V600 or MET Exon 14 Mutations

This is a Phase II, two parallel group study assessing the efficacy and safety of neoadjuvant and adjuvant targeted therapy in patients with stage IB-IIIA NSCLC harboring BRAF V600 or MET exon14 mutations.

开始日期2024-02-01

申办/合作机构

中山大学

100 项与甲磺酸达拉非尼相关的临床结果

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100 项与甲磺酸达拉非尼相关的转化医学

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100 项与甲磺酸达拉非尼相关的专利（医药）

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1,587

项与甲磺酸达拉非尼相关的文献（医药）

2024-03-15·International Journal of Cancer

BRAF and MEK inhibitor combinations induce potent molecular and immunological effects in NRAS‐mutant melanoma cells: Insights into mode of action and resistance mechanisms

Article

作者: Müller, Anja ; Niessner, Heike ; Sergon, Mildred ; Lesche, Mathias ; Seliger, Barbara ; Tunger, Antje ; Karitzky, Paula C ; Dinter, Lisa ; Meier, Friedegund ; Schmitz, Marc ; Wehner, Rebekka ; Käubler, Theresa ; Wurm, Alexander A ; Mehnert, Marie-Christin ; Dahl, Andreas ; Westphal, Dana ; Beissert, Stefan ; Schulz, Alexander

Abstract:

About 25% of melanoma harbor activating NRAS mutations, which are associated with aggressive disease therefore requiring a rapid antitumor intervention. However, no efficient targeted therapy options are currently available for patients with NRAS‐mutant melanoma. MEK inhibitors (MEKi) appear to display a moderate antitumor activity and also immunological effects in NRAS‐mutant melanoma, providing an ideal backbone for combination treatments. In our study, the MEKi binimetinib, cobimetinib and trametinib combined with the BRAF inhibitors (BRAFi) encorafenib, vemurafenib and dabrafenib were investigated for their ability to inhibit proliferation, induce apoptosis and alter the expression of immune modulatory molecules in sensitive NRAS‐mutant melanoma cells using two‐ and three‐dimensional cell culture models as well as RNA sequencing analyses. Furthermore, NRAS‐mutant melanoma cells resistant to the three BRAFi/MEKi combinations were established to characterize the mechanisms contributing to their resistance. All BRAFi induced a stress response in the sensitive NRAS‐mutant melanoma cells thereby significantly enhancing the antiproliferative and proapoptotic activity of the MEKi analyzed. Furthermore, BRAFi/MEKi combinations upregulated immune relevant molecules, such as ICOS‐L, components of antigen‐presenting machinery and the “don't eat me signal” molecule CD47 in the melanoma cells. The BRAFi/MEKi‐resistant, NRAS‐mutant melanoma cells counteracted the molecular and immunological effects of BRAFi/MEKi by upregulating downstream mitogen‐activated protein kinase pathway molecules, inhibiting apoptosis and promoting immune escape mechanisms. Together, our study reveals potent molecular and immunological effects of BRAFi/MEKi in sensitive NRAS‐mutant melanoma cells that may be exploited in new combinational treatment strategies for patients with NRAS‐mutant melanoma.

2024-03-01·European Journal of Cancer

Efficacy and safety of ‘Second Adjuvant’ therapy with BRAF/MEK inhibitors after local therapy for recurrent melanoma following adjuvant PD-1 based immunotherapy

Article

作者: Woodford, Rachel ; Hoeller, Christoph ; Dimitriou, Florentia ; Rutkowski, Piotr ; Neyns, Bart ; Michielin, Olivier ; Festino, Lucia ; Carlino, Matteo S ; Schwarze, Julia K ; Johnson, Douglas B ; Ressler, Julia M ; Yeoh, Hui-Ling ; Ascierto, Paolo A ; Menzies, Alexander M ; Hauschild, Axel ; Kahler, Katharina ; Jacques, Sarah K ; Placzke, Joanna ; Long, Georgina V ; Lo, Serigne ; Dummer, Reinhard ; Haydon, Andrew ; Taylor, Amelia M ; McKeown, Janet ; Lebbe, Celeste ; Galea, Claire ; Wicky, Alexandre ; Allayous, Clara ; Zimmer, Lisa

BACKGROUND:

Anti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. BRAFV600-mutated (BRAFmut) melanoma patients who recur with isolated disease following adjuvant therapy may be suitable for 'second adjuvant' treatment after local therapy. We sought to examine the efficacy and safety of 'second adjuvant' BRAF/MEKi.

PATIENTS AND METHODS:

Patients with BRAFmut melanoma treated with adjuvant PD-1 based immunotherapy who recurred, underwent definitive local therapy and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres (second adjuvant group). Demographics, disease and treatment characteristics and outcome data were examined. Outcomes were compared to BRAFmut patients who did not receive 'second adjuvant' therapy (no second adjuvant group).

RESULTS:

73 patients were included; 61 who received 'second adjuvant' therapy and 12 who did not. Most initially recurred on PD-1 therapy (66%). There were no differences in characteristics between groups. 92% of second adjuvant group received dabrafenib and trametinib and median duration of therapy was 11.8 months (0.4, 34.5). 72% required dose adjustments, 23% had grade 3 + toxicity and 38% permanently discontinued drug due to toxicity. After median 26.1 months (1.9, 56.3) follow-up, recurrence-free survival (RFS) was improved in second adjuvant group versus no second adjuvant group (median 30.8 vs 4 months, HR 0.35; p = 0.014), largely driven by a delay in early recurrence, with no difference in overall survival (p = 0.59).

CONCLUSION:

This is the first study examining outcomes of 'second adjuvant' targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. Data suggest a short-term improvement in RFS, but at the cost of toxicity. Alternative strategies and more data on sequencing adjuvant therapies are required to improve outcomes.

2024-02-01·Therapeutic Drug Monitoring

Clinical Relevance of High Plasma Trough Levels of the Kinase Inhibitors Crizotinib, Alectinib, Osimertinib, Dabrafenib, and Trametinib in NSCLC Patients

Article

作者: Beijnen, Jos H ; Huitema, Alwin D R ; Smit, Egbert F ; de Langen, Adrianus J ; Steeghs, Neeltje ; Lin, Lishi ; Barkman, Hannerieke J

Background::

the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of toxicity in non–small-cell lung cancer patients.

Methods::

In this retrospective cohort study, patients with non–small-cell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (Cmin,ss) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first Cmin,ss. The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups.

Results::

A total of 542 patients were included in the different K.I. groups. A high Cmin,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62) correlated with a Cmin,ss ≥490, ≥870, ≥405, ≥150, and ≥25 ng/mL, respectively. DLTs were more common in the alectinib high group than in the alectinib non-high group (64% vs. 29%, P = 0.036). Liver toxicity was observed in 4 (36%) patients in the high group and 5 (5%) patients in the non-high group (P = 0.007). For other K.I.s, no significant differences were observed in the frequency of DLTs between the high and non-high groups.

Conclusions::

For alectinib, high Cmin,ss was correlated with a higher risk of DLT. No differences in the frequency of DLTs were observed between the high and non-high groups for crizotinib, osimertinib, dabrafenib, and trametinib.

152

项与甲磺酸达拉非尼相关的新闻（医药）

2024-04-24

·FiercePharma

Day One takes on Novartis with FDA nod for Ojemda in broader common childhood brain tumor use

Day One Biopharmaceuticals’ Ojemda is approved by the FDA as the first drug for a common type of childhood brain tumors with a BRAF fusion or rearrangement. Another drug is in town for common pediatric brain tumors. Compared with an incumbent offering from Novartis, the newcomer boasts an FDA approval covering a broader patient population. The FDA on Tuesday handed out an accelerated approval to Day One Biopharmaceuticals’ Ojemda, also known as tovorafenib, as a treatment for patients 6 months of age and older with certain relapsed or refractory pediatric low-grade glioma (pLGG). The nod sanctions the type 2 RAF inhibitor to be used in tumors with a BRAF fusion or rearrangement, or BRAF V600 mutation. The go-ahead puts Ojemda toe to toe with Novartis’ Tafinlar-Mekinist combo, which, thanks to an FDA approval last year, is allowed in pLGG but only for cases with BRAF V600 mutations. Ojemda ushers in a new day as the first FDA-approved medicine to treat pLGG marked by BRAF fusions, and it’s also Day One’s first commercial product, CEO Jeremy Bender, Ph.D., said in a statement Tuesday. BRAF gene fusions are much more prevalent than BRAF V600 mutations, Day One’s head of R&D, Samuel Blackman, M.D., Ph.D., told Fierce Pharma in an interview ahead of the FDA approval. PLGG is the most common form of childhood brain tumor. As the most prevalent type of pLGG, BRAF alterations make up about 1,100 new diagnoses in the U.S. each year out of 1,500 total cases. Among the BRAF alterations, about 80% have a gene rearrangement, while the rest 20% have a V600 mutation. About a third of pLGG patients can undergo complete tumor resection, after which 90% of children don’t need any additional therapy. And for the majority of kids for whom surgery alone can’t tackle the disease, that’s where Ojemda comes in. This translates into about 2,000 to 3,000 pLGG patients who needs systemic therapy at any given time in the relapse setting, Blackman said. Based on the broad patient population and the lack of a boxed warning on the label, analysts at JPMorgan pegged Ojemda could reach around $750 million in peak sales, which they noted is slightly ahead of Wall Street’s consensus estimates, according to a Tuesday note. With the approval, Day One gained a rare pediatric disease priority review voucher, although the company has not specified whether it will monetize the regulatory fast pass. Priority review vouchers, which can speed up the FDA’s review of drugs, are typically sold for around $100 million these days. Ojemda proved its case in the phase 2 FIREFLY-1 trial. Among 76 efficacy-evaluable patients, Ojemda’s best overall response rate clocked in at 51%, which means the drug successfully shrank tumors in those patients at any time from treatment start. The response rates were 52% and 50% for patients with BRAF fusions and V600 mutations, respectively. Even among those who received a targeted therapy along the MAPK pathway—including traditional BRAF-MEK inhibitors such as the Tafinlar-Mekinist duo—Ojemda triggered a response in 49% of patients. The duration of response, based on a pLGG-specific assessment, was 13.8 months at the median for Ojemda. Back in March 2023, Tafinlar and Mekinist got its FDA go-ahead based on an overall response rate of 47% in BRAF V600 mutation pLGG as well as a 69% reduction in the risk of disease progression or death compared with chemotherapy. Tafinlar belongs to what’s known as type 1 BRAF inhibitors, which specifically block the V600 form of the protein mutation. That design means those drugs may enhance cancer signaling and fuel tumor growth in BRAF fusion cases, Blackman explained. And Mekinist is added to reduce this damaging “paradoxical activation effect” while also adding to the regimen’s efficacy, Blackman explained. In contrast, Ojemda’s mechanism allows it to inhibit the fusions and V600 without causing the toxic activation seen in type 1 BRAF inhibitors, he added. Another advantage of Ojemda is that it’s given once weekly, whereas Tafinlar is dosed twice a day. Under the accelerated approval pathway, Day One is on the hook to provide confirmatory evidence to prove Ojemda’s clinical benefit. The company is conducting the phase 3 FIREFLY-2 randomized trial pitting Ojemda against chemotherapy as a first-line therapy in patients aged 6 months to 25 years. The trial kicked off last year and is still enrolling patients. Day One decided to again use Ojemda as a monotherapy rather than combining it with chemotherapy because it believes chemo doesn’t add benefits for patients, Blackman said. Instead, chemo comes with toxicity and more cumbersome infusions. “We designed this trial with the pediatric oncology community to specifically address the question, ‘can an oral targeted therapy be as good as or ideally better than chemotherapy?’ because chemotherapy has a lot of burdens for patients and for families in the short term and in the long term,” Blackman said. But when it comes to other solid tumors, Day One is exploring pairing Ojemda with its in-house MEK inhibitor candidate, pimasertib, in adult patients with various types of aberrations along the MAPK pathway, not just BRAF. “At the end of the day, for V600 colorectal cancer, for V600-mutant melanoma, there’s obviously so many type 1 RAF inhibitors out there that are approved for these indications,” Blackman said. “The places that aren’t approved—the fusions—they’re just too small in the adult population.”

临床3期临床结果上市批准加速审批临床2期

2024-04-23

·药明康德

超九成患者可获益！这款抗癌疗法是如何诞生的？

▎药明康德内容团队编辑儿科低级别胶质瘤（pLGG）是儿童中最常见的脑瘤，约占所有中枢神经系统肿瘤的30~50%。尽管这种肿瘤通常侵袭性较弱且生长缓慢，但由于它们的发病部位在脑部，依然给临床治疗，尤其是手术治疗带来了极大的挑战性。不仅如此，由于这种疾病的10年总生存率超过90%，为了患儿长远的健康着想，在选择治疗时尤其要注意考虑避免因治疗带来的长期或迟发性的副作用。因此，由于化疗和放疗潜在的长期副作用，它们并非pLGG患者的最佳选择。而除了手术、放化疗外，目前pLGG可用的靶向疗法很少，该领域急需新的疗法来打破这一局面。今日，Day One Biopharmaceuticals公司用于治疗pLGG的泛RAF激酶抑制剂Ojemda（tovorafenib）成功越过了上市的终点线。在该疗法用于上市申请的2期临床试验中，接受tovorafenib治疗的pLGG患者的疾病控制率（DCR）高达93%。在今天的文章中，药明康德内容团队将结合公开资料为大家介绍这款针对pLGG的疗法的诞生故事。图片来源：123RF一种不易致死却易致残的肿瘤如文章开头所说，pLGG的长期总生存率非常高，但由于大多数患者无法通过手术完全切除肿瘤，其10年无进展生存率（PFS）大约只有55%。尽管放疗可以一定程度上改善患者的无进展生存期，但这种治疗手段很可能会对患儿的认知能力造成影响，并带来内分泌功能障碍、生长异常、血管损伤和继发性恶性肿瘤等长期副作用。除了放疗，化疗也是pLGG选择之一。不过，新确诊的pLGG患者对化疗的总缓解率仅有30%-35%，并且与治疗相关的不良事件发生率也很高，超过95%的患者会经历至少一次3级或4级不良事件。图片来源：123RF对于pLGG患者来说，他们的病程会很长，因此其治疗目标是最大限度地控制肿瘤，减少手术、化疗和放疗的治疗相关毒性。鉴于此，开发一种对广泛患者群体有效、疗效更强且安全性更高的靶向疗法是新药开发人员的目标。pLGG患者的治疗现状近十年来，研究人员发现，pLGG中最常见的致癌驱动因素为KIAA1549-BRAF融合突变（50%-60%）和BRAF V600E激活突变（5%-15%）。BRAF蛋白由调节BRAF活性的调节结构域和催化激酶结构域组成，然后激活下游信号转导以促进细胞生长。而不论是BRAF融合还是BRAF突变都会导致BRAF蛋白发出独立于RAS激活的信号。这种激酶活性可导致下游致癌信号传导的激活，从而加剧肿瘤生长。目前，小分子RAF抑制剂已在患有BRAF V600E突变癌症的成年患者中显示出疗效。FDA已批准3种第一代BRAF抑制剂（vemurafenib、dabrafenib和encorafenib）用于治疗某些携带BRAF V600E或V600K突变的实体瘤，但尚未有BRAF抑制剂获批用于单药治疗pLGG。▲不同RAF抑制剂对RAF激酶单体或RAF激酶二聚体的影响（图片来源：参考资料[5]）尽管RAF抑制剂为pLGG患者增加了新的潜在治疗选择，但如dabrafenib这样的第一代RAF抑制剂存在着脑渗透性不佳的问题。除此以外，还有一些第一代RAF抑制剂（I型拮抗剂，靶向激酶活性构象）与BRAF V600E/K的结合会刺激RAF激酶二聚体的形成，从而在RAF野生型细胞中引起反常的激活，增加MAP激酶信号转导，最终导致肿瘤的重新生长。由于野生型RAF的反常激活也会发生在非肿瘤组织中，这可能会增加患者发生继发性皮肤癌的风险。为了避免患者耐药或导致RAF的反常激活，I型RAF抑制剂需要与MEK抑制剂联合使用。去年3月，FDA批准了首款用于治疗BRAF V600E突变pLGG患者的联合靶向疗法（RAF抑制剂dabrafenib+MEK抑制剂trametinib）。不过，这种联合疗法仅适用于BRAF V600E/K突变患者，BRAF融合的pLGG患者依然存在着巨大的未竟需求。脑渗透性良好，pLGG潜在靶向疗法通过临床前考验一些研究表明，靶向激酶无活性构象的下一代RAF抑制剂（II型拮抗剂）可以同时靶向BRAF蛋白的单体和二聚体形式。但对于pLGG患者来说，这还不够。研究人员最希望的是找到一款能够针对在pLGG患者中占比更高的BRAF融合的靶向疗法，这种靶向疗法不仅需要有良好的脑渗透性，还不会引起RAF的反常激活从而产生继发疾病。2017年，来自Dana-Farber癌症研究所的一个研究团队公布了一项临床前研究结果，他们通过体外细胞实验找到了两款对BRAF V600E突变和KIAA1549-BRAF融合均有活性的II型RAF抑制剂MLN2480（也被称为TAK-580、DAY101、tovorafenib）和AZD628。在后续的动物实验中，MLN2480和AZD628被证实可靶向多种形式的BRAF蛋白，且不会触发RAF的反常激活。不过，药代动力学研究结果表明，只有MLN2480具有良好的脑渗透性，能够在中枢神经系统中显著积累，具有进行进一步探索的价值。尽管实验进行到这儿只剩下了一款候选分子，好在MLN2480最终没有让研究人员失望，它成功延缓了小鼠大脑中BRAF V600E突变肿瘤和KIAA1549-BRAF融合肿瘤的生长，并被证实对BRAF突变的人类LGG细胞具有抗肿瘤活性。在动物实验中取得积极结果后，MLN2480下一步将接受临床试验的考验了。▲MLN2480延缓了BRAF V600E突变肿瘤和KIAA1549-BRAF融合肿瘤的生长，并延长了小鼠的生存期（图片来源：参考资料[2]）2018年2月，Dana-Farber癌症研究所的Karen D. Wright博士发起了一项针对MLN2480的1期临床试验，以评估该候选分子在对其他治疗无应答的LGG患者（1-25岁）中的安全性和疗效。Day One公司的智慧布局Day One Biopharmaceuticals是一家致力于弥合儿童和成人癌症靶向疗法之间的开发速率的创新公司。通常来说，用于即使是同一款癌症疗法，其针对儿科患者的适应症总是比针对成人患者的适应症要晚获批好几年。为了改变这一现状，该公司把工作重心放在了发掘那些有潜力迅速获批上市的儿科癌症疗法上，希望能够尽快为儿童癌症患者提供有效的治疗选择。在Day One公司寻找潜在迅速获批疗法的过程中，MLN2480凭借它在临床前研究中的出色表现进入了该公司的视线。不仅如此，MLN2480已在成人和儿童人群中显示出了早期临床活性，接受治疗的患者的RAS/MAP激酶通路发生了特异性的遗传改变。Day One公司很快便决定要将这款候选疗法收入囊中。 2020年5月，Day One公司在完成6000万美元A轮融资的同时，宣布他们完成了对武田（Takeda）与Sunesis Pharmaceuticals合作开发的MLN2480的收购，并将MLN2480更名为DAY101。临床试验积极数据频传在Day One公司完成收购后的第6个月，DAY101就交出了自己的第一份临床试验答卷。在8例携带BRAF融合的18岁以下的复发性LGG患者中，2例患者达到了完全缓解（CR），3例患者获得部分缓解（PR），2例患者获得了长期的稳定疾病（SD），只有1例患者出现疾病进展（PD）。基于这些积极结果，FDA授予了DAY101突破性疗法认定和孤儿药资格，并启动了DAY101的2期临床试验。2021年6月和7月，DAY101又迅速获得了欧盟委员会授予的孤儿资格和FDA授予的罕见儿科疾病资格。2022年6月，Day One公司公布了已更名为tovorafenib的候选疗法DAY101的2期试验的初步积极结果。在前22名可评估疗效的患者中，tovorafenib的总缓解率（ORR）达64%，包括14名获得PR的患者，6名获得SD的患者，DCR高达91%。不仅如此，所有SD患者均出现了肿瘤缩小，缩小幅度为19%到34%。值得一提的是，不论是携带BRAF融合的患者还是携带BRAF V600E突变的患者，都能获得缓解。▲Tovorafenib的疗效数据（图片来源：Day One Biopharmaceuticals公司官网）2023年9月，Day One公司更新了这项关键2期试验的数据。这次公布的数据中共有69例可评估的复发性或进展性pLGG患者，公布的ORR和DCR获得了进一步提高，分别为67%和93%。17%（n=12）的患者获得了CR，49%（n=34）的患者获得了PR，26%（n=18）的患者为SD。基于这项研究的积极结果，Day One公司完成了向FDA滚动递交tovorafenib的新药申请（NDA）。2个月后，tovorafenib获得了FDA授予的优先审评资格。早跨过终点线，踏上新的征程2024年4月，距离Day One公司收购tovorafenib还不到4年，tovorafenib成功越过了上市的终点线，获FDA批准用于单药治疗复发性或进展性pLGG。对于Day One公司而言，tovorafenib不仅是公司成立以来首个成功上市的药物，更是公司使命的鲜活象征。最为重要的是，tovorafenib的上市为急需新疗法的pLGG患者带来了全新、有效的治疗选择。不过，在tovorafenib获批后，等待着它的是更多的机遇和挑战。首先是，pLGG患者的治疗需要长期给药，tovorafenib的长期疗效和安全性仍有待考察。而在已获批的pLGG适应症之外，tovorafenib还有望在其他罕见儿科肿瘤类型中发挥其治疗潜力。Day One公司已积极与学术研究人员和儿科肿瘤学合作小组开展合作，发起了针对朗格汉斯细胞组织细胞增多症和颅咽管瘤等罕见儿科肿瘤的临床试验。期待tovorafenib能够再获突破，为罕见儿科肿瘤患者带来新的希望。▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Yaman I, Bouffet E. How will tovorafenib change our treatment of pediatric low-grade glioma? Expert Opin Emerg Drugs. 2024 Jan 31:1-3. doi: 10.1080/14728214.2024.2312817. Epub ahead of print. PMID: 38293894.[2] Sun Y, Alberta JA, Pilarz C, Calligaris D, Chadwick EJ, Ramkissoon SH, Ramkissoon LA, Garcia VM, Mazzola E, Goumnerova L, Kane M, Yao Z, Kieran MW, Ligon KL, Hahn WC, Garraway LA, Rosen N, Gray NS, Agar NY, Buhrlage SJ, Segal RA, Stiles CD. A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro Oncol. 2017 Jun 1;19(6):774-785. doi: 10.1093/neuonc/now261. PMID: 28082416; PMCID: PMC5464455.[3] Sidaway, P. Tovorafenib effective against low-grade gliomas harbouring BRAF fusions. Nat Rev Clin Oncol 21, 83 (2024). https://doi.org/10.1038/s41571-023-00845-z[4] Day One says drug shrinks tumors in common pediatric brain cancer, setting up potential approval. Retrieved March 25, 2024, from https://www.statnews.com/2023/01/08/day-one-says-drug-shrinks-tumors-in-common-pediatric-brain-cancer-setting-up-potential-approval/[5] UNITED STATES SECURITIES AND EXCHANGE COMMISSION FORM 10-K. Retrieved March 25, 2024, from https://ir.dayonebio.com/node/8501/html[6] Sunesis Announces Initiation of Phase 1 Study of MLN2480 in Advanced Solid Tumors. Retrieved March 25, 2024, from https://www.globenewswire.com/en/news-release/2011/09/26/457067/14761/en/Sunesis-Announces-Initiation-of-Phase-1-Study-of-MLN2480-in-Advanced-Solid-Tumors.html[7] Day One Announces Preliminary Phase 1 Results for DAY101 in Pediatric Low-Grade Glioma, Receipt of Breakthrough Therapy Designation (BTD) and New Phase 2 Study. Retrieved March 25, 2024, from https://ir.dayonebio.com/news-releases/news-release-details/day-one-announces-preliminary-phase-1-results-day101-pediatric免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床2期免疫疗法

2024-04-19

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【Cell子刊/柳叶刀子刊】齐发！陆军军医大学卞修武院士等最新研究发布

本文为转化医学网原创，转载请注明出处作者：Sophia 研究一 01 单核细胞衍生的肿瘤相关巨噬细胞(Mo-TAMs)密集浸润弥漫性胶质瘤，具有显著的异质性。 2024年4月18日，陆军军医大学第一附属医院（重庆西南医院）全军临床病理学研究所卞修武院士、时雨副教授、平轶芳教授团队联合陆军军医大学第一附属医院脑胶质瘤医学研究中心、神经外科李飞副教授、华中科技大学武汉光电国家研究中心张智红教授团队的祁淑红副研究员在《Cancer Cell》上发表了题为“Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization”的研究论文，系统揭示了恶性胶质瘤内Mo-TAM的转录表型和空间分布异质性特征，鉴定出缺氧坏死微环境内富集的TAM缺氧亚群（Hypoxia-TAM）并证实其诱导微血管渗漏表型，阐明了靶向该亚群对胶质瘤血管正常化和提高抗肿瘤药物递送效率的治疗学意义。 https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00119-3 本研究，使用单细胞转录组学，我们绘制了 51 名异柠檬酸脱氢酶（IDH）野生型胶质母细胞瘤或 IDH 突变胶质瘤患者的 Mo-TAM 的空间分辨转录图景。我们表征了一个 Mo-TAM 子集，该子集定位于坏死周围生态位，并被缺氧生态位线索偏斜以获得缺氧反应特征。缺氧-TAM 通过激活肾上腺髓质素旁分泌信号传导来破坏内皮粘附连接的稳定性，从而刺激高渗透性新生血管系统，从而阻碍胶质母细胞瘤异种移植物中的药物递送。因此，由缺氧TAM产生的肾上腺髓质素的基因消融或药理学阻断可恢复血管完整性，提高抗肿瘤药物达拉非尼的瘤内浓度，并实现组合治疗益处。缺氧 TAM 或肾上腺髓质素表达比例增加可预测肿瘤血管通透性过高和胶质母细胞瘤预后较差。我们的研究结果强调了弥漫性胶质瘤中 Mo-TAM 的多样性和空间生态位引导的 Mo-TAM 重编程，并指出了靶向缺氧 TAM 使肿瘤脉管系统正常化的潜在治疗方法。研究二 02 安罗替尼是一种新型酪氨酸激酶抑制剂，能够靶向至少4大类10种靶点，包括血管内皮生长因子受体（VEGFR1、VEGFR2、VEGFR3）、血小板衍生生长因子受体（PDGFRα、PDGFRβ）、成纤维细胞生长因子受体（FGFR1、FGFR2、FGFR3、FGFR4）和肥大/干细胞生长因子受体（c-Kit），对肿瘤血管生成和肿瘤生长具有广谱抑制作用，已被证明对HER2阴性晚期乳腺癌有效，但是对三阴性早期乳腺癌的疗效尚不明确。这项 2 期研究旨在评估在 TNBC 患者新辅助化疗中加入安罗替尼的疗效和安全性。 2024年4月11日，陆军军医大学齐晓伟、张毅、卞修武、姜军共同通讯在柳叶刀子刊《EClinicalMedicine》上发表题为“Safety and efficacy of anlotinib combined with taxane and lobaplatin in neoadjuvant treatment of clinical stage II/III triple-negative breast cancer in China (the neoALTAL trial): a single-arm, phase 2 trial”的研究报告，首次探讨了安罗替尼加入早期三阴性乳腺癌术前新辅助化疗的有效性和安全性。 https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00164-0/fulltext#%20 本研究从 2021 年 1 月到 2022 年 8 月，共评估了 48 名患者，并入组了 45 名患者。所有患者都接受了至少一剂研究治疗并接受了手术。中位年龄为 48.5 岁（SD：8.7），71% 为淋巴结受累，20% 为 III 期。在意向治疗人群中，45 例患者中有 26 例达到 pCR（57.8%;90% CI，44.5%-70.3%），39 例达到残余癌症负担 0-I 级（86.7%;95% CI，73.2%-94.9%）。 bpCR和apCR率分别为64.4%（29/45）和71.9%（23/32）。短期随访期间未发生复发或转移。基于FUSCC IHC的亚型，免疫调节亚型的pCR率分别为68.8%（11/16）、基础样免疫抑制亚型的pCR率为58.3%（7/12）和管腔雄激素受体亚型的pCR率分别为33.3%（4/12）。NGS显示，MYC扩增型和野生型患者的pCR分别为77%（10/13）和50%（14/28），gBRCA1/2突变型和野生型患者的pCR分别为78%（7/9）和53%（17/32）。该研究的中位随访时间为14.9个月（95%CI：13.5-16.3个月）。新辅助治疗期间没有疾病进展或死亡。术后随访期间未发生死亡。在安全人群（N=45）中，29例患者（64%）发生3级或4级治疗紧急不良事件，最常见的事件分别为中性粒细胞减少（38%）、白细胞减少（27%）、血小板减少（25%）、贫血（13%）和高血压（13%）。总之，该研究结果首次证实，对于临床II或III期三阴性乳腺癌术前患者，安罗替尼加入新辅助化疗的抗肿瘤活性令人鼓舞、毒性可控，故有必要进一步开展多中心大样本随机对照临床研究长期随访进行验证。参考资料： https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00119-3 https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00164-0/fulltext#%20 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！点击对应文字查看详情

临床2期

100 项与甲磺酸达拉非尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10104	甲磺酸达拉非尼	L01XE23	DB08912

研发状态

适应症	最高研发状态	国家/地区	公司
BRAF V600E阳性黑色素瘤	批准上市	美国更多	Novartis Pharmaceuticals Corp. 更多
BRAF V600 突变阳性肿瘤	临床2期	巴西更多	Novartis Pharmaceuticals Corp. 更多
BRAFV600突变结直肠癌	临床申请批准	中国更多	Novartis Europharm Ltd. 更多
发热	无进展	斯洛伐克更多	Novartis Pharmaceuticals Corp. 更多
BRAF V600 突变阳性黑色素瘤	无进展	匈牙利更多	Novartis Pharmaceuticals Corp. 更多

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


LiBRA (ESMO_ELCC2024) 人工标引	N/A	BRAF V600E突变非小细胞肺癌一线 BRAF V600E \| TP53	41	Dabrafenib + trametinib	觸醖築衊憲顧築廠鏇齋(網鹹製壓壓選淵築獵築) = 夢觸獵觸鹽夢製遞顧夢構襯繭鹽廠選築膚廠夢 (繭蓋淵構遞衊遞簾築壓, 16.5 ~ NR) 更多	积极	2024-03-22
NCT03551626 (CTgov)	临床3期	BRAF V600 突变阳性黑色素瘤 \| 发热	552	Dabrafenib+Trametinib (Dabrafenib+Trametinib)	繭醖糧鏇襯糧製製鑰衊(齋廠積顧選鑰壓窪憲膚) = 艱鬱簾網鏇鹹衊憲鏇製艱顧齋築願齋鹹獵構積 (積壓糧獵膚餘鹽餘鹹築, 範製選製淵衊鏇鏇獵窪 ~ 壓餘鏇積網襯鏇夢襯壓) 更多	-	2024-03-18
				Dabrafenib+Trametinib (Dabrafenib+Trametinib (On-treatment))	鬱夢網繭廠網觸簾鬱齋(鹽憲構網壓獵醖膚鑰顧) = 觸繭廠窪網襯襯願壓顧襯觸選醖蓋鹹範餘齋夢 (簾願繭廠艱遞選壓選壓, 鬱餘觸衊顧餘顧顧淵襯 ~ 網衊糧獵選鏇鏇遞膚範) 更多
ESMO_TAT2024 人工标引	临床阶段不明	BRAF突变阳性黑色素瘤 BRAF mutations \| V600E/K mutation	228	Dabrafenib-trametinib	衊製蓋簾夢廠顧獵齋壓(鹽艱蓋醖簾簾壓餘鹽簾) = 壓鬱憲壓廠廠遞獵觸壓衊淵衊鹽壓鬱窪淵糧觸 (遞醖簾壓築鑰淵夢繭淵 ) 更多	积极	2024-02-26
ESMO_ASIA2023	N/A	BRAF V600E突变非小细胞肺癌 EGFR \| BRAF V600E	-	Dabrafenib, Trametinib, Osimertinib	願鏇鹹選淵夢選齋簾膚(獵壓廠範窪鹽糧醖膚鑰) = 醖膚廠顧醖範簾窪顧鏇鏇選窪獵製艱顧繭襯願 (餘衊膚觸遞壓選衊簾願 ) 更多	-	2023-12-02
NCT02684058 (Pubmed)	临床2期	BRAF V600E 突变阳性低级别胶质瘤 \| 婴儿期促纤维增生性脑星形细胞瘤 \| 胶质母细胞瘤 ... BRAF V600 mutation 更多	41	Dabrafenib plus Trametinib	願壓遞繭遞鑰製積顧蓋(蓋淵壓築簾蓋糧鹹願築) = 網淵遞築廠顧鏇糧鹽築憲鏇窪鹹鏇簾醖壓窪壓 (構膚艱願觸醖廠鑰鬱顧, 40 ~ 72) 更多	积极	2023-11-20
NCT02625337 (IMPemBra, ESMO2023) 人工标引	临床2期	黑色素瘤一线	32	dabrafenib+trametinib+pembrolizumab (All patients)	餘淵艱窪醖簾網顧鹽願(遞網範繭艱積顧醖窪鏇) = 遞鹽艱醖夢顧簾顧廠膚餘鬱選顧範願衊壓製顧 (網窪窪衊餘積衊衊範選, 32.5 ~ 67.3) 更多	积极	2023-10-22
				dabrafenib+trametinib+pembrolizumab (patients started with 2 cycles of PEM 200mg (Q3W), followed by randomization to either PEM monotherapy)	餘淵艱窪醖簾網顧鹽願(遞網範繭艱積顧醖窪鏇) = 製範繭膚窪艱觸壓遞鹹餘鬱選顧範願衊壓製顧 (網窪窪衊餘積衊衊範選, 7.5 ~ 83.0) 更多
EUCTR2013-002616-28-NL (REDUCTOR, ESMO2023) 人工标引	临床2期	黑色素瘤新辅助 BRAF-mutated	21	dabrafenib + trametinib	範壓鏇簾淵構鹹觸築簾(憲網餘積鑰蓋鏇窪鑰齋) = 網觸廠鹹鏇製鏇齋夢顧淵鏇醖網齋範鏇壓鹹廠 (壓衊蓋餘製壓鹽獵範鑰 ) 更多	积极	2023-10-22
				dabrafenib + trametinib (underwent surgery)	願窪鹽顧鏇願衊簾壓鹹(憲膚範鬱廠鏇鑰醖積鑰) = 醖遞齋繭獵觸鏇窪夢積醖壓夢廠廠壓願顧選範 (廠淵選艱顧簾網鏇餘鹽, 8.89 ~ NR) 更多
EUCTR2016-005228-27-GB \| ISRCTN18183156 (INTERIM17, ESMO2023) 人工标引	临床2期	局部晚期黑色素瘤 BRAF V600E	79	Continuous dosing + dabrafenib+trametinib	積鬱醖構壓選壓夢蓋鏇(構襯壓選壓餘製鏇鬱選) = 鑰選壓繭餘構願鑰壓構齋繭醖餘憲鑰製糧顧窪 (齋夢壓鏇淵顧襯簾範獵 ) 更多	不佳	2023-10-22
				Intermittent dosing + dabrafenib+trametinib	積鬱醖構壓選壓夢蓋鏇(構襯壓選壓餘製鏇鬱選) = 淵簾範鏇醖遞艱壓夢淵齋繭醖餘憲鑰製糧顧窪 (齋夢壓鏇淵顧襯簾範獵 ) 更多
ESMO2023 人工标引	N/A	BRAF突变阳性黑色素瘤一线 BRAF	583	Vemurafenib + Cobimetinib	憲鏇範製醖鬱襯遞壓憲(鹽觸夢選膚壓憲襯鏇鏇) = 艱構顧範選糧齋壓構憲鏇觸鹹艱鹽鑰積糧獵衊 (選築顧積獵簾鑰壓蓋窪 ) 更多	积极	2023-10-22
				Dabrafenib + Trametinib	憲鏇範製醖鬱襯遞壓憲(鹽觸夢選膚壓憲襯鏇鏇) = 獵鹹淵糧艱築簾獵窪壓鏇觸鹹艱鹽鑰積糧獵衊 (選築顧積獵簾鑰壓蓋窪 ) 更多
NCT02231775 \| NCT02519322 (ESMO2023) 人工标引	临床2期	黑色素瘤新辅助	97	dabrafenib + trametinib+nivolumab+ ipilimumab+ relatlimab (pCR)	衊餘鏇夢遞鬱蓋糧顧鏇(顧築襯餘顧網壓範糧顧) = 膚壓簾醖鬱艱鏇願鑰膚壓淵製築選獵鏇蓋簾鹹 (憲衊觸鑰餘廠鬱鹽憲夢 ) 更多	积极	2023-10-22
				dabrafenib + trametinib+nivolumab+ ipilimumab+ relatlimab (<pCR)	壓築簾築鹹鏇積蓋築範(鑰積積築範繭糧鹹鹽鏇) = 膚簾構顧鏇淵餘鹽壓顧艱積範積製鏇構製壓製 (鹽範築夢製願夢選憲鬱, 11.3to30.5)