PO.CTP01.02 · 进行中的临床试验
FORTE：一项评估plixorafenib治疗BRAF改变癌症的2期主方案（master protocol）
FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景
Plixorafenib（FORE8394；PLX8394）是一种新颖的口服小分子BRAF抑制剂和悖论阻断剂（paradox breaker），对BRAF V600单体和含BRAF的二聚体（包括融合体）具有高度选择性。Plixorafenib结合可破坏RAF二聚化并阻止悖论性MAPK通路激活，从而避免了与MEK抑制剂联合的需要。Plixorafenib在体外显示出对V600和非V600突变型BRAF蛋白的活性，并且在BRAF V600和非V600非临床模型中证明了抗肿瘤活性。
在一项1/2a期研究中，plixorafenib在具有BRAF V600突变和BRAF融合的肿瘤中，在所测试的一系列剂量范围内显示出有前景的安全性和临床活性。最常见的不良事件主要包括1-2级肝功能检查改变以及1级疲劳、恶心、腹泻和呕吐。
正在进行的FORTE篮子研究（basket study）正在评估plixorafenib作为单药治疗BRAF改变的晚期实体瘤参与者的安全性和疗效。
方法
FORTE研究目前正在将年龄≥10岁的参与者（在N=6名儿童患者入组且经独立数据监查委员会[IDMC]批准后将扩展至≥8岁）入组4个篮子。研究详情见表。符合条件的参与者已接受过针对晚期疾病的现有治疗，有可测量病灶，且在研究入组时Karnofsky（≥16岁）或Lansky（<16岁）体能评分≥60。所有参与者在餐后30分钟内每日一次连续给药plixorafenib。除下文另有说明外，既往MAPK抑制剂治疗被排除。
截至2026年1月，该试验正在全球11个国家招募参与者，目前已启动64个中心。迄今已有超过100名患者入组。临床试验注册号：NCT05503797。
表 子方案A 子方案B 子方案C 子方案D 参与者人群 携带BRAF融合的晚期实体瘤和原发性CNS肿瘤 BRAF V600突变的复发性原发性CNS肿瘤 罕见¹ BRAF V600突变的晚期实体瘤 BRAF V600突变的特定实体瘤² 计划入组数 约100 约50 约75 约15-30 设计 单臂、开放标签BOP2设计 单臂、开放标签设计 计划的疗效期中分析 N=25、N=50 N=25（已完成） N=25、N=50 无 主要终点 ORR³ PK 关键附加终点 DOR、DCR、PFS、OS、PK、安全性 安全性、ORR、DOR、DCR、PFS、OS 关键探索性终点 纵向ctDNA评估⁴
¹ 每年在≤40,000名美国患者中发生的BRAF V600突变肿瘤（例如卵巢/妇科癌症、胆管癌、小肠及除结直肠腺癌外的其他胃肠道癌症、神经内分泌癌）。
² 包括晚期皮肤黑色素瘤、MAPK抑制剂初治的甲状腺癌，以及既往接受过≤1种MAPK抑制剂的其他实体瘤。
³ 由盲态独立中心审查（BICR）使用RECIST v1.1（实体瘤）或RANO HGG或LGG（原发性CNS肿瘤）评估反应。使用RANO 2.0评估原发性CNS肿瘤的ORR为探索性终点。肿瘤在第1周期第1天评估，此后48周内每9周评估一次，然后每12周评估一次。
⁴ 对所有患者进行血浆ctDNA评估；对原发性CNS肿瘤患者进行血浆和脑脊液（CSF）评估。
BICR：盲态独立中心审查；BOP2：贝叶斯最优2期；CSF：脑脊液；ctDNA：循环肿瘤DNA；DCR：疾病控制率；DOR：缓解持续时间；HGG：高级别胶质瘤；LGG：低级别胶质瘤；MAPK：丝裂原活化蛋白激酶；ORR：客观缓解率；OS：总生存期；PFS：无进展生存期；PK：药代动力学；RANO：神经肿瘤学反应评估；RECIST：实体瘤反应评价标准。
查看英文原文 English abstract
BACKGROUND
Plixorafenib (FORE8394; PLX8394) is a novel, oral, small-molecule BRAF inhibitor and paradox breaker highly selective for BRAF V600 monomers and BRAF-containing dimers, including fusions. Plixorafenib binding disrupts RAF dimerization and prevents paradoxical MAPK pathway activation, avoiding the need for combination with a MEK inhibitor. Plixorafenib demonstrated in vitro activity against V600 and non-V600 mutant BRAF proteins, and anti-tumor activity has been demonstrated in BRAF V600 and non-V600 nonclinical models.
In a phase 1/2a study, plixorafenib demonstrated promising safety and clinical activity across a range of doses tested in tumors with BRAF V600 mutations and BRAF fusions. The most common adverse events included predominantly grade 1-2 liver function test changes and grade 1 fatigue, nausea, diarrhea, and vomiting.
The ongoing FORTE basket study is assessing the safety and efficacy of plixorafenib as monotherapy in participants with BRAF-altered advanced solid tumors.
METHODS
The FORTE study is currently enrolling participants ≥10 years of age (to be expanded to ≥8 years upon N=6 pediatric patients and IDMC approval) into 4 baskets. Study details are shown in the Table. Eligible participants have received available therapies for advanced disease, have measurable disease, and have a Karnofsky (≥16 years) or Lansky (<16 years) Performance Score of ≥60 at study entry. All participants receive plixorafenib continuous dosing once daily within 30 minutes following a meal. Prior MAPK inhibitor therapy is excluded unless otherwise specified below.
As of January 2026, the trial is recruiting participants in 11 countries globally, with 64 sites currently activated. To date, over 100 patients are enrolled. Clinical trial registry number: NCT05503797.
Table Sub-Protocol A Sub-Protocol B Sub-Protocol C Sub-Protocol D Participant Population Advanced solid and primary CNS tumors harboring BRAF fusions BRAF V600-mutated recurrent primary CNS tumors Rare 1 BRAF V600-mutated advanced solid tumors BRAF V600-mutated selected solid tumors 2 Planned Enrollment Approximately 100 Approximately 50 Approximately 75 Approximately 15-30 Design Single-arm, open-label BOP2 design Single-arm, open-label design Planned Efficacy Interim Analyses N=25
N=50 N=25 (completed) N=25
N=50 None Primary Endpoint ORR 3 PK Key Additional Endpoints DOR, DCR, PFS, OS, PK, Safety Safety, ORR, DOR, DCR, PFS, OS Key Exploratory Endpoint Longitudinal ctDNA assessments 4 1 BRAF V600-mutated tumors occurring in ≤40,000 US patients annually (eg, ovarian/gynecologic cancers, cholangiocarcinoma, small intestinal and other gastrointestinal cancers other than colorectal adenocarcinoma, neuroendocrine cancers).
2 Including advanced cutaneous melanoma, MAPK inhibitor-naïve thyroid cancer, and other solid tumors with ≤1 prior MAPK inhibitor.
3 Response assessed by BICR using either RECIST v1.1 for solid tumors or RANO HGG or LGG for primary CNS tumors. ORR for primary CNS tumors using RANO 2.0 is an exploratory endpoint. Tumors assessed at cycle 1 day 1, every 9 weeks for 48 weeks, then every 12 weeks.
4 Plasma ctDNA assessments for all patients; plasma and CSF assessments for patients with primary CNS tumors.
BICR, blinded independent central review; BOP2, Bayesian optimal phase 2; CSF, cerebrospinal fluid; ctDNA, circulating tumor DNA; DCR, disease control rate; DOR, duration of response; HGG, high-grade glioma; LGG, low-grade glioma; MAPK, mitogen-activated protein kinase; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; RANO, Response Assessment in Neuro-oncology; RECIST, Response Evaluation Criteria in Solid Tumors.
利益披露 Disclosure
E. Fontana,
Fore Biotherapeutics Travel, Other, Funding to Institution.
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European Organisation for Research and Treatment of Cancer (EORTC); GITCG secretary (2021-2023) ASCO Annual Meeting Scientific Programme Committee GI cancers; g., Board of Directors, non-salaried role).
Colorectal and Anal Track (2024-2026) ESMO Lecturer g., Board of Directors, non-salaried role).
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GCAR ), Other, Clinical trial support to Institution.
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J. Yachnin,
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M. Touat,
Sanofi ).
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