Open-label Phase 2 Study of Avutometinib (RAF/MEK Clamp) in Combination With Defactinib (FAK Inhibitor) and Cetuximab in Patients With Unresectable, Anti-EGFR-Refractory Advanced Colorectal Cancer

To learn if avutometinib in combination with defactinib and cetuximab can help to control unresectable, anti-EGFR-refractory, advanced colorectal cancer.

开始日期2025-02-24

申办/合作机构

The University of Texas MD Anderson Cancer Center

NCT06630260

/ Recruiting临床1/2期IIT

A Phase 1/2 Trial of the Doublet Combination of Avutometinib and Defactinib and As a Triplet in Combination with Temozolomide in Patients with High Grade Malignant Brain Tumours Within the 5G Platform

The purpose of this clinical trial is to evaluate the safety and tolerability of avutometinib and defactinib and to determine the preliminary antitumour activity of avutometinib and defactinib administered at the recommended Phase 2 dose (RP2D). In the Phase 1b of this study parallel biomarker defined arms will be opened, initially in the relapsed GMB setting, enrolling 12 patients onto each arm. These patients will be treated with avutometinib and defactinib double therapy. Avutometinib will be administered orally at 3.2mg twice a week (e.g., on Monday / Thursday or Tuesday / Friday) with or without a meal. The total weekly dose of avutometinib is 6.4mg. Defactinib will be administered orally, at 200mg, twice a day within 30 min after a meal. The total daily dose of defactinib is 400mg.
Once a treatment in any biomarker arm has met the "GO" decision (≥3 successes/12 patients) for relapsed GBM in Phase 1b, that arm can progress to Phase 2. The primary objective of Phase 2 is to determine the antitumour activity of investigational agents administered at the RP2D in patients with molecularly defined malignant brain tumours.

开始日期2024-11-15

申办/合作机构

The Institute of Cancer Research: Royal Cancer Hospital

[+5]

NCT06682572

/ Recruiting临床2期

A Phase 2 Study of Avutometinib (VS-6766, a Dual RAF/MEK Inhibitor) In Combination With Defactinib (FAK Inhibitor) in Recurrent Low-Grade Serous Ovarian Cancer (LGSOC) in Japanese Patients

This study will confirm the safety and efficacy of avutometinib in combination with defactinib in Japanese patients with recurrent Low-Grade Serous Ovarian Cancer (LGSOC)

开始日期2024-10-30

申办/合作机构

Verastem, Inc.

100 项与 Avutometinib 相关的临床结果

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100 项与 Avutometinib 相关的转化医学

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100 项与 Avutometinib 相关的专利（医药）

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项与 Avutometinib 相关的文献（医药）

2025-05-01·Journal of Orthopaedic Translation

RO5126766 attenuates osteoarthritis by inhibiting osteoclastogenesis and protecting chondrocytes through mediating the ERK pathway

Article

作者: Wu, Zuoxing ; Ling, Zemin ; Yuan, Xiwen ; Han, Jie ; Shen, Rong ; Wang, Han ; Luo, Zhengqiong ; Guo, Chenyang ; Huang, Jianming ; Yuan, Guixin ; Shi, Fan ; Chen, Zihan ; He, Xuemei ; Ma, Zheru ; Xu, Ren ; Meng, Lin

Background:

Osteoarthritis (OA) is a degenerative joint disease that remains challenging to treat due to lack of complete understanding of its pathogenesis. Previous studies have identified RO5126766 (RO) as a small molecule compound that inhibited RAF/MEK-ERK pathway and garnered much interest for its anti-cancer properties. But its role in the treatment of OA remains unclear.

Methods:

This study employed the anterior cruciate ligament transection (ACLT) procedure to create an OA model in mice. The effects of RO on pathological changes in articular cartilage and subchondral bone were assessed using micro-CT and histological staining. Mice received peritoneal injections of RO at 1 mg/kg and 5 mg/kg biweekly for 4 weeks after ACLT, while control mice received saline. In vitro, bone marrow-derived macrophages were cultured to examine the effects of RO on osteoclast activation using immunofluorescence, TRAP staining, and bone resorption assays. The inflammatory degeneration of chondrocytes and gene expression levels were evaluated using staining and RT-qPCR. Western blot and immunohistochemistry were used to analyze MAPK signaling and autophagy-related protein expression, investigating RO's molecular mechanism in OA treatment. Human single-cell data were also analyzed to identify genes and pathways upregulated in OA tissues.

Results:

Our findings showed that RO protects subchondral bone by inhibiting osteoclast formation in the ACLT mouse model of OA. In vitro, RO was shown to inhibit osteoclast differentiation and reduce inflammatory degeneration of chondrocytes. Mechanistically, RO counteracted subchondral osteoclast hyperactivation by suppressing the ERK/c-fos/NFATc1 signaling pathway. Additionally, RO inhibited LPS-induced inflammatory degeneration of chondrocytes and enhanced autophagy via the ERK pathway. Single-cell analysis further confirmed significant upregulation of the ERK signaling pathway in human OA tissues.

Conclusions:

Overall, our findings suggested that RO inhibited osteoclast differentiation and protected articular cartilage, suggesting its potential as a novel treatment for OA.

Translational potential of this article:

In this study, we have, for the first time, substantiated the therapeutic potential of RO in the treatment of OA. By demonstrating its ability to inhibit osteoclast differentiation and protect articular cartilage, RO could offer a new avenue for disease-modifying treatments in OA. Thus, this paper provides valuable insights into understanding the molecular mechanisms and treatment of OA.

2025-04-01·INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER

GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: a phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer

Article

作者: Lustgarten, Stephanie ; Oaknin, Ana ; Monk, Bradley J ; Harter, Philipp ; Grisham, Rachel ; Van Nieuwenhuysen, Els ; Colombo, Nicoletta ; Cobb, Lauren ; Mirza, Mansoor Raza ; Lee, Yeh Chen ; Aghajanian, Carol A ; O'Malley, David M ; Oza, Amit M ; Gershenson, David ; Thaker, Premal ; Moore, Kathleen Nadine ; Banerjee, Susana ; Youssoufian, Hagop ; Coleman, Robert L ; Fabbro, Michel ; Choi, Chel Hun

Background:

There are no approved treatments specifically for low grade serous ovarian cancer; current standard of care treatment options are limited in efficacy and tolerability. The combination of avutometinib with defactinib has demonstrated efficacy and a consistent safety profile in two clinical trials in recurrent low grade serous ovarian cancer, and a lower discontinuation rate due to adverse events compared with historical rates for standard of care.

Primary Objective:

To compare the progression free survival of the combination of avutometinib with defactinib versus investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer.

Study Hypothesis:

Combination treatment with avutometinib–defactinib will significantly improve progression free survival compared with investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer.

Trial Design:

GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301 is a phase 3, randomized, international, open label study designed to compare avutometinib with defactinib versus investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer who have progressed on a previous platinum based therapy. On confirmation of disease progression using a blinded independent central review, patients on the investigator’s choice of treatment arm may cross over to the avutometinib–defactinib arm.

Major Inclusion/Exclusion Criteria:

Patients must have recurrent low grade serous ovarian cancer (KRASmutant or wild-type) and have documented progression (radiographic or clinical) or recurrence of low grade serous ovarian cancer after at least one platinum based chemotherapy regimen. Unlimited additional previous lines of therapy are allowed, including previous MEK/RAF inhibitor. Patients will be excluded if they have co-existing high grade ovarian cancer or had previous treatment with avutometinib, defactinib, or any other FAK inhibitor.

Primary Endpoint:

Progression free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded-independent central review.

Sample Size:

Approximately 270 patients will be randomized in a 1:1 fashion to either the combination avutometinib with defactinib arm (n~135) or the investigator’s choice of treatment arm (n~135).

Estimated Dates for Completing Accrual and Presenting Results:

The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031.

Trial Registration:

ClinicalTrials.govNCT06072781

2025-03-01·CANCER CELL

FAK inhibition combined with the RAF-MEK clamp avutometinib overcomes resistance to targeted and immune therapies in BRAF V600E melanoma

Article

作者: Bacchiocchi, Antonietta ; Gutkind, J Silvio ; Adame-Garcia, Sendi R ; Martini, Claudia ; Sato, Kuniaki ; Rigiracciolo, Damiano C ; Officer, Adam ; Ferguson, Fleur M ; Wang, YiYu ; Cervantes-Villagrana, Rodolfo Daniel ; Coma, Silvia ; Pachter, Jonathan A ; Lubrano, Simone ; Aplin, Andrew E ; Arang, Nadia ; Ramirez, Sydney ; Holmen, Sheri L ; Halaban, Ruth ; Faraji, Farhoud ; Anguiano Quiroz, Paola Y

Widespread BRAF mutations result in persistent RAS-RAF-MEK-ERK (MAPK) signaling in melanoma. BRAF (BRAFi) and MEK (MEKi) inhibitors are approved for BRAF V600E melanomas, including those progressing on immunotherapy; however, rapid resistance to these agents highlights the need for novel strategies. Here, transcriptome analysis of BRAF V600E melanomas from patients resistant to BRAFi and MEKi shows activation of focal adhesion signaling. Consistently, BRAFi, MEKi, and the RAF-MEK clamp avutometinib activate focal adhesion kinase (FAK) in melanoma cells. Mechanistically, inhibition of an MAPK-RhoE (RND3) feedback loop results in the adaptive activation of RhoA-FAK-AKT. In turn, FAK inhibitors (FAKi) exert potent pro-apoptotic activity when combined with MAPK pathway inhibition. FAKi plus avutometinib overcomes resistance in multiple models derived from BRAFi plus MEKi-resistant melanoma patients and immunotherapy-resistant syngeneic mouse models. These findings provide a rationale for the development of avutometinib in combination with FAKi for patients with BRAF V600E melanoma progressing on BRAFi plus MEKi or immunotherapy.

项与 Avutometinib 相关的新闻（医药）

2025-05-23

·药明康德

超90%“癌症之王”患者肿瘤缩小的小分子组合；罗氏突破性小分子组合显著延长晚期癌症生存期…… | ASCO

2025年5月30日至6月3日，美国临床肿瘤学会（ASCO）年会将在美国芝加哥及线上同步举行。作为全球规模最大的临床肿瘤学会议之一，ASCO年会是众多生物医药公司发布最新临床研究成果的重要平台。昨日，大会已正式公布会议摘要，本文将聚焦小分子药物领域，梳理其中的最新研究进展。图片来源：123RF超90%“癌症之王”患者肿瘤缩小！小分子组合最新临床结果亮眼Verastem Oncology公布了1/2期临床试验RAMP 205的最新积极安全性与疗效数据。该试验旨在评估小分子抑制剂avutometinib与defactinib，以及吉西他滨（gemcitabine）和白蛋白结合型紫杉醇（nab-paclitaxel）构成的组合疗法，一线治疗转移性胰腺导管腺癌（PDAC）患者的效果。截至2025年4月25日，剂量水平1队列患者的客观缓解率（ORR）达到83%，该剂量被选定为2期临床试验推荐剂量（RP2D）。截至2025年4月25日，共有60名患者（每个队列12名）分别接受了五种不同给药方案的治疗。其中剂量水平1队列展现出最高的缓解率。在所有五个剂量队列中，92%（48/52）可评估疗效的患者出现肿瘤缩小。在剂量水平1队列的12名患者中，10名患者获得了部分缓解，其中8例为已确认，另2例尚未确认且仍在治疗中。鉴于这些显著且一致的疗效数据，该公司已选择剂量水平1为RP2D，目前正在以该剂量继续招募最多29名患者。Avutometinib是一种RAF/MEK抑制剂，它能够诱导MEK与ARAF、BRAF和CRAF形成非活性复合物，可能通过最大程度地抑制RAS信号通路产生更全面和持久的抗肿瘤反应。Defactinib是一款FAK抑制剂。这两款药物构成的组合疗法在今年5月8日获得FDA的批准，用于治疗复发性低级别浆液性卵巢癌成年患者，这些患者曾接受过系统性治疗并且其肿瘤携带KRAS突变。突破性menin抑制剂达1b/2期临床终点，新药申请递交在即Kura Oncology与Kyowa Kirin宣布，其在研口服Menin抑制剂ziftomenib在1b/2期KOMET-001临床试验中取得积极结果，并计划基于此数据于今年第二季度向美国FDA递交新药申请（NDA）。新闻稿指出，ziftomenib是获得FDA突破性疗法认定用于治疗复发或难治性（R/R）NPM1突变型急性髓系白血病（AML）的首款在研药物。临床数据显示，ziftomenib在试验中达成主要终点——完全缓解（CR）或部分血液学恢复的完全缓解（CRh）。在1b/2期试验患者中，CR/CRh率为25%（28/112；95% CI：17–34），总缓解率为35%（39/112；95% CI：26–44）。在2期试验部分患者中，CR/CRh率为23%（21/92；95% CI：15–33）。治疗耐受性良好，仅引发有限的骨髓抑制，因药物相关不良事件导致停药的比例为3%。Ziftomenib是一种靶向menin与KMT2A/MLL蛋白复合体相互作用的候选药物，旨在治疗携带NPM1突变的AML患者。NPM1突变是最常见的AML变异之一，约占全部病例的30%。罗氏突破性剂组合疗法显著延长晚期癌症生存期罗氏（Roche）公布其INAVO120临床3期研究的最新总生存期（OS）结果。该研究评估其口服小分子疗法Itovebi（inavolisib）与CDK4/6抑制剂Ibrance（palbociclib）和氟维司群（fulvestrant）联用，治疗肿瘤携带PIK3CA突变、激素受体（HR）阳性、人类表皮生长因子受体2（HER2）阴性的局部晚期或转移性乳腺癌成年患者，这些患者在接受辅助内分泌治疗时或完成辅助内分泌治疗后疾病复发。截至2024年11月15日，中位随访时间为34.2个月。Itovebi组合疗法组患者的中位OS为34.0个月（95% CI：28.4-44.8），安慰剂组的中位OS为27.0个月（95% CI：22.8-38.7），两组数据具统计学差异（p=0.0190），且各关键亚组的OS获益一致。此外，Itovebi组合疗法组患者在6、12、18、24和30个月的生存率分别为96.8%、87.0%、74.3%、65.8%和56.5%，安慰剂组则分别为90.1%、76.7%、67.2%、56.3%和46.3%。Itovebi组合疗法组与安慰剂组患者的客观缓解率分别为62.7%（95% CI：54.8-70.2）和28.0%（95% CI：21.3-35.6），差异具统计学意义（p<0.0001）。Itovebi是一种口服疗法，具有高度的体外PI3Kα抑制效力和选择性，能够特异性触发PI3Kα蛋白突变体的分解。通过这种独特的双重作用机制，Itovebi可能为HR阳性/HER2阴性、PIK3CA突变的晚期乳腺癌患者提供耐受良好、持久的疾病控制和潜在改善的结局。它曾经获得美国FDA授予的突破性疗法认定。小分子联合疗法显著延长癌症患者生命！已递交监管申请Jazz Pharmaceuticals公布IMforte临床3期试验的总生存期结果，该试验评估Zepzelca（lurbinectedin）与PD-L1抑制剂Tecentriq（atezolizumab）联合作为广泛期小细胞肺癌（ES-SCLC）成人患者（≥18岁）一线维持疗法的效果。根据此积极结果，该公司已向美国FDA提交了Zepzelca组合疗法用于此类患者群体的监管申请。分析显示，在中位随访15.0个月时，与Tecentriq单药相较，接受Zepzelca与Tecentriq联合疗法患者的死亡风险降低了27%（HR=0.73，95% CI：0.57-0.95，P=0.0174）。接受Zepzelca组合疗法治疗患者的中位总生存期为13.2个月，而活性对照组患者的中位总生存期为10.6个月。Zepzelca又名PM1183，是一种烷基化药物，可结合DNA内的鸟嘌呤碱基。这触发了一系列级联反应，可影响DNA结合蛋白（包括一些转录因子）的活性，以及DNA修复通路，从而导致细胞周期的破坏和最终的细胞死亡。该疗法在2020年6月获美国FDA加速批准上市，用于治疗接受铂类药物化疗时或化疗后疾病进展的转移性小细胞肺癌成人患者。PD-L1抑制剂Tecentriq已经在美国，欧盟等国家获得批准，可以单独使用，也可以与靶向疗法或化疗联合使用，用于治疗多种癌症类型。肺癌突破性小分子疗法达主要终点，即将递交上市申请大鹏药品工业株式会社（Taiho Pharmaceutical）、Taiho Oncology和Cullinan Therapeutics宣布，其在研疗法zipalertinib作为单药，在治疗携带表皮生长因子受体（EGFR）外显子20插入突变（ex20ins）的非小细胞肺癌（NSCLC）患者的1/2期临床试验中达到主要终点，显著改善患者的客观缓解率。NSCLC是常见的肺癌类型，其中高达4%的病例携带EGFR外显子20插入突变，使其成为第三常见的EGFR突变亚型。之间公布的新闻稿指出，公司计划于2025年下半年向美国FDA提交该药物的上市申请。分析显示，在中位随访9.3个月时，在总疗效人群（n=176）中，确认的客观缓解率为35%，中位缓解持续时间（mDOR）为8.8个月。在之前仅接受过铂类化疗的患者中（n=125），ORR为40%，mDOR为8.8个月。而在接受过化疗和EGFR/MET靶向抗体amivantamab治疗（未添加其他ex20ins靶向治疗）的患者（n=30）中，ORR为30%，mDOR为14.7个月。在接受过化疗和amivantamab治疗（联合或不联合其他ex20ins靶向治疗）的患者（n=51）中，ORR为24%，mDOR为8.5个月。在脑转移患者（n=68）中，ORR则为31%，mDOR为8.3个月。Zipalertinib是一款靶向EGFR激活性突变体的口服小分子抑制剂。它能够抑制携带外显子20插入突变的EGFR变体，同时避免对野生型EGFR的抑制。Zipalertinib旨在作为下一代不可逆EGFR抑制剂，用于治疗特定基因亚型的NSCLC患者。它已获得FDA授予的突破性疗法认定。参考资料：[1] Verastem Oncology Announces Positive Updated Results from RAMP 205 Evaluating Avutometinib Plus Defactinib in Combination with Standard-of-Care Chemotherapy in Frontline Metastatic Pancreatic Ductal Adenocarcinoma. Retrieved May 23, 2025, from https://www.businesswire.com/news/home/20250522753974/en/Verastem-Oncology-Announces-Positive-Updated-Results-from-RAMP-205-Evaluating-Avutometinib-Plus-Defactinib-in-Combination-with-Standard-of-Care-Chemotherapy-in-Frontline-Metastatic-Pancreatic-Ductal-Adenocarcinoma[2] Kura Oncology and Kyowa Kirin Announce Pivotal Monotherapy Data for Ziftomenib in Oral Presentation at the 2025 ASCO Annual Meeting. Retrieved May 23, 2025, from https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-and-kyowa-kirin-announce-pivotal-monotherapy-data[3] Ziftomenib in relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML): Phase 1b/2 clinical activity and safety results from the pivotal KOMET-001 study. Retrieved May 23, 2025, from https://meetings.asco.org/abstracts-presentations/244205[4] INAVO120: Phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with PIK3CA-mutated, hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-resistant advanced breast cancer (aBC). Retrieved May 23, 2025 from https://meetings.asco.org/abstracts-presentations/244382[5] Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): Primary results of the phase 3 IMforte trial. Retrieved May 23, 2025 from https://meetings.asco.org/abstracts-presentations/243670[6] Cullinan Therapeutics, Taiho Pharmaceutical, and Taiho Oncology to Present Positive Results from Pivotal Phase 2b REZILIENT1 Trial of Zipalertinib at ASCO 2025. Retrieved May 23, 2025 from https://www.globenewswire.com/news-release/2025/05/22/3087169/0/en/Cullinan-Therapeutics-Taiho-Pharmaceutical-and-Taiho-Oncology-to-Present-Positive-Results-from-Pivotal-Phase-2b-REZILIENT1-Trial-of-Zipalertinib-at-ASCO-2025.html[7] Cullinan Therapeutics Provides Corporate Update and Reports First Quarter 2025 Financial Results. Retrieved May 23, 2025 from https://investors.cullinantherapeutics.com/news-releases/news-release-details/cullinan-therapeutics-provides-corporate-update-and-reports-3免责声明：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：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

ASCO会议临床结果突破性疗法临床2期临床1期

2025-05-22

·Firstwordpharma

ASCO25: Verastem's doublet posts encouraging response data in pancreatic cancer

Fresh off a regulatory win for its doublet therapy in ovarian cancer, Verastem Oncology is now looking to duplicate that success in pancreatic cancer.The biotech is evaluating Avmapki (avutometinib) and Fakzynja (defactinib) — a RAF/MEK clamp and selective FAK inhibitor, respectively — in combination with chemotherapy in the Phase I/II RAMP 205 study as a front-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (PDAC).Earlier this month, the FDA approved Avmapki Fakzynja Co-pack for adults with KRAS-mutated, recurrent, low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy after the doublet demonstrated a confirmed overall response rate of 44% in the Phase II RAMP 201 trial. In PDAC, early data from RAMP 205 — shared in an abstract ahead of the American Society of Clinical Oncology (ASCO) meeting — showed that the combo led to an overall response rate (ORR) of 83% in a dozen patients. Verastem's shares ticked up about 3% during after-hours trading on Thursday, after initially gaining 12%."The exciting results from the RAMP 205 trial reinforce our commitment to maximising the synergistic potential of the avutometinib plus defactinib combination in other advanced solid tumors," CEO Dan Paterson said in a company release. At the April 25 data cutoff, 60 patients in RAMP 205 were randomised evenly across five different dosing cohorts. According to Verastem, the 12 participants who received dose level 1 — a 2.4-mg dose of Avmapki twice a week, plus 200-mg Avmapki twice-daily for three weeks out of every four — saw "strong and consistent results" with the combination treatment. Eight patients experienced a confirmed partial response, while two have unconfirmed partial responses and remain on treatment. Verastem has selected this regimen for the recommended Phase II dose, and plans to enrol up to 29 patients in the cohort. The biotech has also begun planning a registrational Phase III study evaluating Avmapki and Fakzynja for front-line metastatic PDAC, which it expects to launch next year.

临床结果ASCO会议临床2期临床3期

2025-05-17

·ioncology

妇瘤前沿丨Bradley Monk点评：复发性KRAS突变低级别浆液性卵巢癌治疗新选择

点击蓝字关注我们2025年5月8日，FDA加速批准Avutometinib/Defactinib联合疗法，用于治疗至少接受过1次全身治疗的KRAS突变复发性低级别浆液性卵巢癌（LGSOC）成年患者。[1]此项批准基于II期ENGOT-ov60/RAMP-201/GOG-3052试验（NCT04625270）的结果。该试验结果显示，在57例KRAS突变复发性LGSOC患者中，该联合疗法的确认客观缓解率（ORR）为44%（95%CI: 31%-58%），缓解持续时间（DoR）范围为3.3-31.1个月。美国妇瘤专家Bradley Monk, MD, FACOG, FACS对这项审批予以点评。Bradley Monk, MD, FACOG, FACSFDA加速批准Avutometinib/Defactinib用于治疗KRAS突变复发性低级别浆液性卵巢癌患者，这在临床上有何意义？1Monk：这是FDA首次批准针对低级别浆液性卵巢癌的疗法。大多数卵巢癌病例是高级别浆液性卵巢癌（HGSOC），而LGSOC是一种较为罕见的卵巢癌亚型。70%的LGSOC病例由RAS驱动（MAPK通路）。大约30%的LGSOC病例携带KRAS突变，还可能存在NRAS、BRAF、NF1和其他RAS通路相关基因突变。KRAS突变尤为重要，此次加速批准是针对KRAS突变肿瘤。此项批准基于RAMP 201研究结果。2021年3月，FDA授予Avutometinib/Defactinib用于治疗低级别卵巢癌的突破性疗法认定，该认定基于研究者发起的I期FRAME试验（NCT03875820）的结果。[2]过去约4年以来，我们一直在研究LGSOC这种罕见肿瘤类型（包括约30%的KRAS突变肿瘤）以进行剂量优化。我们最终实现Avutometinib/Defactinib的剂量优化。RAMP 201研究结果计划发表在一份高影响力的临床肿瘤学期刊上。此外，根据加速批准要求，后续需完成III期验证试验，这项名为RAMP 301（NCT06072781）的试验目前已启动。RAF/MEK钳合剂（Avutometinib）和FAK抑制剂（Defactinib）组合如何在作用机制上克服KRAS突变浆液性卵巢癌的生物学复杂性？1Monk：这种药物组合可以改善LGSOC这种罕见肿瘤类型患者的预后。该组合包括口服Avutometinib（一种RAF/MEK钳合剂，能抑制MEK）；以及口服选择性FAK抑制剂Defactinib。该组合在肿瘤患者中的ORR为44%，已获得长期安全性和有效性数据。临床工作者可以立即使用该方案。我们设计RAMP 201试验的理念是，如果能够同时抑制MEK和FAK，就能克服MEK抑制本身固有的耐药性。请谈一谈这种联合方案的给药方案和安全性1Monk：患者每周两次口服3.2 mg的Avutometinib（分别在每周的第1天和第4天）；每日两次口服200 mg的Defactinib。这种联合方案需要在每个周期（4周）的前3周服用，这使得情况更加复杂。该方案包含激酶抑制剂，并且给药方案具有特异性，口服疗法需长期服用。常见的不良反应（AE）包括疲劳、肌肉骨骼疼痛、水肿以及皮疹等。不过，目前有一种积极的缓解策略可以治疗和预防痤疮样皮疹。LGSOC是一种独特的卵巢癌亚型，并非BRCA相关肿瘤，而是一种MAPK相关疾病。一旦确诊LGSOC，就可以进行全身治疗。如果患者在一线治疗后出现疾病进展，并且携带KRAS突变，则可接受Avutometinib/Defactinib治疗。目前，III期RAMP 301试验将继续在美国以及世界各地招募KRAS突变或野生型肿瘤患者。参考文献1.FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer. FDA. May 8, 2025. Accessed May 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-combination-avutometinib-and-defactinib-kras-mutated-recurrent-low2. Verastem Oncology receives breakthrough therapy designation for VS-6766 with defactinib in recurrent low-grade serous ovarian cancer. News release. Verastem, Inc. May 24, 2021. Accessed May 9, 2025. https://investor.verastem.com/news-releases/news-release-details/verastem-oncology-receives-breakthrough-therapy-designation-vs（来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

加速审批临床结果临床2期突破性疗法临床3期

100 项与 Avutometinib 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
交界性卵巢浆液性肿瘤	申请上市	美国	Verastem, Inc.	2024-05-24
卵巢浆液性肿瘤	临床3期	澳大利亚	Verastem, Inc.	2024-03-18
卵巢浆液性肿瘤	临床3期	比利时	Verastem, Inc.	2024-03-18
卵巢浆液性肿瘤	临床3期	加拿大	Verastem, Inc.	2024-03-18
卵巢浆液性肿瘤	临床3期	法国	Verastem, Inc.	2024-03-18
卵巢浆液性肿瘤	临床3期	德国	Verastem, Inc.	2024-03-18
卵巢浆液性肿瘤	临床3期	爱尔兰	Verastem, Inc.	2024-03-18
卵巢浆液性肿瘤	临床3期	意大利	Verastem, Inc.	2024-03-18
卵巢浆液性肿瘤	临床3期	荷兰	Verastem, Inc.	2024-03-18
卵巢浆液性肿瘤	临床3期	新西兰	Verastem, Inc.	2024-03-18

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临床结果

适应症

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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


phase 1 trial (AACR2025)	临床1期	转移性乳腺癌 CDK4/6 inhibitor (CDK4/6i)	16	Avutometinib 3.2 mg PO BIW	鬱襯選衊襯構遞鹽積襯(鬱窪顧築觸構襯繭廠遞) = 獵觸鑰鏇積顧鹽憲築顧壓鬱鹹壓顧齋構憲鏇構 (膚鑰廠觸衊蓋構蓋網艱 ) 更多	积极	2025-04-28
NCT05074810 (RAMP 203, BusinessWire) 人工标引	临床1/2期	KRAS G12C突变非小细胞肺癌 KRAS G12C	3	Defactinib，Avutometinib, sotorasib	積鏇鏇膚鏇襯艱獵蓋糧(遞網遞衊齋構鬱醖衊餘) = None 鏇衊襯蓋夢膚獵廠觸醖 (選憲願鬱窪鑰餘窪觸遞 ) 更多	积极	2024-12-18
NCT04625270 (ENGOT-OV60/GOG-3052/RAMP 201 Part A, SGO2024)	临床2期	卵巢浆液性肿瘤 RAS/MAPK pathway alterations	29	Avutometinib + Defactinib	壓獵鹽鹽獵簾衊鑰艱窪(選網鹹遞網鏇選選網簾) = 夢繭憲壓積淵鹹餘艱獵繭醖齋壓蓋淵窪窪淵夢 (蓋觸鹹餘鹽製夢衊鹹積, 26 ~ 64)	积极	2024-11-01
NCT04625270 (RAMP 201 \| ENGOTov60/GOG3052, Company_Website \| FDA) 人工标引	临床2期	卵巢浆液性肿瘤	109	Avutometinib and Defactinib Combination	願網遞獵鑰願餘淵鹽糧(淵觸醖網淵醖窪憲觸憲) = 顧築窪壓鹹顧築獵艱遞觸鬱遞襯鏇餘壓鏇窪製 (齋鏇簾鑰遞艱膚獵廠選, 23 ~ 41) 更多	积极	2024-10-17
				Avutometinib and Defactinib Combination (KRAS mutant)	願網遞獵鑰願餘淵鹽糧(淵觸醖網淵醖窪憲觸憲) = 網觸襯艱艱鑰構壓鹹齋觸鬱遞襯鏇餘壓鏇窪製 (齋鏇簾鑰遞艱膚獵廠選, 31 ~ 58) 更多
NCT05669482 (RAMP 205, ASCO2024) 人工标引	临床1/2期	转移性胰腺导管腺癌一线	18	Avutometinib/defactinib + gemcitabine/nab-paclitaxel	積齋衊衊膚糧廠蓋製鹹(衊夢遞願觸蓋鏇鏇鏇襯) = 簾鬱選鹹廠簾獵憲築襯膚築觸鹽艱壓蓋積衊範 (願鹽壓淵醖醖壓鹹構齋 ) 更多	积极	2024-05-24
NCT05074810 (RAMP 203, Corporate Publications) 人工标引	临床1/2期	KRAS G12C突变非小细胞肺癌 KRAS G12C	-	Avutometinib+sotorasib	鬱製願壓衊範鬱構鏇觸(範衊窪糧夢築鏇夢積積) = Avutometinib 4.0 mg PO BIW 21/28 days + sotorasib 960 mg PO QD 28/28 days 蓋簾製夢蓋鏇積糧製壓 (鹹衊構築艱淵衊夢鏇淵 )	积极	2023-10-14
NCT04625270 (ENGOT-Ov60/GOG-3052/RAMP 201, ESGO2023)	临床2期	卵巢浆液性肿瘤 KRAS mutant \| KRAS wild-type	151	Avutometinib	憲醖壓簾憲製遞糧鏇鑰(糧壓積積蓋鹹淵鑰選製) = 蓋襯遞窪廠鹽築顧膚壓選築憲製範醖顧壓選構 (鹽繭願糧鏇窪鹽餘簾餘 ) 更多	积极	2023-09-27
				Avutometinib + Defactinib	憲醖壓簾憲製遞糧鏇鑰(糧壓積積蓋鹹淵鑰選製) = 壓繭艱齋顧範鹹膚廠餘選築憲製範醖顧壓選構 (鹽繭願糧鏇窪鹽餘簾餘 ) 更多
NCT04625270 (RAMP 201, ASCO 12023 \| ASCO 22023) 人工标引	临床2期	卵巢癌	121	avutometinib 4 mg	憲襯淵憲淵觸鹹廠觸憲(膚範窪築膚窪餘襯鹽鬱) = 淵廠範鬱蓋醖醖壓襯襯製鑰顧鑰範積選窪襯築 (顧淵遞構衊顧淵構鹽鏇 ) 更多	积极	2023-05-31
				avutometinib 3.2 mg+defactinib 200 mg	憲襯淵憲淵觸鹹廠觸憲(膚範窪築膚窪餘襯鹽鬱) = 積築鏇積齋襯廠築鹹顧製鑰顧鑰範積選窪襯築 (顧淵遞構衊顧淵構鹽鏇 ) 更多
NCT04620330 (RAMP 202, ASCO 12023 \| ASCO 22023) 人工标引	临床2期	KRAS突变非小细胞肺癌 KRAS G12V Mutantion	35	Avutometinib	鹹觸淵衊構餘蓋積淵襯(淵膚築夢鹹鏇築遞淵糧) = 齋膚憲鹹廠糧醖獵積糧觸築選壓窪構憲餘襯鏇 (築築選廠築顧築鹽壓選 )	不佳	2023-05-26
				Defactinib+Avutometinib	鹹觸淵衊構餘蓋積淵襯(淵膚築夢鹹鏇築遞淵糧) = 糧製餘襯壓淵糧窪鬱齋觸築選壓窪構憲餘襯鏇 (築築選廠築顧築鹽壓選 )
NCT04620330 (RAMP 202, Corporate Publications) 人工标引	临床2期	非小细胞肺癌	56	VS-6766+defactinib (KRAS G12V NSCLC)	構醖齋鹹蓋壓製願餘鏇(壓鬱願築餘窪窪蓋鏇壓) = 淵鑰壓鹹餘製鹽艱觸顧壓願鏇夢壓鹽製繭選憲 (鹹鹽鬱積膚繭夢構鹹網 ) 更多	不佳	2022-10-04
				VS-6766+defactinib (non-G12V KRAS mutations)	構醖齋鹹蓋壓製願餘鏇(壓鬱願築餘窪窪蓋鏇壓) = 窪艱夢製築膚蓋鹹鏇鬱壓願鏇夢壓鹽製繭選憲 (鹹鹽鬱積膚繭夢構鹹網 ) 更多