A Phase 1a/1b Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of BBO-8520 in Subjects with Advanced KRASG12C Mutant Non-Small Cell Lung Cancer - the ONKORAS-101 Study

A first in human study to evaluate the safety and preliminary antitumor activity of BBO-8520, a KRAS G12C (ON and OFF) inhibitor, as a single agent and in combination with pembrolizumab in subjects with locally advanced and unresectable or metastatic non-small cell lung cancer with a KRAS (Kirsten rat sarcoma) G12C mutation.

开始日期2024-05-22

申办/合作机构

TheRas, Inc.

100 项与 BBO-8520 相关的临床结果

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100 项与 BBO-8520 相关的专利（医药）

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项与 BBO-8520 相关的文献（医药）

2025-04-01·TRENDS IN MOLECULAR MEDICINE

Targeting the Yin and Yang of KRASG12C

Article

作者: Papavassiliou, Athanasios G ; Adamopoulos, Christos ; Papavassiliou, Kostas A

In a recent study in Cancer Discovery, Maciag et al. introduce BBO-8520, a novel inhibitor targeting both the active and inactive states of KRAS^G12C. This dual inhibition shows superior target engagement and prolonged tumor suppression, offering a compelling strategy to overcome resistance development and improve outcomes in KRAS^G12C-mutant cancers.

2025-03-03·Cancer Discovery

Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF) KRASG12C

Article

作者: Sinkevicius, Kerstin W. ; Mehdizadeh, Sadaf ; Abreu Blanco, Maria ; Esposito, Dominic ; Simanshu, Dhirendra K. ; Larsen, Erik K. ; Wallace, Eli ; Dyba, Marcin ; Wong, Kwok-Kin ; Ranieri, Michela ; Denson, John-Paul ; Stephen, Andrew G. ; Jeknic, Stevan ; Yang, Yue ; Alexander, Patrick A. ; Zhang, Zuhui ; Nissley, Dwight V. ; Beltran, Pedro J. ; Turner, David M. ; Meynardie, Mary ; Maciag, Anna E. ; Chan, Albert H. ; Wang, Keshi ; Smith, Brian P. ; Singh, Devansh ; Rabara, Dana ; Setoodeh, Saman ; Xu, Rui ; Lin, Ken ; McCormick, Frank ; Ju, Jin Hyun ; Sharma, Alok K. ; Stice, James P. ; Lightstone, Felice C. ; Wang, Bin

Abstract:

Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine, and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor–activated states, in which current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in phase 1 clinical trials in patients with KRASG12C non–small cell lung cancer.Significance: BBO-8520 is a first-in-class direct, small molecule covalent dual inhibitor that engages KRASG12C in the active (ON) and inactive (OFF) conformations. BBO-8520 represents a novel mechanism of action that allows for optimal target coverage and delays the emergence of adaptive resistance seen with (OFF)-only inhibitors in the clinic.See related commentary by Zhou and Westover, p. 455

2025-03-03·Cancer Discovery

Beyond First-Generation KRAS Inhibitors: BBO-8520 Tests the Dual Mechanism Hypothesis

Article

作者: Westover, Kenneth D. ; Zhou, Zhiwei

Summary::

This issue highlights the development of a first-in-class small-molecule covalent KRASG12C inhibitor, BBO-8520, which targets both the active (ON) and inactive (OFF) states of KRAS. This dual-state targeting offers a significant opportunity to overcome the resistance mechanisms that have limited the efficacy of first-generation KRAS inhibitors and addresses critical challenges in KRAS-targeted therapy.See related article by Maciag et al., p. 578

项与 BBO-8520 相关的新闻（医药）

2025-04-17

·frederick.cancer.gov

Drugs targeting KRAS cancers co-developed by FNL to be featured at AACR Annual Meeting 

Study results of two investigational drugs that target KRAS-driven cancers co-developed by RAS Initiative investigators at the Frederick National Laboratory for Cancer Research (FNL) and now being tested in patients will be presented at the American Association for Cancer Research Annual Meeting April 25-30 at McCormick Place in Chicago.  Both compounds, BBO-8520 and BBO-11818, were developed in partnership via Cooperative Research and Development Agreement (CRADA) with BridgeBio Oncology Therapeutics (BBOT) and Lawrence Livermore National Laboratory.  Representatives of BBOT, sponsor of the clinical trials for both agents, will present the data during the AACR meeting.  James P. Stice, an associate director at BBOT, will discuss results of pre-clinical studies on BBO-8520 in a mini symposium on novel antitumor agents, Monday, April 28 in room S103. BBO-8520 targets KRAS G12C, the most common KRAS variant in lung cancer.   On Tuesday, April 29, BBOT Associate Director Carlos Stahlhut will present a poster on preclinical studies of BBO-11818, which shows activity against multiple KRAS mutants, and falls into the category of a pan-KRAS inhibitor.  The poster is in section 21 from 9 a.m. to noon.  Laboratory tests show BBO-8520 blocks the active “ON” and inactive “OFF” states of KRAS G12C, resulting in rapid KRAS inhibition. While existing treatments for KRAS G12C-driven cancer have shown promising clinical efficacy, they block the KRAS G12C “OFF” state only, and patients develop resistance to the drug. The collaborators published results of pre-clinical assays in Cancer Discovery.   There are no approved targeted therapies against other KRAS variants, which drive several major cancer types including pancreatic, colorectal and non-small cell lung cancer. BBO-11818 has shown activity against multiple KRAS mutants including KRAS G12D and KRAS G12V in their active and inactive states. The National Cancer Institute established the RAS Initiative in 2013 to explore and target RAS, the most frequently mutated oncogene in cancer, which at the time had no viable treatments. FNL is at the center of the hub-and-spoke model of a worldwide collaboration to investigate the complexity of RAS biology and therapy through the RAS Initiative.   Mary Ellen Hackett Manager, Communications Office 301-401-8670

AACR会议临床研究

2025-04-09

·ioncology

2025 ELCC | KRAS突变NSCLC领域创新疗法与联合策略探索进展

点上方蓝字“ioncology”关注我们，然后点右上角“…”菜单，选择“设为星标”ELCC 2025 微专辑扫描二维码可查看更多内容2025年欧洲肺癌大会(ELCC)于2025年3月26日至29日在法国巴黎举行，本次会议公布了众多对临床诊疗决策有重要参考意义的临床试验结果。《肿瘤瞭望》精选与临床医生关系密切的口头汇报进行编译，为临床医生的诊疗决策提供依据。Adagrasib联合帕博利珠单抗一线治疗携带KRAS G12C突变且PD-L1≥50%的晚期非小细胞肺癌患者的疗效及安全性：II期KRYSTAL-7研究研究背景对于携带KRAS G12C突变且PD-L1≥50%的患者，II期KRYSTAL-7研究展示了KRAS G12C抑制剂联合帕博利珠单抗的抗肿瘤活性，本研究报道了更新后的随访数据。研究方法该研究中，符合入组标准的患者接受一线Adagrasib 400 mg，口服，每日两次联合帕博利珠单抗200 mg，静脉，每三周一次的治疗，主要研究终点为研究者评估的ORR，次要研究终点包括DOR、PFS、OS安全性。研究结果至2024年8月23日，共计149例患者入组，在54例PD-L1≥50%的患者中，ORR为59.3%，中位DOR为26.3个月，中位PFS为27.7个月，18个月PFS率为50.7%，中位OS未达到，18个月OS率为62.4%。在149例患者中，治疗相关不良反应发生率为94.6%，3度以上治疗相关不良反应发生率为68.4%。3例患者出现5度治疗相关不良反应，包括2例为肺炎，1例肺纤维化。最常见的任何级别治疗相关不良反应包括：恶心55.7%，腹泻47.0%，转氨酶升高39.6%，因治疗相关不良反应而导致Adagrasib和帕博利珠单抗治疗终止的比例分别为13.4%和23.5%。研究结论经过更长的随访时间后，一线Adagrasib联合帕博利珠单抗展示了持久的抗肿瘤活性，安全性可管理。在这部分患者中，旨在比较一线Adagrasib联合帕博利珠单抗或帕博利珠单抗单药的III期临床研究正在进行中。RMC-6236在RAS突变非小细胞肺癌患者中的安全性及抗肿瘤活性研究背景经治非小细胞肺癌患者的后线治疗存在较大的未满足的临床需求，文献报道的中位OS时间＜1年，RAS基因突变是较常见的非小细胞肺癌患者的驱动突变，RMC-6236是一款口服RAS抑制剂，研究报道了该药在RAS突变非小细胞肺癌患者中的I期临床研究数据。研究方法携带RAS基因突变的晚期实体瘤患者，纳入剂量爬坡，剂量为120~300 mg。在非小细胞肺癌患者中，200 mg，每日一次是后续推荐的给药剂量。安全性报道了给予120~220 mg的73例患者的数据，临床活性报道了接受120 mg-220 mg剂量治疗的患者的活性。研究结果患者中位治疗线数为2线，81%的患者PS评分1分。任何级别发生率≥20%的治疗相关不良反应包括：皮疹90%，腹泻63%，恶心49%，呕吐40%，胃肠粘膜炎34%，3度以上皮疹发生率为7%，没有出现4度及5度治疗相关不良反应，因治疗相关不良反应而导致剂量修订的患者占比为41%，4%的患者因不良反应而导致治疗永久终止。中位治疗强度为88%，ORR为38%，中位DOR和中位PFS分别为15.5个月和9.8个月，中位OS为17.7个月。研究结论RM-6236 120~220 mg，口服，每日一次治疗携带RAS突变的非小细胞肺癌患者展示了良好的抗肿瘤活性以及持久的响应和可管理的安全性。这项数据支持以多西他赛为对照组的III期临床研究开展。氟泽雷塞联合西妥单抗在 KRAS G12C突变的晚期非小细胞肺癌患者的疗效及安全性： KROCUS研究的疗效及安全性更新研究背景EGFR上游通路的激活被认为是导致KRAS抑制剂耐药的主要机制。KRAS G12C抑制剂与针对EGFR抗体的联合需要进一步探索。本研究报道了氟泽雷塞联合妥昔单抗的疗效及安全性。研究方法KROCUS研究是一项国际、多中心、单臂、II期临床研究，入组患者接受氟泽雷塞600 mg，口服，每日两次联合西妥昔单抗500 mg/m2，每两周一次的治疗。主要研究终点为研究者评估的ORR，其他研究终点包括安全性、DCR、DOR、PFS和OS等。研究结果共计47例患者纳入分析，中位随访时间12.8个月，中位PFS为12.5个月，中位DOR和OS均为未达到，ORR为80.8%，57.8%的患者瘤体缩小超过50%，有脑转移的患者ORR为71.4%，不同PD-L1表达水平的患者获益都有获益，＜1%、1~49%和≥50%的患者，ORR分别为57.1%、62.5%和75%。免疫组化染色并未观察到EGFR蛋白表达水平与响应之间的关系。 STK-11(62.5% vs. 69.4%)或KEAP-11(66.7% vs. 68.3%)是否共突变的患者均观察到了响应，联合治疗展示了良好的安全性及耐受性，分别有6.4%和29.8%的患者因不良反应而导致治疗永久终止以及治疗中断。最常见的治疗相关不良反应为皮疹53.2%(3度2.1%)。研究结论氟泽雷塞联合西妥昔单抗一线治疗KRAS G12C突变的非小细胞肺癌患者展示了持久的抗肿瘤活性，提供了一个免化疗的治疗选择。以帕博利珠珠单抗联合化疗作为对照组的III期临床研究正在计划中。小结及思考KRAS突变是较早发现的驱动基因突变，由于其特殊的蛋白结构，该靶点的成药一直存在很大困难，导致这部分患者的治疗选择按照突变阴性的患者进行。Sotorasib和Adagrasib为患者提供了靶向治疗选择。但两款药物的注册性关键研究均是II期、单臂研究，且为附条件获得二线治疗适应症。在与多西他赛的头对头研究中，两款靶向治疗药仅展示了轻微获益，一线单药治疗恐难以击败当前的标准治疗选择——化疗联合免疫，因此，如何将这一治疗选择推广至更加广泛的一线人群非常重要。目前已经有了几种策略：第一：与传统的细胞毒类药物联合。这是最常见也是最容易想到的联合治疗方式。近期，JTO杂志发表了一项单臂、II期临床研究，探索了对于携带KRAS G12C突变的患者，一线接受Sotorasib联合含铂双药治疗的疗效及安全性。研究纳入30例患者，27例纳入疗效分析，ORR为88.9%，展示了良好的抗肿瘤活性，DCR为92.6%，中位PFS为6.6个月，12个月PFS率41.0%，全组患者中位OS为20.6个月，12个月OS率为66.7%。第二，与EGFR单克隆抗体联合。以本届ELCC公布的KROCUS研究为代表。从间接比较的数据看，该治疗策略无论是疗效还是安全性，似乎优于与化疗联合。第三、新型RAS抑制剂的研发。KRAS G12C有两种状态——与与GTP结合的激活状态和与GDP结合的失活状态。Sotorasib和Adagrasib、同类的Divarasib，只能结合失活状态的KRAS G12C突变，且耐药发生迅速。新一代的RAS抑制剂，如BBO-8520，无论KRAS G12C处于激活状态还是失活状态，都可以有效结合。目前，在肺癌中的I期临床研究ONKORAS-101已经开启。当前，除KRAS G12C抑制剂外，G12D抑制剂以及泛KRAS抑制剂均在研发，靶向蛋白水解技术同样有涉及。有望为患者的治疗带来新的选择。《肿瘤瞭望》在ELCC现场报道（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。

临床3期临床结果临床2期

2025-04-02

·PipelineReview

BBOT Announces First Patient Dosed with BBO-11818, a PanKRAS Dual Inhibitor, in the Phase 1 KONQUER-101 Trial for Advanced Solid Tumors

SOUTH SAN FRANCISCO, CA, USA I April 01, 2025 I TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (“BBOT” or the “Company”), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, today announced that the first patient has been dosed with BBO-11818 in the Phase 1 KONQUER-101 trial for advanced solid tumors. BBO-11818 is an orally bioavailable small molecule dual inhibitor that directly binds to both the “ON” and “OFF” states of KRAS. KONQUER-101 will enroll patients globally with certain KRAS mutations. “The dosing of the first patient is a major milestone in assessing BBO-11818’s potential benefit for patients with tumors driven by mutant KRAS,” said Dr. Ignacio Garrido-Laguna, MD, PhD, Principal Investigator at Huntsman Cancer Institute at the University of Utah. “We are committed to bringing cutting-edge therapies to patients with advanced cancer in the Mountain Region. BBO-11818 has the potential to safely achieve optimal target inhibition and combine with other targeted therapies. We look forward to evaluating it in the KONQUER-101 trial.” BBO-11818 was designed to non-covalently bind both the inactive GDP-bound “OFF” and active GTP-bound “ON” forms of KRAS G12D and KRAS G12V . In cellular assays, EC 50 values for pERK inhibition in selected KRAS G12D and G12V-mutant cell lines range from sub-nanomolar to single-digit nanomolar potency. BBO-11818 is similarly effective in reducing cell viability in KRAS G12D , KRAS G12V , and KRAS G12C -mutant cell lines. Further, NRAS and BRAF mutant cell lines show insensitivity to BBO-11818, and the molecule exhibits more than 500-fold selectivity for KRAS over H- and NRAS. “There is a great need for new therapies that can safely treat patients with tumors driven by KRAS mutations, as the current standard of care lacks satisfactory options as monotherapy or to enable combinations of KRAS targeted therapies with other targeted agents,” said Yong (Ben) Ben, MD, Chief Medical and Development Officer of BBOT. “BBO-11818 marks the third molecule entering the clinic for BBOT, further proving our capability to advance novel programs into the clinic. Of note, our portfolio is uniquely positioned to deliver the combination of MAPK (BBO-8520 and BBO-11818) and PI3Kα/AKT (BBO-10203) co-inhibition, with a therapeutic index. We hope this will bring unprecedented benefit to patients with RAS-driven cancers.” The discovery of BBO-11818 was the result of a collaboration between the RAS Initiative at Frederick National Laboratory, Lawrence Livermore National Laboratory, and BBOT. About BBOT BBOT is a clinical-stage biopharmaceutical company advancing a next-generation pipeline of novel small molecule therapeutics targeting RAS and PI3Kα malignancies. Initially formed as a subsidiary of BridgeBio Pharma, Inc. (Nasdaq: BBIO), BBOT has the goal of improving outcomes for patients with cancers driven by the two most prevalent oncogenes in human tumors. For more information, visit bridgebiooncology.com . SOURCE: BridgeBio Oncology Therapeutics

临床1期

100 项与 BBO-8520 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
KRAS G12C突变非小细胞肺癌	临床1期	美国	TheRas, Inc.	2024-05-22
KRAS G12C突变非小细胞肺癌	临床1期	澳大利亚	TheRas, Inc.	2024-05-22
转移性非小细胞肺癌	临床1期	美国	TheRas, Inc.	2024-05-22
转移性非小细胞肺癌	临床1期	澳大利亚	TheRas, Inc.	2024-05-22
KRAS G12C突变的实体瘤	临床申请批准	美国	BridgeBio Pharma, Inc.	2024-01-03