Sotorasib

关注并星标CPHI制药在线 在医药领域备受瞩目的第五届 RAS 倡议研讨会上，加科思药业以壁报展示的形式，对外公布了其自主研发的 SHP2 抑制剂 JAB-3312 与 KRAS G12C 抑制剂戈来雷塞联合用药的最新临床前研究成果。作为加科思精心打造的新一代 SHP2 抑制剂，JAB-3312 脱颖而出，成为全球范围内率先挺进 III 期临床研究的同类药物，开创了该领域的先河，而在当下，这一领域尚未有任何药物成功获批上市，JAB-3312 的前景备受瞩目。 时光回溯至 2024 年 8 月，加科思与艾力斯达成了一项意义重大的合作协议，毅然将戈来雷塞和 JAB-3312 在中国大陆、中国香港、中国澳门以及中国台湾地区的权益授予艾力斯。依据双方签订的协议具体条款，艾力斯需向加科思支付高达 1.5 亿元的首付款，同时，在后续的开发与销售进程中，若达成特定里程碑，还将支付最高可达 7.0 亿元的款项，此外，加科思还将享有以两位数比例计算的销售提成，这无疑是双方基于各自优势资源实现互利共赢的有力举措。同年 9 月，加科思顺利收到了来自艾力斯的 1.72 亿元合作款项，这笔资金不仅涵盖了先前约定的 1.5 亿元首付款，还包括 2279 万元的研发费用补偿以及其他相关款项，为加科思的持续研发与创新注入了强劲动力，也进一步稳固了双方合作的基石，有望共同推动这两款药物在国内市场的发展，为广大患者带来新的治疗希望。 一、KRAS G12C肺癌 KRAS G12C 阳性肺癌是肺癌的一种特定亚型，具有独特的分子特征和临床意义。 KRAS 基因属于 RAS 基因家族，是细胞内重要的信号转导分子。正常情况下，KRAS 蛋白在细胞的生长、增殖、分化以及存活等生理过程中发挥着精确调控的作用。然而，当 KRAS 基因发生突变时，其编码的蛋白会失去正常的调控机制，持续处于激活状态，导致下游一系列细胞信号通路的异常激活，进而促使细胞无限制地增殖、逃避凋亡，并获得侵袭和转移能力，最终引发肿瘤的发生和发展。 在 KRAS 基因的众多突变类型中，G12C 突变是较为常见且具有重要研究价值的一种。这种突变发生在 KRAS 蛋白的第 12 个氨基酸残基上，由甘氨酸（G）突变为半胱氨酸（C）。KRAS G12C 突变导致蛋白的构象发生改变，使其与鸟苷三磷酸（GTP）的亲和力增强，从而使 KRAS 蛋白长时间处于 GTP 结合的活性状态，持续向细胞内传递异常的生长信号，推动肿瘤细胞的恶性进展。 KRAS G12C 阳性肺癌在非小细胞肺癌（NSCLC）中占有一定比例，通常多见于吸烟人群，且以腺癌居多。这类肺癌往往具有较强的侵袭性和转移性，疾病进展相对较快，患者的预后情况不太乐观。传统的化疗药物对于 KRAS G12C 阳性肺癌的治疗效果并不理想，难以有效控制肿瘤的生长和扩散，且患者在接受化疗后容易出现耐药现象，导致疾病复发。同时，早期的一些针对其他常见驱动基因突变（如 EGFR、ALK 等）的靶向药物对 KRAS G12C 突变的肺癌患者几乎无效，这使得 KRAS G12C 阳性肺癌的治疗成为临床上的一大难题。 近年来，随着医学研究的深入，针对 KRAS G12C 突变的特异性靶向药物研发取得了显著突破。例如，Sotorasib 等药物的出现为 KRAS G12C 阳性肺癌患者带来了新的治疗选择。这些药物通过与 KRAS G12C 突变蛋白的特定区域结合，抑制其活性，从而阻断异常的细胞信号传导，达到抑制肿瘤生长的目的。在临床研究中，部分患者接受 KRAS G12C 靶向药物治疗后，肿瘤得到了一定程度的控制，症状有所缓解，生存期也有所延长。此外，联合治疗策略也成为研究的热点方向，如将 KRAS G12C 抑制剂与其他靶向药物、免疫治疗药物等联合使用，旨在进一步提高治疗效果，克服肿瘤的耐药性，为患者提供更优化的治疗方案，改善其生存质量和预后。但目前仍需要更多的临床研究来深入探索这些治疗方法的长期疗效、安全性以及最佳使用方式等问题，以不断完善 KRAS G12C 阳性肺癌的治疗体系。 二、关于JAB-3312 JAB-3312高效抑制肿瘤 JAB-3312 作为新一代靶向药，在肿瘤治疗方面展现出了强大的实力。它可以阻断 KRAS-MAPK 信号通路，对多种实体瘤患者具有显著疗效，包括非小细胞肺癌、结直肠癌、胰腺癌等。多项实验表明，JAB-3312 能够显著强化其他药物的抗肿瘤效能，实现较高的客观缓解率和中位无进展生存期。例如，在口服新药 KRAS 突变 glecirasib 联合 JAB-3312 对晚期肺癌的治疗中，疾病控制率达 100%。在 50 例非小细胞肺癌患者中，28 例首次接受 KRAS G12C 抑制剂治疗的可评估患者，客观缓解率（ORR）为 50%、疾病控制率达到了 100%。对于既往 KRAS G12C 抑制剂治疗耐药的 NSCLC 患者而言，ORR 为 14.3%、DCR 为 57.1%。 JAB-3312 在体内具有良好的生物利用度，血浆蛋白结合率高，药物清除率低。在各种动物模型中，JAB-3312 显示了快速的口服吸收。药物相互作用研究表明，JAB-3312 对常见的 CYP 酶无明显抑制作用，体内药物相互作用的风险较低。例如，在 glecirasib 与 JAB-3312 联合治疗中，JAB-3312 的药代动力学特征与其单药治疗相当，这表明 glecirasib 与 JAB-3312 之间的药物相互作用风险较低。 同类最佳潜力 JAB-3312 是全球唯一的第二代 SHP2 抑制剂，临床剂量低于第一代分子 20 倍，具备提升药效和降低毒性等优势。美银证券认为加科思的二代 SHP2 抑制剂 JAB-3312 有三大优势：临床前数据优于同类，特别是结合动力学显著优于 RMC-4550；更强大的抗肿瘤活性，更低的剂量（每日仅 1 - 8 毫克）；IC50 仅 1.5nM，显著低于同类产品。加科思在 2023 年欧洲肿瘤内科学会年会发布的数据显示，在 129 位非小细胞肺癌患者中，有 58 位一线治疗的患者（包括 7 个剂量组）ORR（客观缓解率）为 65.5%，DCR（疾病控制率）为 100%。其中在 800 毫克戈来雷塞（每日一次）及 2 毫克 JAB-3312（每日一次，给药一周停药一周）联用的剂量组中，ORR 为 86.7%。 三、JAB-3312 临床研究数据 2019 年，加科思的新一代靶向药 JAB-3312 在 2019 年可谓迈出了关键的一步。这一年，JAB-3312 获得了美国 FDA 和中国 NMPA 的新药临床试验许可，标志着其正式踏上了临床研究的征程。随后，在美国和中国多家医院启动的临床 I 期研究，为后续的研发工作奠定了坚实的基础。 2023 年，欧洲肿瘤内科学会年会发布的数据显示，JAB-3312 在非小细胞肺癌患者中的治疗效果显著。2023 年欧洲肿瘤内科学会年会成为了 JAB-3312 的重要展示舞台。会上发布的数据显示，JAB-3312 在非小细胞肺癌患者中展现出了显著的治疗效果。在 129 位非小细胞肺癌患者中，有 58 位一线治疗的患者（包括 7 个剂量组），客观缓解率（ORR）为 65.5%，疾病控制率（DCR）为 100%。其中在 800 毫克戈来雷塞（每日一次）及 2 毫克 JAB-3312（每日一次，给药一周停药一周）联用的剂量组中，ORR 为 86.7%。这些数据充分证明了 JAB-3312 在非小细胞肺癌治疗中的巨大潜力。 2024 年，JAB-3312 与 KRAS G12C 抑制剂戈来雷塞联合用药获国家药监局批准注册性三期临床试验，成为全球首个与 KRAS G12C 抑制剂联合用药进入三期注册性临床研究的 SHP2 抑制剂。这一成就让 JAB-3312 成为全球首个与 KRAS G12C 抑制剂联合用药进入三期注册性临床研究的 SHP2 抑制剂。此次在中国获批的研究是一项随机阳性药对照的三期临床试验，旨在评估 JAB-3312 与戈来雷塞联合用于 KRAS G12C 突变的一线非小细胞肺癌患者的疗效及安全性，试验的对照组是目前一线非小细胞肺癌的标准疗法，即 PD-1 抗体和化疗联合治疗。这一批准不仅是对 JAB-3312 临床价值的高度认可，也为全球非小细胞肺癌患者带来了新的希望。 四、JAB-3312 的未来展望 作为目前研发进展最快的 SHP2 抑制剂，JAB-3312 承载着众多期望。业界曾一度认为针对 SHP2 的新药开发难度极大，有 “不可成药” 的说法，但加科思的 JAB-3312 正努力打破这一魔咒。天风证券预计，JAB-3312 有望于 2026 年在中国获批上市，2027 年在海外获批上市。如果成功获批，它将为肿瘤患者带来全新的治疗选择，尤其是对于那些患有 KRAS G12C 突变的非小细胞肺癌患者来说，无疑是一个重大的福音。 参考文献： [1] 王卡拉. “不可成药” 魔咒或将破除，全球首个 SHP2 抑制剂进入三期临床 [EB/OL]. http://m.toutiao.com/group/7337666847686885903/ upstream_biz=doubao, 2024-02-20. [2] 探秘抗肿瘤新锐：SHP2 变构抑制剂 JAB-3312 的发现与优化 [EB/OL]. https://www-zhihuiya-com.libproxy1.nus.edu.sg/news/info_4954.html, 2024-09-28. [3] SHP2 “增敏剂” 效果显著，与 KRAS G12C 联用一线疗法 ORR 达 86.7%[EB/OL]. https://zhuanlan.zhihu.com/p/662927475, 2023-10-23. [4] 张敏。全球首个 SHP2 抑制剂进入三期临床 加科思领跑 [EB/OL]. http://m.toutiao.com/group/7337299995760067107/ upstream_biz=doubao, 2024-02-19. [5] “不可成药靶点” 突破！疾病控制率 100%，口服新药助力中国晚期肺癌患者缓解 [EB/OL]. https://k.sina.cn/article_5284329303_13af87757019012obi.html, 2023-10-20. [6] 傅苏颖，刘月楼。加科思董事长王印祥：在研治疗非小细胞癌药品有望年内完成临床试验 [EB/OL]. http://m.toutiao.com/group/7246743997312762379/ upstream_biz=doubao, 2023-06-20. END 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

BOSTON--( BUSINESS WIRE )--Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, today announced preliminary clinical data for the triplet combination of avutometinib and sotorasib plus defactinib in the RAMP 203 Phase 1/2 study in KRAS G12C mutant advanced non-small cell lung cancer (NSCLC). No dose-limiting toxicities (DLTs) have been observed in the triplet combination. RAMP 203 continues to progress, with additional enrollment expected and an interim update is planned to be presented at a medical meeting in the second half of 2025. “We continue to make progress across our pipeline to develop novel therapies alone or in synergistic combinations that have the potential to improve outcomes in RAS/MAPK pathway-driven cancers. Defactinib, our oral FAK inhibitor, has been an important addition to multiple clinical trials with avutometinib to address key resistance mechanisms in parallel pathway signaling,” said Dan Paterson, chief executive officer at Verastem Oncology. “Recently, we added defactinib to the combination of avutometinib and sotorasib in our RAMP 203 trial. Preliminary data for the triplet combination have shown a generally favorable tolerability profile and encouraging initial anti-tumor activity. We look forward to progressing enrollment and evaluating the safety and efficacy of the triplet combination in treating KRAS G12C mutant non-small cell lung cancer.” RAMP 203 Clinical Update As of a November 21, 2024, data cutoff, three patients whose cancer previously progressed on a G12C inhibitor have been treated with the triplet combination of sotorasib 960 mg administered daily on a continuous schedule and avutometinib 3.2 mg twice-weekly (BIW) plus defactinib 200 mg twice-daily (BID). Avutometinib and defactinib are administered on a three out of four weeks schedule.​ Two of the three patients demonstrated initial tumor reductions of at least 20% at the first scan. As of the data cutoff, all three patients remain on treatment.​ With no DLTs observed in the first triplet combination cohort, the Company anticipates the enrollment of additional patients to the triplet combination prior to presenting the data at a medical meeting next year.​ As previously reported, the doublet combination of avutometinib with sotorasib has completed enrollment (n=28) in the G12C inhibitor treatment-naïve Stage 1 Part B cohort.​ The KRAS G12C inhibitor prior-treated Stage I Part B cohort is still enrolling patients and is anticipated to complete enrollment in early 2025. Patients in both cohorts continue to be followed for safety and efficacy to determine if observed efficacy supports expanded enrollment. The Company plans to complete enrollment and evaluate the safety and efficacy of the triplet combination, before expanding either of the doublet cohorts. “We are encouraged by the initial data from the triplet combination of avutometinib and sotorasib plus defactinib in the RAMP 203 trial, which shows early evidence of tumor reductions for patients who have limited treatment options,” said John Hayslip, M.D., chief medical officer at Verastem Oncology. “While the data matures for the doublet combination across cohorts, we are now focused on completing the enrollment in the triplet combination, guided by preclinical data that indicates that the addition of a FAK inhibitor increases the anti-tumor efficacy of avutometinib plus sotorasib in KRAS G12C mutant NSCLC models, and tumors that progress on a G12C-inhibitor treatment can be made to respond again upon treatment with a FAK inhibitor plus avutometinib. As planned, the triplet combination builds on the experience from the RAMP 201 study in recurrent low-grade serous ovarian cancer, where there was a clear advantage to adding defactinib. Based on the RAMP 201 results, we did an assessment of our clinical programs and made the decision to add defactinib to almost all our studies.” About RAMP 203 RAMP 203 is a Phase 1/2, multicenter, open label, dose evaluation/expansion study evaluating the efficacy and safety of avutometinib and sotorasib with or without defactinib in patients with KRAS G12C mutant non-small cell lung cancer (NSCLC) who have not been previously treated with a KRAS G12C inhibitor as well as in patients who have been previously treated with a KRAS G12C inhibitor (NCT05074810). RAMP 203 is being conducted in collaboration with Amgen. About the Avutometinib and Defactinib Combination Avutometinib is an oral RAF/MEK clamp that potentially inhibits MEK1/2 kinase activities and induces inactive complexes of MEK with ARAF, BRAF, and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition. In contrast to currently available MEK-only inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of the MEK-only inhibitors. Defactinib is an oral, selective inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2), the two members of the focal adhesion kinase family of non-receptor protein tyrosine kinases. FAK and Pyk2 integrate signals from integrin and growth factor receptors to regulate cell proliferation, survival, migration, and invasion. FAK activation has been shown to mediate resistance to multiple anti-cancer agents including RAF and MEK inhibitors. Verastem Oncology is currently conducting clinical trials with avutometinib with and without defactinib in RAS/MAPK driven tumors as part of its Raf And Mek Program or RAMP. Verastem is currently enrolling patients and activating sites for RAMP 301 (GOG-3097;ENGOT-ov81/NCRI) (NCT06072781) an international Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent low-grade serous ovarian cancer (LGSOC). Verastem completed its rolling New Drug Application (NDA) submission to the to the U.S. Food and Drug Administration (FDA), for the investigational combination of avutometinib and defactinib in adults with recurrent KRAS mutant LGSOC who received at least one prior systemic therapy, in October 2024. The FDA granted Breakthrough Therapy Designation for the treatment of patients with recurrent LGSOC after one or more prior lines of therapy, including platinum-based chemotherapy. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC. Verastem Oncology has established a clinical collaboration with Amgen to evaluate LUMAKRAS™ (sotorasib) in combination with avutometinib and defactinib in both treatment-naïve patients and in patients whose cancer progressed on a G12C inhibitor as part of the RAMP 203 trial (NCT05074810). Verastem has received Fast Track Designation from the FDA for the triplet combination in April 2024. RAMP 205 (NCT05669482), a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer, is supported by the PanCAN Therapeutic Accelerator Award. FDA granted Orphan Drug Designation to the avutometinib and defactinib combination for the treatment of pancreatic cancer. About Verastem Oncology Verastem Oncology (Nasdaq: VSTM) is a late-stage development biopharmaceutical company committed to the development and commercialization of new medicines to improve the lives of patients diagnosed with cancer. Our pipeline is focused on RAS/MAPK-driven cancers, specifically novel small molecule drugs that inhibit critical signaling pathways in cancer that promote cancer cell survival and tumor growth, including RAF/MEK inhibition and FAK inhibition. For more information, please visit www.verastem.com and follow us on LinkedIn . Forward Looking Statements This press release includes forward-looking statements about, among other things, Verastem Oncology’s programs and product candidates, strategy, future plans and prospects, including statements related to, the expected additional enrollment and expansion of cohorts in the Company’s RAMP 203 trial, the expected timing of the presentation of updated RAMP 203 data by the Company, and the potential clinical value of various of the Company’s clinical trials, including the RAMP 203 trial. The words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue," “can,” “promising” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Forward-looking statements are not guarantees of future performance and are subject to risks and uncertainties that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements we make. Applicable risks and uncertainties include the risks and uncertainties, among other things, regarding: the success in the development and potential commercialization of our product candidates, including avutometinib in combination with other compounds, including defactinib, LUMAKRAS™ and others; the uncertainties inherent in research and development, such as negative or unexpected results of clinical trials, the occurrence or timing of applications for our product candidates that may be filed with regulatory authorities in any jurisdictions; whether and when regulatory authorities in any jurisdictions may approve any such applications that may be filed for our product candidates, and, if approved, whether our product candidates will be commercially successful in such jurisdictions; our ability to obtain, maintain and enforce patent and other intellectual property protection for our product candidates; the scope, timing, and outcome of any legal proceedings; decisions by regulatory authorities regarding trial design, labeling and other matters that could affect the timing, availability or commercial potential of our product candidates; whether preclinical testing of our product candidates and preliminary or interim data from clinical trials will be predictive of the results or success of ongoing or later clinical trials; that the timing, scope and rate of reimbursement for our product candidates is uncertain; that the market opportunities of our drug candidates are based on internal and third-party estimates which may prove to be incorrect; that third-party payors (including government agencies) may not reimburse; that there may be competitive developments affecting our product candidates; that data may not be available when expected; that enrollment of clinical trials may take longer than expected, which may delay our development programs, including delays in review by the FDA of our NDA submission in recurrent KRAS mutant LGSOC if enrollment in our confirmatory trial is not well underway at the time of submission, or that the FDA may require the Company to have completed enrollment or to enroll additional patients in the Company’s ongoing RAMP-301 confirmatory Phase 3 clinical trial prior to the FDA taking action on our NDA seeking accelerated approval; risks associated with preliminary and interim data, which may not be representative of more mature data, including with respect to interim duration of therapy data; that our product candidates will cause adverse safety events and/or unexpected concerns may arise from additional data or analysis, or result in unmanageable safety profiles as compared to their levels of efficacy; that we may be unable to successfully validate, develop and obtain regulatory approval for companion diagnostic tests for our product candidates that require or would commercially benefit from such tests, or experience significant delays in doing so; that the mature RAMP 201 data and associated discussions with the FDA may not support the scope of our NDA submission for the avutometinib and defactinib combination in LGSOC, including with respect to KRAS wild type LGSOC; that our product candidates may experience manufacturing or supply interruptions or failures; that any of our third party contract research organizations, contract manufacturing organizations, clinical sites, or contractors, among others, who we rely on fail to fully perform; that we face substantial competition, which may result in others developing or commercializing products before or more successfully than we do which could result in reduced market share or market potential for our product candidates; that we will be unable to successfully initiate or complete the clinical development and eventual commercialization of our product candidates; that the development and commercialization of our product candidates will take longer or cost more than planned, including as a result of conducting additional studies or our decisions regarding execution of such commercialization; that we may not have sufficient cash to fund our contemplated operations, including certain of our product development programs; that we may not attract and retain high quality personnel; that we or Chugai Pharmaceutical Co., Ltd. will fail to fully perform under the avutometinib license agreement; that the total addressable and target markets for our product candidates might be smaller than we are presently estimating; that we or Secura Bio, Inc. (Secura) will fail to fully perform under the asset purchase agreement with Secura, including in relation to milestone payments; that we will not see a return on investment on the payments we have and may continue to make pursuant to the collaboration and option agreement with GenFleet Therapeutics (Shanghai), Inc. (GenFleet), or that GenFleet will fail to fully perform under the agreement; that we may not be able to establish new or expand on existing collaborations or partnerships, including with respect to in-licensing of our product candidates, on favorable terms, or at all; that we may be unable to obtain adequate financing in the future through product licensing, co-promotional arrangements, public or private equity, debt financing or otherwise; that we will not pursue or submit regulatory filings for our product candidates; and that our product candidates will not receive regulatory approval, become commercially successful products, or result in new treatment options being offered to patients. Other risks and uncertainties include those identified under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2023 as filed with the Securities and Exchange Commission (SEC) on March 14, 2024 and in any subsequent filings with the SEC, which are available at www.sec.gov . The forward-looking statements contained in this press release reflect Verastem Oncology’s views as of the date hereof, and the Company does not assume and specifically disclaims any obligation to update any forward-looking statements whether as a result of new information, future events or otherwise, except as required by law.