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点击蓝字 关注我们Lung Cancer Considered2025年5月9日，国际肺癌研究协会（IASLC）主办的播客节目“Lung Cancer Considered”第288期内容上线，这期节目由同济大学附属上海市肺科医院苏春霞教授担任主持，并携手华中科技大学同济医学院附属协和医院董晓荣教授与中山大学肿瘤防治中心方文峰教授，三位专家共聚一堂，聚焦EGFR-TKI耐药后非小细胞肺癌（NSCLC）的复杂临床场景，结合分子生物学特征与临床诊疗实践，系统性探讨了不同耐药机制下的诊疗策略、现存挑战及未来研究方向，为临床实践提供了多维度决策参考。“肿瘤界”特整理访谈精粹，以飨读者。播客音频访谈精粹苏春霞 教授大家好，本次学术讨论聚焦于EGFR突变NSCLC获得性耐药的临床诊疗策略。现汇报典型病例如下：患者女性，52岁，无吸烟史。主诉为持续咳嗽，Covid-19检测呈阴性。既往史包括支气管炎、过敏史及胃灼热。9个月后，胸部X线片显示，左上肺叶可见直径5cm肿块，同时双肺可见多个结节。CT及PET-CT检查进一步显示，双侧肺部弥漫性分布结节，左上肺叶存在一个5.2cm的不规则肿块，并伴有纵隔淋巴结肿大，脊柱与骨盆出现多处溶骨性骨质改变，同时存在多个肝转移灶。颅脑MRI显示，顶叶存在3个亚厘米级脑转移灶。CT引导下肝穿刺活检结果显示，患者为甲状腺转录因子1（TTF-1）阳性的肺腺癌。通过聚合酶链式反应（PCR）检测，发现存在EGFR 19外显子缺失（ex19del）突变，液体活检结果与之相符。针对该病例，请问两位教授的首选治疗方案是什么？是否会选择联合治疗方案？董晓荣 教授非常感谢苏教授的提问。这是一个非常典型的病例，针对这种EGFR ex19del突变伴脑转移的晚期NSCLC，本人倾向于采用三代EGFR-TKI单药治疗，用药1个月后复查评估疗效再制定后续方案。至于FLAURA2或MARIPOSA的联合治疗方案，在我看来，如果单药治疗能有效控制病情，我不会选择联合用药。当然，FLAURA2研究结果显示，三代EGFR-TKI联合化疗可提升无进展生存期（PFS），尤其是对脑转移患者。但该分层分析为事后数据，并非预先设定的亚组分析。虽然联合治疗有一定疗效提升，但患者需要每21天到医院接受化疗，这不仅增加了时间和经济成本，不良反应也会增加。因此，对于这例患者，我倾向于采用最精简的方案，即三代EGFR-TKI单药治疗。方文峰 教授我非常认同董教授的观点。在当前国内临床实践过程中，在尚未获得FLAURA2及MARIPOSA研究的总生存期（OS）最终结果之前，我也会优先选择三代EGFR-TKI单药治疗。这主要是因为单药治疗管理方便，副作用较小。不过，今年1月份有消息称，MARIPOSA研究的OS最终结果可能为阳性，中位OS延长超过一年，这无疑是一个振奋人心的消息。需要注意的是，这两种药物（埃万妥单抗、兰泽替尼）目前在中国的可及性并不理想。我们期待未来它们在中国获批上市后，能够大幅提升药物可及性，尤其是在价格方面。在为患者选择联合治疗方案以延长生存期的同时，我们也必须兼顾治疗的安全性。这例52岁的女性患者较为年轻，如果未来这两种药物在中国可及，且患者经济条件允许，我认为可以考虑相关联合治疗方案，但目前可能还需要等待一段时间。苏春霞 教授感谢两位教授的专业见解。需要补充说明的是，该病例已完成液体活检。基于临床实践经验，当患者完成PCR初步检测后，是否有必要进一步开展第二代测序（NGS）检测？方文峰 教授在我中心临床实践中，我们高度重视NGS检测的应用价值。本人尤为倾向于基于组织样本进行NGS检测；若缺乏组织样本，亦会积极探索以液体活检作为替代方案。NGS检测的优势体现在两个层面：其一，从肿瘤发生机制的维度，该技术能够系统性解析肿瘤发生发展的遗传学基础，明确除EGFR突变外是否存在其他驱动基因突变，界定主克隆与亚克隆突变特征，以及评估合并突变的权重等；其二，在临床诊疗层面，NGS检测结果能够为治疗方案优化、疗效预测及耐药机制分析提供重要参考。因此，在患者经济条件允许且样本充足的前提下，我们强烈推荐开展NGS检测。苏春霞 教授谢谢方教授的分享。该病例在接受奥希替尼（80mg/日）单药治疗后，咳嗽症状得到迅速缓解。经复查显示脑部及肝脏转移灶已达到完全缓解，纵隔淋巴结恢复正常，肺部原发病灶亦呈现良好治疗反应。基于当前治疗效果，请问方教授在后续随访管理方面有何建议？方文峰 教授针对TKI药物治疗的随访管理，我通常会安排患者在治疗第一个月进行首次复查，若首次复查确认疾病控制良好，则后续每两个月对可见病灶进行CT复查。鉴于该患者基线存在脑转移，尽管当前脑部病灶控制理想，但考虑到脑转移进展的隐匿性及严重危害性，所以需要同步开展颅脑MRI检查。苏春霞 教授方教授阐述了影像学及血液学在随访管理中的常规应用，在此基础上，我想进一步请教董教授，您是否会开展循环肿瘤DNA（ctDNA）监测？该项检测在临床诊疗中具有何种价值？董晓荣 教授在临床实践中，我们并非对所有患者行ctDNA监测，仅针对部分存在特殊需求的患者开展此项检测。目前，ctDNA检测尚未完全纳入临床治疗决策的标准流程。现有研究数据表明，在接受靶向治疗过程中，若ctDNA水平显著下降甚至清除，通常提示治疗效果良好；反之，ctDNA水平升高则可能预示疾病进展。值得关注的是，当前临床研究正在探索基于ctDNA动态变化的治疗策略优化。例如，当ctDNA由阴性转为阳性或水平上升时，是否需要及时启动靶向联合化疗等强化治疗方案；又如，FLAURA2的治疗模式中，能否依据ctDNA水平变化调整化疗药物的使用。这些探索为未来精准化治疗提供了新方向。不过，需要强调的是，尽管ctDNA监测具有一定提示价值，但在现阶段的临床实践中，定期进行肺部CT及颅脑MRI仍是评估疾病控制状态与监测进展的核心手段。苏春霞 教授补充说明该病例后续病程：患者接受治疗后的12个月内胸部CT及颅脑MRI未见明显病灶变化，但在治疗满12个月的随访时，CT检查显示肝脏出现多个新发转移病灶，累及多个肝叶，而同期颅脑MRI仍未发现异常。基于这一情况，请问两位教授在后续诊疗策略上有何建议？董晓荣 教授针对该患者出现的多发肝转移，结合其既往接受三代EGFR-TKI单药治疗，此情况已构成疾病进展（PD）。在这种临床情境下，我建议立即开展二次穿刺活检以系统分析耐药机制。需特别注意的是，三代EGFR-TKI耐药机制复杂，明确具体耐药机制能为后续治疗方案的选择提供重要依据。方文峰 教授我一般也推荐患者进行二次活检，当然也需充分尊重患者意愿。需要强调的是，尽管近年来针对三代EGFR-TKI耐药后的新型联合治疗方案（如联合MET抑制剂等）展现出一定的潜力，但在尚未获得国家药品监督管理部门正式批准之前，当前二次活检的主要价值在于帮助临床医师解析耐药机制与肿瘤进展原因。然而，受限于现有循证医学证据和获批治疗方案，我们尚无法完全基于二次活检结果直接指导临床决策。因此，在临床实践中，站在耐药机制的角度上我会积极推荐患者行二次活检，但是不会完全根据检测结果左右治疗方案。苏春霞 教授感谢两位教授的分享。需进一步探讨的是，在临床实践中，弥漫性肝转移患者常面临穿刺活检实施困难的问题，如凝血功能异常、转移灶位置深等因素均可能限制组织获取。本病例基线液体活检时显示EGFR ex19del突变，二次活检时不仅显示突变丰度较初诊时升高，同时发现MET扩增。基于该检测结果，请问两位教授将如何制定下一步治疗方案？董晓荣 教授这确实是极具挑战性的临床问题。目前，NGS检测MET基因扩增阳性阈值尚缺乏统一标准，也无法确认MET扩增达到何种程度方可启用MET抑制剂联合治疗。尤其在三代EGFR-TKI耐药机制研究中，已有证据表明超过三分之一的耐药机制与c-MET信号通路相关。针对c-MET状态的评估，荧光原位杂交（FISH）技术可用于检测基因拷贝数，而免疫组化（IHC）则检测蛋白表达水平。一般认为，当FISH检测显示拷贝数增加，或IHC检测提示≥50%肿瘤细胞3+时，可判定为c-MET高表达。参考当前临床研究进展，SAVANNAH、SACHI、SAFFRON研究均显示，在三代EGFR-TKI基础上联合MET抑制剂的治疗模式，可为c-MET高表达患者带来临床获益。研究数据表明，三代EGFR-TKI耐药后仅接受化疗的患者，中位PFS约为4个月；而针对c-MET高表达患者采用三代EGFR-TKI联合MET抑制剂治疗，中位PFS可超7个月，较单纯化疗方案具有显著优势。然而，鉴于该病例仅通过液体活检提示MET扩增，缺乏组织学样本的验证，不符合多数临床试验的入组标准。基于此，建议与患者充分沟通后，提供两种治疗选择：其一，在患者充分知情同意的前提下，可尝试性应用MET抑制剂进行探索性治疗，但需明确该方案尚未获得适应症批准，且需结合MET基因拷贝数具体数值评估潜在疗效；其二，遵循标准治疗路径，若按照iRECIST判定为疾病进展，建议进一步通过血液学检测评估TP53和RB1状态，明确是否发生小细胞肺癌（SCLC）转化。若排除SCLC转化，可参考靶向药物耐药后的相关研究成果，采用化疗联合抗血管生成药物及免疫检查点抑制剂的三联治疗模式（如ORIENT-31研究方案），或新型双特异性抗体联合化疗（如HARMONi-A研究方案）的治疗策略。方文峰 教授假设所有药物可及的情况下，针对该病例，我更倾向于选择EGFR-TKI联合MET抑制剂的治疗方案（但需着重指出该联合治疗方案目前尚未获批）。之所以倾向于优先采用EGFR-TKI联合MET抑制剂方案，主要基于治疗顺序对后续方案选择的影响，即在使用TKI类药物序贯目前已获批的免疫治疗方案，一般不存在明显禁忌；反之，若使用含PD-1抑制剂的免疫治疗序贯TKI治疗，则存在较高不良反应风险。因此，若EGFR-TKI耐药后MET扩增的适应症能够早日获批，临床即可优先应用TKI联合方案，再序贯采用化疗联合抗血管生成药物及免疫检查点抑制剂的治疗策略，从而降低不良反应发生率，提升患者依从性。苏春霞 教授本次MDT模拟讨论中，我们还需探讨另一种耐药场景：若ctDNA检测在EGFR ex19del的基础上新增RET基因融合突变，我本人在临床中已遇到数例此类患者，那么针对该情况，请问两位教授如何制定治疗策略？董晓荣 教授对于新发的RET融合突变，需首先评估其临床意义。既往临床实践中，部分患者在三代EGFR-TKI耐药后的二次活检中，常检出多种驱动基因变异。例如，曾有患者在耐药后同时出现BRAF V600E突变、c-MET高扩增，采用第三代EGFR-TKI联合达拉非尼+曲美替尼（D+T）及c-MET抑制剂治疗后获得长达一年半的PFS，且耐受性良好。该案例提示，多重驱动基因突变介导的耐药模式在临床中具备可干预性。因此，若确认RET融合有临床意义，建议在奥希替尼基础上联用RET抑制剂进行治疗。需特别强调的是，目前国内上市的RET抑制剂尚未纳入国家医保目录，在制定治疗方案时，应充分与患者及家属进行沟通后制定个体化策略。方文峰 教授我非常同意董教授的意见。并补充两点临床考量：其一，对于耐药后新检出的驱动基因突变，需评估其克隆特性与变异丰度。这与初诊时NGS检测评估合并突变的逻辑一致，从"定性"与"定量"两个维度分析：首先明确该基因是否为真正的耐药驱动因素；其次判断其在肿瘤细胞中的占比，区分主克隆与亚克隆突变。若RET融合丰度较低，可能并非主导耐药机制，即便联合抑制剂也难以获得显著疗效；反之，当RET融合丰度接近EGFR突变水平时，联合治疗更有望取得理想效果。其二，从全程治疗策略规划角度，优先使用靶向联合方案有利于后续治疗衔接，若先行其他治疗模式则可能增加序贯靶向治疗的难度与风险。此外，临床决策时需与患者充分沟通联合治疗的潜在风险，包括RET抑制剂相关不良反应及经济负担。尽管TKI类药物总体安全性可控，但针对可能出现的肝毒性、血液学毒性等不良反应，仍需制定完善的管理预案，确保治疗安全性与依从性。苏春霞 教授现假设该病例在疾病进展后，经检测未发现新的驱动基因突变，且患者未参与任何临床研究项目。请问两位教授在此时会首选何种治疗方案？董晓荣 教授对于此类情况，建议与患者家属进行充分的知情沟通。在明确疾病进展后，建议采用ORIENT-31研究或HARMONi-A研究中的治疗方案，这有助于延长后续靶向治疗再次应用的间隔时间。尽管临床上存在采用三代EGFR-TKI联合数个周期化疗以维持疾病控制的做法，当然其初衷是最大化靶向药物作用，但依据iRECIST及现有临床研究结果，一旦明确疾病进展，及时转换治疗方案是一种优选。方文峰 教授我完全认同董教授的观点。目前，HARMONi-A方案及ORIENT-31方案已成为该类患者治疗的主流选择。在这两项研究的总生存期（OS）数据正式公布前，这两种方案均具备临床应用价值。我个人也会优选这两个方案之一。苏春霞 教授若液体活检仅检测到EGFR ex19del突变，而组织活检明确提示发生SCLC转化，在此情况下，两位将如何制定后续治疗方案？董晓荣 教授SCLC转化的发生机制尚存争议，目前主要存在两种学术观点：其一认为肿瘤自起源即为NSCLC与SCLC的混合型，经EGFR-TKI治疗后，小细胞肺癌成分逐渐显现；其二则主张完全转化，即肿瘤由初始的肺腺癌完全转变为SCLC。我建议采用联合治疗策略，即在持续应用EGFR-TKI的基础上联合SCLC标准化疗方案，从而同时控制两种肿瘤细胞克隆。方文峰 教授在临床实践中，EGFR-TKI治疗后SCLC转化的发生率约为5%甚至更低。我在遇到此类患者时也会选择EGFR-TKI基础上联合SCLC标准化疗或化疗+免疫治疗。苏春霞 教授当患者仅出现肺部或肝脏单部位疾病进展时，是否应考虑局部消融治疗？董晓荣 教授局部治疗在肿瘤综合治疗体系中占据重要地位，无论是III期还是IV期肿瘤患者，放疗、消融等局部干预手段均具有不可替代的价值。针对IV期患者，局部治疗对于控制残留原发灶及转移灶非常重要。当临床遇到肝脏或肺部单部位疾病进展，且无法获取病理组织明确耐药机制时，我建议在持续应用原有靶向药物的基础上，联合局部巩固治疗（LCT）。现有研究证据表明，在全身系统治疗的前提下，针对寡转移灶进行局部放疗或消融等干预措施，可显著延长患者的PFS。因此，此类情况下推荐积极开展局部治疗。方文峰 教授我完全赞同董教授的观点。特别是在肝脏单部位病灶的处理上，局部消融治疗具有显著优势，不仅疗效确切，且对患者造成的创伤较小。因此我也建议采用靶向治疗联合局部消融的策略。专家简介苏春霞 教授教授，主任医师，博士生/博士后导师同济大学附属上海市肺科医院肿瘤综合诊治中心（COC）行政主任、临床研究中心主任国家重点研发计划首席科学家上海市优秀学术带头人/上海市东方英才计划拔尖项目美中抗癌协会USCACA Co-President联席主席国际肺癌协作组织多学科协作委员会委员中华医学会肿瘤学分会青年委员中国初级卫生保健基金会肿瘤临床转化研究专委会主委中国抗癌协会肿瘤药物临床研究专委会常委兼秘书长中国临床肿瘤学会患者教育专委会副主委中国临床肿瘤学会转化专委会常委中国临床肿瘤学会免疫治疗专委会常委中国医促会肿瘤免疫治疗学分会常委上海市抗癌协会青年理事会副理事长董晓荣 教授三级教授、主任医师、博士生导师华中科技大学同济医学院附属协和医院肿瘤科/教研室副主任华中科技大学同济医学院附属协和医院肿瘤中心胸部肿瘤科主任 中国临床肿瘤学会理事中国医药教育协会肺部肿瘤专委会副主任委员中国抗癌协会肺癌专业委员会常委中国临床肿瘤学会免疫专家委员会常委中国临床肿瘤学会血管靶向治疗专家委员会常委中国临床肿瘤学会患者教育专家委员会常委中国临床肿瘤学会非小细胞肺癌专家委员会委员湖北省抗癌协会肿瘤免疫治疗专委员会主任委员湖北省抗癌协会肿瘤内科治疗专委员会副主任委员方文峰 教授中山大学肿瘤防治中心主任医师、教授、中肿国家重点实验室PI、博士研究生导师“国家高层次人才项目青年人才”“广东省特支计划百千万工程青年拔尖人才”“广东省杰出青年医学人才”“广州市珠江科技新星”中国临床肿瘤学会非小细胞肺癌专业委员会委员中国临床肿瘤学会鼻咽癌专业委员会委员中国抗癌协会肺癌专业委员会常委广东省抗癌协会鼻咽癌专业青年委员会副主任委员广东省医学会精准医学与分子诊断专业委员会副主任委员广东省临床医学会真实世界临床研究专业委员会副主任委员更多节目信息请前往以下网站了解国际肺癌研究协会（IASLC）官方网址：https://www.iaslc.org/播客《Lung Cancer Considered》官方网址：https://www.iaslc.org/LungCancerConsidered推荐阅读●   盘点2024丨苏春霞教授：2024年度非小细胞肺癌免疫治疗研究进展声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。编辑：lagertha审核：苏春霞教授

IND cleared for pan-RAS molecular glue ERAS-0015 and IND submitted for pan-KRAS inhibitor ERAS-4001, both ahead of schedule; Phase 1 monotherapy data for both programs expected in 2026 Meaningful extension of cash runway guidance from H2 2027 to H2 2028 following strategic decision to pursue partnership opportunities for naporafenib SAN DIEGO, May 13, 2025 (GLOBE NEWSWIRE) -- Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, today announced clearance of an investigational new drug (IND) application by the United States Food and Drug Administration (FDA) for ERAS-0015, a pan-RAS molecular glue with best-in-class potential for patients with RAS-mutant (RASm) solid tumors, and submission of an IND application for ERAS-4001, a potential first-in-class pan-KRAS inhibitor in KRAS-mutant (KRASm) solid tumors. The company also announced a strategic decision to pursue partnership opportunities for naporafenib, enabling a meaningful extension of cash runway guidance from the second half of 2027 to the second half of 2028. “We are pleased to have exceeded our public guidance by advancing our RAS-targeting franchise toward the clinic following our efficient IND execution ahead of schedule. Both ERAS-0015 and ERAS-4001 have the potential to change the treatment paradigm for patients with solid tumors mutated in (K)RAS, the most prevalent oncogenic driver, which is highly enriched across colorectal, pancreatic, and non-small cell lung cancers,” said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. “Our team is excited to build on this momentum to advance these promising product candidates as quickly as possible to deliver meaningful benefits to patients.” Dr. Lim continued, “We remain confident in the strong therapeutic potential of naporafenib in NRAS-mutant (NRASm) melanoma. However, to focus our organizational efforts on our now clinical-stage RAS-targeting franchise, we are seeking a strategic partner to further develop and commercialize naporafenib and are encouraged by our ongoing discussions. We believe that the broad clinical application of these validated RAS targets, the robust excitement for our competitive candidates, and the tremendous progress we have made across both programs since their in-licensing last May strongly position us for success as we aim to help treat the millions of patients with RASm solid tumors. Importantly, this decision allows an extension of our cash runway guidance from the second half of 2027 to the second half of 2028. Having more than three years of cash despite no new infusion of capital in this volatile macroenvironment bolsters our ability to focus on successfully executing our ambitious clinical development plans for ERAS-0015 and ERAS-4001.” RAS-Targeting Franchise Advancing to Clinic ERAS-0015 – Potential Best-in-Class Pan-RAS Molecular Glue IND application cleared by the FDAInitial AURORAS-1 Phase 1 monotherapy data in RASm solid tumors expected in 2026Potential to address unmet medical needs in approximately 2.7 million patients who are diagnosed annually worldwide with RASm tumors ERAS-4001: Potential First-in-Class Pan-KRAS inhibitor IND application submitted to the FDAInitial BOREALIS-1 Phase 1 monotherapy data in KRASm solid tumors expected in 2026Potential to address unmet medical needs in over 2.2 million patients who are diagnosed annually worldwide with KRASm tumors Strategic Pipeline Prioritization After the IND clearance of ERAS-0015 and the IND filing for ERAS-4001, Erasca conducted a strategic pipeline review. Following this review, in order to prioritize organizational focus and resources to advance our differentiated RAS-targeting franchise as rapidly as possible, we have decided to evaluate potential partnership opportunities for the naporafenib programErasca has successfully advanced naporafenib into a pivotal global Phase 3 trial following its in-licensing in December 2022Naporafenib is a pivotal-stage pan-RAF inhibitor with a robust data package in combination with trametinib (MEKINIST®) for the treatment of patients with NRASm melanoma, a disease with no approved targeted therapies and high unmet medical need Potential first-to-market targeted therapy in NRASm melanoma, with the opportunity to address patient needs in the post immuno-oncology (IO) settingCompelling Phase 1 and Phase 2 efficacy data suggesting clinically meaningful extension of progression-free survival and overall survival in NRASm melanoma patients relative to historical benchmarksEstablished safety and tolerability results in more than 600 patients with further improvement of tolerability achieved under Erasca’s development leadershipGlobal regulatory alignment supporting clear registration path, and the program has been granted FDA Fast Track DesignationHigh investigator enthusiasm underscoring significant clinical relevance and commercial potential Key Upcoming Milestones As a result of Erasca’s RAS-targeting franchise advancing into the clinic and the strategic pipeline prioritization, our corporate milestones are as follows: ERAS-0015: AURORAS-1 Phase 1 monotherapy data (safety, pharmacokinetics, and efficacy at relevant dose(s) in relevant population(s) of interest) in RASm solid tumors expected in 2026ERAS-4001: BOREALIS-1 Phase 1 monotherapy data (safety, pharmacokinetics, and efficacy at relevant dose(s) in relevant population(s) of interest) in KRASm solid tumors expected in 2026 About ERAS-0015 ERAS-0015 is an oral, highly potent pan-RAS molecular glue that is designed to inhibit RAS signaling with a potential best-in-class profile. In preclinical studies, ERAS-0015 demonstrated approximately 8-21 times higher binding affinity to cyclophilin A (CypA) versus the most advanced pan-RAS molecular glue in development, approximately 5 times greater potency in RAS inhibition, and greater in vivo antitumor activity evidenced by achieving comparable or greater tumor growth inhibition or regression at doses that are as low as approximately one-tenth the dose of the most advanced pan-RAS molecular glue. ERAS-0015 is also designed to prevent resistance against mutant-selective inhibitors through inhibition of RAS wildtype variants. In addition, ERAS-0015 has demonstrated favorable absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic (PK) properties in multiple animal species. Erasca will evaluate ERAS-0015 in the AURORAS-1 Phase 1 trial in patients with RAS-mutant solid tumors. About ERAS-4001ERAS-4001 is an oral, highly potent, and selective pan-KRAS inhibitor with a potential first-in-class and best-in-class profile. ERAS-4001 demonstrated good preclinical in vitro potency against KRAS G12X mutations, as well as KRAS wildtype amplifications, which may limit treatment resistance mediated through KRAS wildtype activation. No activity was observed for ERAS-4001 against HRAS or NRAS wildtype proteins, which may enable a wider clinical therapeutic window compared to pan-RAS inhibitors. It showed potent activity against both GTP-bound (active state) and GDP-bound (inactive state) KRAS with single digit nanomolar IC50s. In vivo, ERAS-4001 induced tumor regression in multiple KRASm models. In preclinical studies, ERAS-4001 showed encouraging absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic (PK) properties. Erasca plans to evaluate ERAS-4001 in the BOREALIS-1 Phase 1 trial in patients with KRAS-mutant solid tumors. About NaporafenibNaporafenib (formerly LXH254) is a potent and selective pan-RAF inhibitor, with a potential first-in-class and best-in-class profile. Naporafenib has been dosed in over 600 patients to date, whereby safety, tolerability, pharmacokinetics, and pharmacodynamics results have been established in both monotherapy and select combinations. Clinical proof-of-concept (PoC) has been established for naporafenib in combination with trametinib (MEKINIST®) for patients with NRAS-mutant (NRASm) melanoma, including those with NRAS Q61X mutations. A pooled analysis of patients with NRASm melanoma dosed with the combination of naporafenib and trametinib in two different trials demonstrated clinically meaningful extension of median progression-free survival and median overall survival as compared to historical benchmarks. Erasca initiated two clinical trials to further evaluate this combination (neither of which is enrolling patients currently): SEACRAFT-2, a global pivotal Phase 3 trial in patients with NRASm melanoma, and SEACRAFT-1, a Phase 1b trial in patients with RAS Q61X solid tumors. The program has been granted Fast Track Designation by the United States Food and Drug Administration (FDA) for patients with advanced NRASm melanoma. About ErascaAt Erasca, our name is our mission: To erase cancer. We are a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers. Our company was co-founded by leading pioneers in precision oncology and RAS targeting to create novel therapies and combination regimens designed to comprehensively shut down the RAS/MAPK pathway for the treatment of patients with cancer. We believe our team’s capabilities and experience, further guided by our scientific advisory board which includes the world’s leading experts in the RAS/MAPK pathway, uniquely position us to achieve our bold mission of erasing cancer. Cautionary Note Regarding Forward-Looking Statements Erasca cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: our expectations regarding the potential therapeutic benefits of our product candidates, including ERAS-0015, ERAS-4001, and naporafenib; the planned advancement of our development pipeline, including the anticipated IND clearance for the BOREALIS-1 trial; the anticipated timing of data readouts for the AURORAS-1 and BOREALIS-1 trials; our ability to successfully prioritize our pipeline portfolio to focus on existing programs that we believe have the highest probability of success; our plans to partner naporafenib and the outcome of any currently ongoing discussions; and the sufficiency of our cash, cash equivalents, and marketable securities to fund operations into the second half of 2028. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: our approach to the discovery and development of product candidates based on our singular focus on shutting down the RAS/MAPK pathway, a novel and unproven approach; our assumptions about the development potential of ERAS-0015 and ERAS-4001 are based in large part on the preclinical data generated by the licensors and we may observe materially and adversely different results as we conduct our planned studies and trials; results from preclinical studies or early clinical trials not necessarily being predictive of future results; our assumptions around which programs may have a higher probability of success may not be accurate, and we may expend our limited resources to pursue a particular product candidate and/or indication and fail to capitalize on product candidates or indications with greater development or commercial potential; potential delays in the commencement, enrollment, data readout, and completion of clinical trials and preclinical studies, including the risk that our IND for the BOREALIS-1 trial may not be cleared; the comparison of naporafenib plus trametinib clinical data with historical benchmarks evaluates clinical data from multiple trials with different designs and inclusion criteria that cannot be directly compared, and therefore may not be a reliable indicator of progression-free survival and overall survival; due to differences between trial designs and subject characteristics, comparing clinical data across different trials may not be a reliable indicator of such data; our dependence on third parties in connection with manufacturing, research, and preclinical and clinical testing; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval, and/or commercialization, or may result in recalls or product liability claims; unfavorable results from preclinical studies or clinical trials; we may be unable to secure partnerships or other strategic collaborations for naporafenib on acceptable terms or at all; the inability to realize any benefits from our current licenses, acquisitions, and collaborations, and any future licenses, acquisitions, or collaborations, and our ability to fulfill our obligations under such arrangements; regulatory developments in the United States and foreign countries; Fast Track Designation may not lead to a faster development or regulatory review or approval process, and does not increase the likelihood that our product candidates will receive marketing approval; our ability to obtain and maintain intellectual property protection for our product candidates and maintain our rights under intellectual property licenses; we may use our capital resources sooner than we expect; and other risks described in our prior filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in our annual report on Form 10-K for the year ended December 31, 2024, and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.MEKINIST® is a registered trademark owned by or licensed to Novartis AG, its subsidiaries, or affiliates. Contact:Joyce AllaireLifeSci Advisors, LLCjallaire@lifesciadvisors.com Source: Erasca, Inc.