Phase Ib/II Study to Investigate the Safety and Efficacy of Afatinib When Administered As Therapy in Fanconi Anemia Patients with Unresectable and / or Metastatic Locoregionally Advanced Squamous Cell Carcinoma of the Oral Cavity, Oropharynx or Hypopharynx or Larynx.

This research study is a phase Ib/II, single-arm, non-randomized, non-blind, multicenter study designed to determine whether Afatinib is effective and safe in patients with locoregionally unresectable and / or metastatic HNSCC with Fanconi Anemia.
The main hypothesis, based on preclinical evidence, is that treatment with afatinib, an epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), could be an effective treatment option to control cancer for patients with FA - HNSCC.

开始日期2024-11-01

申办/合作机构

Fundacio Institut De Recerca De L'Hospital De La Santa Creu I Sant Pau

NCT06085755 / Not yet recruiting临床1/2期IIT

Ph 1/2 Study of Trastuzumab Deruxtecan(T-DXd) and Afatinib Combination in HER2-low Advanced Gastric Cancer(VIKTORY-2)

Despite recent advances, the prognosis of patients with advanced gastric cancer remains poor. At present, regimens that combine a platinum and fluorouracil agent either alone or in combination with a third drug such as epirubicin or taxane constitute the most effective treatment option in the first-line metastatic setting, resulting in a median OS of approximately 10 months. In the second-line setting, ramucirumab (a vascular endothelial growth factor receptor 2 antagonist) was recently approved by the United States Food and Drug Administration, and has demonstrated modest activity in patients with advanced gastric or GEJ adenocarcinoma who progressed after first-line platinum- or fluoropyrimidine-containing chemotherapy. Median OS was 5.2 months in the ramucirumab group versus 3.8 months in the placebo group.
At the updated DCO of 03 June 2020 in the DS8201-A-J202 (DESTINY-Gastric01) study in HER2-positive GC or GEJ adenocarcinoma subjects assigned to T-DXd 6.4 mg/kg, T-DXd further demonstrated clinically meaningful efficacy. The median OS was 12.5 months for the T-DXd group and 8.9 months for the physician's choice group (HR = 0.60, 95% CI: 0.42, 0.86). In a prespecified subgroup analysis, the percentages of patients with an objective response were analyzed in HER2-low group. The response rate in HER2 2+ was 29% (8 of 28) with T-DXd monotherapy.
Refer to the figure below for the response rate in HER2-low group in previous DESTINY trials.
This is a two part, phase I/Ⅱ, open-label, single center study of afatinib in combination with T-DXd, in 2L/3L gastric cancer patients with HER2-low. The study design allows an investigation of combination dose of afatinib with T-DXd, with intensive safety monitoring to ensure the safety of the patients.

开始日期2024-10-01

申办/合作机构

Samsung Medical Center

100 项与 HER2 x EGFR L858R x EGFR x HER4 x EGFR-Ex19del 相关的临床结果

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100 项与 HER2 x EGFR L858R x EGFR x HER4 x EGFR-Ex19del 相关的转化医学

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0 项与 HER2 x EGFR L858R x EGFR x HER4 x EGFR-Ex19del 相关的专利（医药）

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项与 HER2 x EGFR L858R x EGFR x HER4 x EGFR-Ex19del 相关的文献（医药）

2014-02-01·Drugs1区 · 医学

Afatinib: A Review of Its Use in the Treatment of Advanced Non-Small Cell Lung Cancer

1区 · 医学

Review

作者: Keating, Gillian M

Afatinib (Gilotrif™, Giotrif(®)) is an orally administered, irreversible inhibitor of the ErbB family of tyrosine kinases. Afatinib downregulates ErbB signalling by covalently binding to the kinase domains of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation; it also inhibits transphosphorylation of HER3. Afatinib is approved as monotherapy for the treatment of EGFR tyrosine kinase inhibitor (TKI)-naïve adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutations in the EU, and for the first-line treatment of patients with metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test in the US. In two randomized, open-label, multinational phase III trials, progression-free survival was significantly prolonged with afatinib compared with pemetrexed plus cisplatin (LUX-Lung 3) or gemcitabine plus cisplatin (LUX-Lung 6) in treatment-naïve patients with advanced NSCLC with activating EGFR mutations. The objective response rate was significantly higher with afatinib than with pemetrexed plus cisplatin or gemcitabine plus cisplatin, and patient-reported outcomes for symptoms such as cough and dyspnoea and certain health-related quality of life measures significantly favoured afatinib versus pemetrexed plus cisplatin or gemcitabine plus cisplatin. Afatinib also showed efficacy in EGFR TKI-naïve patients with advanced lung adenocarcinoma and activating EGFR mutations who had received no more than one prior chemotherapy regimen for advanced disease, according to the results of the noncomparative, multinational, phase II LUX-Lung 2 trial. Oral afatinib had a manageable tolerability profile. EGFR-mediated adverse events (e.g. diarrhoea, rash/acne) were generally managed using dose reduction and delays. In conclusion, afatinib is a valuable new option for use in treatment-naïve or EGFR TKI-naïve patients with advanced lung adenocarcinoma and activating EGFR mutations.

2013-09-01·Drugs1区 · 医学

Afatinib: First Global Approval

1区 · 医学

Review

作者: Gillian M. Keating ; Rosselle T. Dungo

Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases, is under development with Boehringer Ingelheim for the once-daily, oral treatment of cancer. Afatinib downregulates ErbB signalling by covalently binding to epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, irreversibly inhibiting tyrosine kinase autophosphorylation. It also inhibits transphosphorylation of HER3. Oral afatinib (Gilotrif™) has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test. Afatinib has also been approved in Taiwan for the first-line treatment of patients with EGFR mutation-positive NSCLC. In addition, the European Medicines Agency's Committee for Medicinal Products for Human Use has recommended the approval of afatinib (Giotrif®) for the treatment of patients with locally advanced or metastatic NSCLC with activating EGFR mutations who are EGFR tyrosine kinase inhibitor naïve. Afatinib is also under regulatory review in Canada, Japan and other Asian countries. This article summarizes the milestones in the development of afatinib, leading to this first approval in patients with metastatic NSCLC.

项与 HER2 x EGFR L858R x EGFR x HER4 x EGFR-Ex19del 相关的新闻（医药）

2023-06-19

·SYNAPSE

EGFR新进展：谁先解决耐药问题？

自从针对EGFR突变的酪氨酸激酶抑制剂（EGFR-TKI）问世以来，大大延长了肺癌患者的生存时间，已成为EGFR突变肺癌一线治疗的最佳选择。然而，其耐药问题一直是肺癌靶向治疗的难点。为克服耐药，EGFR-TKI不断更新迭代，从一代到三代，再到即将上市的四代，“打补丁”式地进行完善。然而，耐药难题仍然存在。那么如何提升药效并降低耐药性，成为药企思考的关键。除了小分子药物外，在攻克EGFR靶点的征途上，还有哪些新兴技术已经呈现？下面我们从EGFR靶点出发，来浅谈一下其研发进展。 EGFR，即表皮生长因子受体（又称ErbB-1或HER1），是HER家族成员之一。该家族包括HER1（erbB1，EGFR）、HER2（erbB2，NEU）、HER3（erbB3）及HER4（erbB4）。EGFR广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞等细胞表面。EGFR信号通路对细胞的生长、增殖和分化等生理过程发挥重要的作用：EGFR受体激活后会发生二聚化，并启动RAS-RAF-MEK-MAPK、PI3K-PTEN-AKT、STAT多种重要信号通路，与肿瘤发生发展密切相关。基于此作用机制，科学家们开始设计酪氨酸激酶抑制剂（TKI）。 EGFR-TKI三代同堂，奥希替尼占市场主流 2003年，第一代EGFR-TKI吉非替尼的获批，被认为是肺癌治疗的一个里程碑式事件。第一代EGFR-TKI主要针对EGFR 21号外显子L858R点突变或19号外显子缺失exon19 del突变，除吉非替尼外，其代表药物还有厄洛替尼和埃克替尼。与接受标准化疗的患者相比，EGFR-TKI一线治疗致敏性EGFR突变可延长无进展生存期（PFS），改善与健康相关的生活质量并减少与治疗相关的严重副作用。随后，以阿法替尼为代表的第二代EGFR-TKI获批上市。尽管第一、二代EGFR-TKI显著改善了NSCLC患者的PFS，但与对照组相比，OS均没有显著获益。而且，几乎所有使用前两代EGFR-TKI的患者最终都会进展，并产生明显的耐药性，主要与EGFR 20号外显子T790M耐药突变有关。于是科学家们开始探索针对T790M突变的第三代EGFR-TKI。2015年11月，奥希替尼获FDA批准用于EGFR T790M突变的NSCLC患者，它成功地创造了EGFR-TKI史上最长PFS和OS，分别达到18.9个月和38.6个月，为NSCLC治疗史上的新高峰。 2020年，奥希替尼又获FDA批准用于早期EGFR突变NSCLC患者的术后辅助治疗。在名为ADAURA的奥希替尼辅助治疗研究中，结果显示，奥希替尼组和安慰剂组的5年OS率分别为88%和78%，奥希替尼组显著降低了死亡风险（HR=0.49, 95%CI 0.34-0.70，P＜0.0001）。卓越的疗效让奥希替尼成为EGFR-TKI的风向标。国内已上市三款自研第三代EGFR-TKI，分别是翰森制药的阿美替尼、艾力斯的伏美替尼以及贝达药业的贝福替尼。它们均是奥希替尼的me too产品，疗效与奥希替尼相差并不大。第四代EGFR-TKI呼之欲出即便强如奥希替尼，依然逃不掉耐药的命运。EGFR基因20号外显子C797S的突变再次成为EGFR抑制剂所面对的新难题，如何开发新的针对性药物成为第四代EGFR-TKI研发的主要思路。目前，国内布局四代EGFR-TKI的药企主要包括贝达药业的BPI-361175、再鼎医药/BlueprintMedicines的BLU-945、正大天晴的TQB3804等。 BPI-361175 贝达药业的BPI-361175是一种强效、选择性第四代EGFR-TKI，拟开发用于治疗携带EGFR C797S突变及其他EGFR相关突变的晚期NSCLC等实体瘤。临床前研究显示，BPI-361175体内外生物学活性一致，能有效抑制携带EGFR C797S突变肿瘤细胞的增殖。 BBT-176 BBT-176是一种可逆的ATP竞争性抑制剂，可靶向复杂的EGFR突变，在临床前研究中已显示出较好的抗肿瘤活性。在2022年的世界肺癌大会上，BridgeBiotherapeutics公布了BBT-176的I期临床研究初步数据。结果显示：在18例接受BBT-176治疗的NSCLC患者中，5例患者存在EGFR耐药三重突变（外显子 19 del/T790M/C797S 或 L858R/T790M/C797S）。接受BBT-176治疗后，2例患者的肿瘤缩小，2例携带外显子19 del/T790M/C797S 三重突变的患者的靶病灶和非靶病灶均有缓解。 BLU-945 BLU-945可靶向常见的EGFR突变和T790M以及C797X耐药突变，同时对EGFR野生型(WT)具有选择性。临床前研究显示，BLU-945与奥希替尼联合使用较单用奥希替尼可增强L858R的药效，延长抗肿瘤疗效的持续性。在今年的ASCO会议上，Blueprint Medicines公布了BLU-945单药或联合奥希替尼治疗既往接受过≥1线EGFR-TKI治疗耐药的晚期NSCLC患者。其中，既往接受过奥希替尼治理的患者，入组后接受BLU-945+奥希替尼治疗。BLU-945单药组入组了112例患者；BLU-945+奥希替尼组入组了55例患者。结果显示，单药治疗队列中，大部分的治疗相关不良反应（TRAEs）为1-2级，共有12例患者出现剂量限制性毒性，最常见的不良反应为3级ALT和AST升高。疗效方面，4例患者部分缓解（PR）（其中2例已经确认）。在BLU-945联合奥希替尼的队列中，≥3级TRAEs发生率为10.9%，3例患者发生剂量限制毒性。在疗效方面，10例患者达到PR，其中4例已确认。总之，在多线治疗后的EGFR突变NSCLC患者中，BLU-945单药治疗展现出一定的疗效，安全性可耐受，不过疗效持续时间有待提高。而BLU-945联合奥希替尼在安全性良好的情况下，奥希替尼耐药患者的疗效可观。 EGFR-PROTAC：另辟蹊径以上四代EGFR-TKI，均是靶向EGFR三磷酸腺苷 (ATP) 结合位点的类似药物设计策略，该策略既有优势又有劣势，这些化合物可能始终难以避免遭受药物诱导的EGFR突变。因此需要一种新的药物设计策略来开发具有不同作用机制的化合物。蛋白降解靶向嵌合体（PROTAC）是一种杂合双功能小分子化合物，结构中含有两种不同配体，一个是E3泛素连接酶的配体，另一个是与细胞中目标靶蛋白结合的配体，两个配体之间通过 Linker 相连，从而形成“三体”聚合物——靶蛋白配体-Linker-E3 配体。PROTAC通过拉近靶蛋白和E3配体之间的距离，利用泛素-蛋白酶体系统同时结合靶蛋白和E3配体复合物，进而引起泛素转移并启动，最终使靶蛋白被蛋白酶体降解。其独特的降解机制可以有效避免耐药性突变的产生，而其独特的三元复合物结构形式更是可以从现有的EGFR抑制剂出发来设计相应分子结构。近年来，PROTAC 技术在肿瘤药物开发领域深受欢迎，不过国内布局的企业还比较少，且大部分处于早期阶段。国内海思科、贝达药业、百济神州、先导药物等布局了EGFR PROTAC项目。其中海思科药业的PROTAC药物HSK40118于今年3月15日获NMPA批准开展临床试验，拟用于治疗不可手术的、携带EGFR突变的晚期NSCLC患者。这是全球首款申报临床的EGFR靶向PROTAC药物。临床前研究表明，HSK40118在体外对突变型EGFR蛋白具有良好的抑制以及降解活性，对EGFR L858R-T790M双突变、ex19del(或L858R)-T790M-C797S三突变体内移植瘤的生长具有显著的抑制效果，提示HSK40118对3代EGFR-TKI诱导的获得性耐药突变患者将产生显著疗效，有望延缓甚至克服由于长期使用EGFR-TKI导致的EGFR耐药突变问题。 EGFR-ADC：崭露头角抗体偶联药物（ADC）是近年来研发火热的赛道之一，对于EGFR突变NSCLC患者来说，ADC药物的出现也为奥希替尼进展后的临床需求提供了支持。事实上，针对EGFR开发ADC药物已有很长时间，艾伯维先后开发了ABBV-221、ABT-414等多款EGFR ADC药物。尽管在临床前和早期临床研究中，ABBV-221、ABT-414具有强大的抗肿瘤活性，但在III期临床试验中两者均以失败告终。无独有偶，Forbius公司的AVID100是一种高效力的EGFR靶向ADC，在临床前研究中，AVID100在对已上市EGFR抑制剂耐药的EGFR过表达肿瘤模型中显示出显著的抗癌活性，而且仅观察到了轻微的皮肤毒性。但在Ia / IIa期临床试验中，由于缺乏疗效，Forbius于2021年终止了AVID100的临床研究。国内方面，虽然布局EGFR-ADC的药企较多。不过在NSCLC治疗领域进入临床阶段的仅有乐普生物、石药集团等。乐普生物的MRG003，作为一种新型ADC药物，能特异性识别并结合肿瘤细胞表面的EGFR，然后通过EGFR介导的内吞作用而内化至肿瘤细胞中。连接子被溶酶体蛋白酶裂解后，细胞毒有效载荷释放到细胞质中，发挥抗肿瘤作用。MRG003目前正在国内进行II期临床试验。石药集团的CPO301于今年6月12日获FDA授予快速通道资格，用于治疗复发/难治性或EGFR靶向治疗(包括奥希替尼)无效的转移性EGFR突变NSCLC患者。临床前研究显示，CPO301在含有针对第三代EGFR-TKI奥希替尼耐药的EGFR三重突变(Exon19Del、T790M及C797S)的人源化NSCLC PDX模型中显示出很强的抗肿瘤效果。临床前毒理学和安全药理学研究中已显示良好的安全性和耐受性。目前其I期剂量递增及剂量扩展临床研究正在美国和加拿大开展，拟评估CPO301用于治疗晚期NSCLC的安全性和疗效。除了ADC药物外，今年的ASCO年会上，百利天恒公布了其新型EGFR/HER3双抗ADC——BL-B01D1在治疗EGFR突变NSCLC患者中的I期临床数据。BL-B01D1的载荷为新型 TOP1 抑制剂ED04（属于一种喜树碱类物质），其通过阻止肿瘤细胞的DNA复制和RNA合成，破坏DNA的结构，实现对肿瘤细胞的直接杀伤。BL-B01D1的单抗部分SI-B001针对EGFR和HER3两个不同的靶点，更强的特异性增加了药物的安全性；同时通过交联作用促进两个靶点的协同内吞，提高毒素进入肿瘤细胞的效率，并进一步通过减少受体蛋白在细胞膜上的表达量来抑制肿瘤细胞生长信号，实现更好的治疗效果。 BL-B01D1结合双抗和小分子毒素实现了对EGFR依赖肿瘤的靶向杀伤并防止HER3引起的耐药，既精准杀伤肿瘤细胞，又减少毒素对体内正常细胞的破坏。在今年ASCO大会上公布的I期临床数据显示，BL-B01D1治疗经治的EGFR突变NSCLC的客观缓解率（ORR）达63.2%，不同耐药突变均有疗效，治疗经治的EGFR野生型NSCLC的ORR也达44.9%，且未见间质性肺病报告。 EGFR突变作为中国NSCLC患者的第一大驱动基因，已成为NSCLC药物开发的热点。目前针对第三代EGFR-TKI耐药，已经开发出了多种类型的药物，如第四代EGFR-TKI、PROTAC、ADC、双抗（此文未涉及）、双抗ADC等，均已进入攻坚阶段。相信随着对耐药机制认识的愈加清晰，EGFR靶点将老而弥新，未来会有更加多样化形式的药物上市，为肺癌慢病化再添一臂之力。参考资料： 1.Liu X, Wang P, Zhang C, Ma Z. Epidermal growth factor receptor (EGFR): A rising star in the era of precision medicine of lung cancer. Oncotarget. 2017 Jul 25;8(30):50209-50220. doi: 10.18632/oncotarget.16854. 2.Cantor, A. J., et al. Deep mutational analysis reveals functional trade-offs in the sequences of EGFR autophosphorylation sites. Proc. Natl Acad. Sci. USA. 115, E7303-E7312(2018). 3.BLU-945 monotherapy and in combination with osimertinib in previously treated patients with advanced EGFR-mutant NSCLC in the phase 1/2 SYMPHONY study. 4.Zhang H, Zhao HY, Xi XX, Liu YJ, Xin M, Mao S, Zhang JJ, Lu AX, Zhang SQ. Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC). Eur J Med Chem. 2020 Mar 1;189:112061. 5.Zhao HY, Yang XY, Lei H, Xi XX, Lu SM, Zhang JJ, Xin M, Zhang SQ. Discovery of potent small molecule PROTACs targeting mutant EGFR. Eur J Med Chem. 2020 Dec 15;208:112781. 6.2023 ASCO Abstract 3001.