Lazertinib

Approval is supported by the Phase 3 PAPILLON study, which showed amivantamab plus chemotherapy significantly reduced the risk of disease progression or death by 60 percent compared to chemotherapy alone 1 BEERSE, Belgium I June 28, 2024 I Janssen-Cilag International NV, a Johnson & Johnson company, announced today that the European Commission (EC) has approved a Type II variation for RYBREVANT ® (amivantamab) in combination with chemotherapy (carboplatin and pemetrexed) for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. 1 “Patients with NSCLC harbouring EGFR exon 20 insertion driver mutations have high unmet needs and urgently require innovative treatment options to tackle the significant disease burden and poor prognosis they may face,” said trial investigator Professor Nicolas Girard, Head of Medical Oncology, Institut Curie, and Professor of Thoracic Oncology and Respiratory Medicine at the Paris Saclay University, France.* “Treatment with amivantamab has already been established in the second-line setting and with this approval in the first-line setting, amivantamab combined with chemotherapy has the potential to redefine the standard of care, offering improved patient outcomes both in terms of clinical efficacy and quality of life.” EGFR exon 20 insertion mutations are the third most common activating EGFR mutation and are associated with real-world five-year overall survival rates as low as eight percent, 2 making the introduction of new targeted therapeutic approaches tailored to address the unique complexities of EGFR exon 20 insertion mutations critical. “At Johnson & Johnson, we are dedicated to advancing more effective and personalised innovations targeting novel disease pathways, that enable patients diagnosed with lung cancer to receive the treatment that is optimised for their individual characteristics,” said Henar Hevia, Ph.D, Senior Director, EMEA Therapeutic Area Lead, Oncology, Johnson & Johnson Innovative Medicine. “Today’s approval is an important development for patients with EGFR exon 20 insertion-mutated non-small-cell lung cancer, who may now benefit from amivantamab plus chemotherapy at the start of their treatment journey.” The expanded indication for amivantamab is based on positive results from the Phase 3 PAPILLON study, comparing the efficacy and safety of amivantamab in combination with chemotherapy (n=153) to chemotherapy alone (n=155) in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. 3 Data from the study were previously published in The New England Journal of Medicine. 1 The PAPILLON study met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS; as measured by blinded independent central review [BICR]) in patients receiving amivantamab in combination with chemotherapy versus chemotherapy alone (hazard ratio [HR]=0.395; 95 percent confidence interval [CI], 0.30–0.53; P<0.0001). 4 An interim overall survival (OS) analysis showed a favourable trend for patients treated with amivantamab plus chemotherapy, compared to those treated with chemotherapy alone (HR=0.675; 95 percent CI, 0.42–1.09; P=0.106). 4 The combination of amivantamab and chemotherapy demonstrated a safety profile consistent with the safety profiles of the individual agents, with low rates of treatment-related discontinuation with amivantamab (7 percent). 4 The rates of overall adverse events (AEs) and AEs leading to death were comparable between both treatment arms. 4 The rate of Grade ≥3 AEs was higher with amivantamab and chemotherapy, compared to chemotherapy alone (75 percent vs. 54 percent). 4 Serious AEs (SAEs) occurred in 37 percent of patients with amivantamab and chemotherapy, compared to 31 percent with chemotherapy alone. 4 EGFR and MET-related AEs were increased with amivantamab-chemotherapy (primarily Grade 1-2). 4 Chemotherapy-associated haematologic and gastro-intestinal toxicities were comparable, except for the rate of neutropenia, which increased with amivantamab-chemotherapy compared to chemotherapy alone, but only occurred transiently. 4 Pneumonitis was reported in three percent of patients in the amivantamab-chemotherapy arm. 4 As a result of the EC approval, the conditional marketing authorisation (MA) for amivantamab, received in December 2021, has been converted to a standard MA. 5 “We are committed to advancing the science of EGFR-mutated non-small cell lung cancer for patients, with a focus on precision medicine-based approaches that target earlier stage disease,” said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumours, Johnson & Johnson Innovative Medicine. “Today’s approval marks another important milestone in our pursuit of transforming care for these patients.” #ENDS# About PAPILLON PAPILLON ( NCT04538664 NCT04538664) is a randomised, open-label Phase 3 study evaluating the efficacy and safety of amivantamab in combination with chemotherapy, compared with chemotherapy alone, in newly diagnosed patients with advanced or metastatic NSCLC characterised by EGFR exon 20 insertion mutations (n=308). 3 The primary endpoint of the study is PFS as assessed by BICR. 4 Secondary endpoints include overall response rate (ORR), PFS after first subsequent therapy (PFS2), duration of response (DOR), time to subsequent therapy (TTST) and overall survival (OS). 4 Patients who received chemotherapy alone were allowed to receive amivantamab monotherapy in the second-line setting after confirmation of disease progression. 4 About Amivantamab Amivantamab is a fully-human EGFR-MET bispecific antibody that acts by targeting tumours with activating and resistance EGFR mutations and MET mutations and amplifications, and by harnessing the immune system. 5,6,7,8 The European Commission (EC) granted conditional marketing authorisation of amivantamab in December 2021 for the treatment of adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations, after failure of platinum-based therapy. 5 Amivantamab is the first approved treatment in the European Economic Area specifically targeting EGFR exon 20 insertion mutations for NSCLC. 5 In November 2023, a Type II extension of indication application was submitted to the European Medicines Agency (EMA) based on the MARIPOSA-2 study seeking approval of amivantamab in combination with chemotherapy (carboplatin and pemetrexed) for the treatment of adult patients with advanced NSCLC with EGFR ex19del or L858R substitution mutations, after failure of prior therapy including a third-generation EGFR TKI. 9 This was recently followed, in February 2024, with the submission of a Type II extension of indication application to the EMA based on the MARIPOSA study for amivantamab, in combination with lazertinib, for the first-line treatment of adult patients with advanced NSCLC with common EGFR exon 19 deletions (ex19del) or exon 21 L858R (L858R) substitution mutations. 10 In May 2024, an application for the extension of amivantamab marketing authorisation was submitted seeking approval for the use of a subcutaneous (SC) formulation of amivantamab in combination with lazertinib for the first-line treatment of adult patients with advanced NSCLC with EGFR ex19del or L858R mutations in the first-line treatment setting, and for the use of SC amivantamab in adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations after failure of platinum-based therapy. 11 For a full list of adverse events and information on dosage and administration, contraindications and other precautions when using amivantamab, please refer to the Summary of Product Characteristics . 5 ▼ In line with EMA regulations for new medicines, amivantamab is subject to additional monitoring. About Non-Small Cell Lung Cancer In Europe, it is estimated that 484,306 people were diagnosed with lung cancer in 2022. 12 NSCLC accounts for 85 percent of all lung cancer cases. 13 Lung cancer is Europe’s biggest cancer killer, with more deaths than breast cancer and prostate cancer combined. 13 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma. 14 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division. 14,14 EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients. 15,16,17,18 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations. 19 The five-year survival rate for patients with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) is less than 20 percent. 20 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation. 21 Patients with EGFR exon 20 insertion mutations have a real-world five-year OS of eight percent in the frontline setting, which is lower than patients with EGFR ex19del or L858R mutations. 2 About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at www.janssen.com/emea . Follow us at www.linkedin.com/company/jnj-innovative-medicine-emea. Janssen-Cilag International NV, is a Johnson & Johnson company. *Professor Nicolas Girard has served as a consultant to Janssen-Cilag International NV; they have not been paid for any media work. References 1 Zhou C, et al. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med 2023;389(22):2039-2051. 2 Girard N, et al. Comparative clinical outcomes for patients with NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore. 3 ClinicalTrials.gov. A Study of Combination Amivantamab and Carboplatin-Pemetrexed Therapy, Compared With Carboplatin-Pemetrexed, in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Characterized by Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions (PAPILLON). Available at: https://clinicaltrials.gov/ct2/show/NCT04538664 . Last accessed: June 2024. 4 Girard N, et al. Amivantamab Plus Chemotherapy vs Chemotherapy as First line Treatment in EGFR Exon 20 Insertion-mutated Advanced Non-small Cell Lung Cancer (NSCLC): Primary Results From PAPILLON, a Randomized Phase 3 Global Study. 2023 European Society for Medical Oncology Congress. October 21, 2023. 5 European Medicines Agency. Amivantamab Summary of Product Characteristics. June 2024. Available at: https://www.ema.europa.eu/en/documents/product-information/rybrevant-epar-product-information_en.pdf . Last accessed: June 2024. 6 Grugan KD, et al. Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells. MAbs 2017;9(1):114-126. 7 Moores SL, et al. A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors. Cancer Res 2016;76(13)(suppl 27216193):3942-3953. 8 Yun J, et al. Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR–MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion–Driven NSCLC. Cancer Discov 2020;10(8):1194-1209. 9 Janssen.com/EMEA. Janssen Submits Type II Extension of Indication Application to the European Medicines Agency Seeking Approval of RYBREVANT®▼ (amivantamab), in combination with Lazertinib, for the First-Line Treatment of Patients with EGFR Mutated Non-Small Cell Lung Cancer. Available at: https://www.janssen.com/emea/sites/www_janssen_com_emea/files/amivantamab_mariposa_ema_filing_release_2024_2.pdf . Last accessed: June 2024. 10 Janssen.com/EMEA. Janssen Submits Type II Extension of Indication Application to the European Medicines Agency Seeking Approval of RYBREVANT®▼ (amivantamab), in combination with Lazertinib, for the First-Line Treatment of Patients with EGFR Mutated Non-Small Cell Lung Cancer. Available at: https://www.janssen.com/emea/sites/www_janssen_com_emea/files/amivantamab_mariposa_ema_filing_release_2024_2.pdf . Last accessed: June 2024. 11 Janssen EMEA. Johnson & Johnson submits application to the European Medicines Agency seeking approval of subcutaneous formulation of RYBREVANT®▼ (amivantamab) for the treatment of patients with EGFR-mutated non-small cell lung cancer. Available at: https://www.globenewswire.com/news-release/2024/05/31/2891769/0/en/Johnson-Johnson-submits-application-to-the-European-Medicines-Agency-seeking-approval-of-subcutaneous-formulation-of-RYBREVANT-amivantamab-for-the-treatment-of-patients-with-EGFR-m.html. Last accessed: June 2024. 12 Global Cancer Observatory. Cancer Today. Available at: https://gco.iarc.fr/en . Last accessed: June 2024. 13 Zappa C, et al. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res 2016;5(3):288–300. 14 Wee P, Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers 2017;9(5):52. 15 Pennell NA, et al. A phase II trial pf adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant non-small cell lung cancer. J Clin Oncol 2019;37(7);97-104. 16 Burnett H, et al. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review. Abstract presented at: World Conference on Lung Cancer Annual Meeting; January 29, 2021; Singapore. 17 Zhang YL, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 2016;7(48):78985-78993. 18 Midha A, et al. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity. Am J Cancer Res 2015;5(9):2892-2911. 19 American Lung Association. EGFR and Lung Cancer. Available at: https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/biomarker-testing/egfr . Last accessed: June 2024. 20 Lin JJ, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol 2016 Apr;11(4):556-65. 21 Arcila M, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Molecular Cancer Therapeutics 2013;12(2):220-9. SOURCE: Johnson & Johnson

关注并星标CPHI制药在线 日前，阿斯利康递交的「甲磺酸奥希替尼片」的2.4类进口申请获CDE受理，这是奥希替尼在国内递交的第五项上市申请，其中前四项上市申请已被批准：EGFR-TKI治疗时或治疗后出现疾病进展，并且经检测确认存在EGFR T790M突变阳性的局部晚期或转移性成人NSCLC（2017.03)；一线治疗EGFR突变阳性晚期或转移性成人NSCLC（2019.08）；EGFR敏感突变的NSCLC成人患者肿瘤切除术后的辅助治疗(2021.04)；联合化疗一线治疗携带EGFR突变的NSCLC（2024.06）。 根据奥希替尼在国内的临床试验进展，笔者推测其申报的第五项适应症分别是：接受含铂根治性放化疗后未出现疾病进展、具有EGFR外显子19缺失（Ex19del）或外显子21（L858R）置换突变的 III 期不可切除成人NSCLC。该适应症于今年6月被CDE纳入突破性治疗品种程序。 奥希替尼（osimertinib，Tagrisso）是阿斯利康开发的一种不可逆第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），自2015年11月在美国获批以来，已在NSCLC领域获批多项适应症，其中联合铂类化疗一线治疗具有EGFR外显子19缺失或外显子21（L858R）置换突变的局部晚期或转移性NSCLC的上市申请已于今年2月在美国获批。 作为首个上市的第三代EGFR-TKI，Tagrisso（奥希替尼）的市场潜力还没有被完全挖掘，销售额不断刷新，2023年达到57.99亿美元。预计随着新适应症的拓展，Tagrisso销售额还将持续增长。 EGFR-TKIs现状 EGFR是NSCLC最常见的驱动基因。外显子19缺失（Del19）和外显子21 L858R突变是最常见的EGFR突变类型，称为经典突变，约占85%。此外，还有7%-23%的NSCLC患者伴EGFR非经典突变，如外显子20插入（~6%）、G719X （~3%）、L861Q （~1%）、S768I （~1%）和外显子19插入（0.6%）等。 EGFR -TKIs是EGFR敏感突变晚期NSCLC的标准治疗，目前全球监管机构已批准多款EGFR-TKIs，详见下表。EGFR-TKIs的研发非常内卷，目前已上市产品可分为三代，其中第三代EGFR-TKIs的开发主要是针对第一代和第二代EGFR-TKIs使用后出线的EGFR T790M耐药突变。 从产品数量上看，第三代EGFR-TKIs竞争十分激烈，全球已获批产品高达7款，其中国内已批准6款。从表格可以看出，国内已批准的6款EGFR-TKIs均被批准用于既往经EGFR-TKI治疗时或治疗后出现疾病进展，并且经检测确认存在EGFR T790M突变阳性的局部晚期或转移性NSCLC成人患者的治疗，其中奥希替尼获批适应症最多，还被批准一线治疗EGFR突变NSCLC和EGFR敏感突变NSCLC的术后辅助治疗，阿美替尼和伏美替尼还被批准一线治疗EGFR外显子19缺失或外显子 21（L858R）置换突变的NSCLC。 市场表现上，奥希替尼表现最佳，2023年其在国内销售额大约在70亿元左右。阿美替尼次之，约35亿元。伏美替尼排名第三，约19.8亿元。贝福替尼上市较晚，约有0.6亿元。这四款EGFR-TKIs均已进入国家医保，且已开始打价格战，其中奥希替尼、阿美替尼和伏美替尼的月治疗费用在5000元左右，贝福替尼月治疗费用为8400元。随着新一轮医保谈判的到来，瑞齐替尼、瑞厄替尼预计也将加入价格战。新竞争对手的入局势必将加速国内第三代EGFR-TKIs之争。 此外，目前国内还有多款在研第三代EGFR-TKIs，其中limertinib（奥赛康）、兰泽替尼（强生）已在国内申请上市。TY-9591（同源康医药）、FHND-9041（正大丰海）、艾维替尼（艾森医药）等进入3期临床试验阶段。 在激烈的竞争中要想胜出，差异化布局非常关键。以上三代EGFR-TKIs中，奥希替尼占据先发优势，也是后继者想分杯羹的存在。从结构和现有临床数据来看，阿美替尼较奥希替尼似乎并未表现出明显优势。伏美替尼是以三氟乙氧基吡啶取代奥希替尼中的甲氧基苯，具有更高的药效和更好的跨血脑屏障，其还打破了三代EGFR-TKIs一线治疗20个月的mPFS。此外，伏美替尼一线治疗EGFR 20外显子插入突变的局部晚期或转移性NSCLC的适应症先后被FDA和CDE授予突破性疗法认定。贝福替尼在一线治疗EGFR突变晚期NSCLC、二线治疗EGFR T790M突变阳性NSCLC的临床试验中都刷新了奥希替尼、阿美替尼和伏美替尼的纪录，而且其在一线治疗21外显子突变NSCLC中有优势，PFS长达17.9个月（奥希替尼14.4个月，阿美替尼13.4个月）。 三代EGFR-TKIs耐药的破局法 耐药是临床上无可避免会遇到的问题，第三代EGFR-TKIs也不例外。以奥希替尼为例，其耐药机制主要分为四类：EGFR通路突变；旁路激活；组织学转化；原因未明的耐药机制。EGFR通路突变包括EGFR C797S突变、T790M减少或消失、EGFR扩增等，其中EGFR C797突变最常见。旁路激活主要发生在一线治疗中，主要包括MET扩增、MET突变（H1094Y） 、KRAS突变（G12A） 、BRAF融合、RET融合等。组织学转化包括小细胞肺癌转化、上皮细胞-间充质转化、大细胞肺癌和鳞癌转化等。至于原因未明的耐药在一线治疗中比较常见，高达60%（不同研究数据有差异）的患者找不到耐药原因。 而针对EGFR -TKIs耐药的药物研发方向主要包括以下三种：开发靶向EGFR驱动的耐药突变的药物、靶向特定分子驱动的耐药突变的药物以及EGFR抑制剂与其他类型药物联合治疗策略。由此诞生了针对奥希替尼耐药的第四代EGFR -TKIs，如BLU-945和BBT-176，不过由于临床数据不理想，这两款药物相关试验被暂停或终止。此外，第四代EGFR -TKIs还针对一些罕见的EGFR突变，其中BDTX-1535可靶向NSCLC一系列经典/非经典EGFR驱动基因突变和耐药突变（包括C797S、G719X和S768I等），且具有很强的脑渗透性，其治疗EGFR突变NSCLC的1期初步临床数据（排除了EGFR T790M突变，外显子20插入突变，KRAS突变，MET扩增）显示：在12例可评估患者中，5例经 RECIST 1.1 确认实现了放射学部分缓解，另有1名患者表现出未经证实的PR等待确认，其余6名患者病情稳定，ORR达到50%，DCR为100%。 总结 肺癌是全球第一大癌，EGFR是一种常见的肺癌驱动基因。全球针对EGFR靶点不仅开发除了小分子化药，还开出了单抗、双抗。其中小分子EGFR-TKIs是NSCLC治疗领域非常重要的一类靶向药，目前已取得巨大成功，且经历了三代更迭。据Frost&Sullivan预计，2021年我国EGFR-TKIs市场规模达130亿元年，预计2025年和2030年有望分别达到285亿元和522亿元。鉴于目前国内EGFR-TKIs的市场格局，尤其是第三代EGFR-TKIs，未来该领域的竞争必将更加白热化。 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~