山东罗欣药业集团股份有限公司招标公告
10月20日至24日，2023年欧洲肿瘤内科学会（ESMO）大会在西班牙马德里隆重召开。罗欣药业集团股份有限公司（简称“罗欣药业”）旗下抗肿瘤创新药LX-039片I期临床研究入选2023年ESMO年会壁报展示。
图：ESMO官网页面
ESMO作为全球最具影响力的肿瘤学会议之一，每年有来自150多个国家和地区的超过30000名专业人士参加会议。大会涵盖了基础研究、转化研究以及最新临床研究进展，为临床诊疗、学术讨论等提供了广阔的交流学习平台。
LX-039片是一种新型口服选择性雌激素受体下调剂（SERD），此次入选的研究是LX-039片在内分泌治疗失败的雌激素受体阳性（ER+）、人表皮生长因子受体2阴性（HER2-）绝经后晚期乳腺癌患者中的剂量递增与扩展I期临床试验。旨在探索其安全耐受性、药代/药效动力学（PK/PD）特征与初步抗肿瘤活性。复旦大学附属肿瘤医院胡夕春教授作为主要研究者牵头开展。
该研究采用传统“3+3”设计，探索了从50mg每日一次剂量组递增至1200mg每日一次剂量组的安全耐受性，并选择2个剂量组进行扩展。同时，使用18F-氟雌二醇PET/CT检查进行药效动力学探索。入组的44例患者均接受过多线抗肿瘤内分泌治疗（72.7%≥2线），其中半数以上曾使用过氟维司群。亦有超过一半受试者接受了晚期化疗，40.9%受试者曾使用过CDK4/6抑制剂。
该研究未探索到最大耐受剂量，同时与LX-039片相关的不良事件多数为1-2级。PK呈剂量线性，未见蓄积。所有参与PD探索的受试者均观察到ER通路的抑制。共4例受试者达到部分缓解，客观缓解率10.8%，24周临床获益率40%。LX-039片对ER+、HER2-晚期乳腺癌具有良好的耐受性和PK/PD特性，已经探索到初步抗肿瘤活性，具备进一步开发前景，目前正计划进行II期临床试验。
ER+乳腺癌约占所有乳腺癌的75%，该类肿瘤对ER信号通路呈依赖性，主要治疗策略为从各个途径抑制ER信号通路。既往虽然已经有诸如他莫昔芬、氟维司群等作用于ER通路的药物应用于临床，但他莫昔芬的耐药及氟维司群的用药依从问题导致该领域仍有未被满足的临床需求。
LX-039片作为罗欣药业自主研发的口服SERD，可直接作用于雌激素信号通路，不仅可拮抗雌激素受体，还可加速乳腺癌细胞内ER的泛素化降解，下调ER水平，相比选择性雌激素受体调节剂和芳香化酶抑制剂表现出独特的药物优势。另外，口服剂型能极大方便用药，提高依从性，降低注射风险。目前国内尚无该机制口服药物上市。
Luoxin Pharmaceutical’s LX-039 (Innovative Anti-Tumor Drug):
Phase I Clinical Study Data Presented at ESMO 2023
From October 20 to 24, the 2023 ESMO Congress was held in Madrid, Spain. LX-039, an innovative anti-tumor drug developed by Luoxin Pharmaceuticals Group Stock Co., Ltd. (Luoxin Pharmaceutical), was selected for poster presentation at the 2023 ESMO Annual Congress.
Source: ESMO website
ESMO is one of the most influential oncology conferences globally, attracting over 30,000 professionals every year from more than 150 countries and regions. The Congress covers basic research, translational research, and the latest advancements in clinical studies, providing an exchange platform in clinical diagnosis, treatment, and academic discussions.
LX-039 is an innovative selective estrogen receptor degrader (SERD) for oral administration. The aims of the dose escalation and expansion phase I study was to explore the safety, tolerability, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) profiles of LX-039 in postmenopausal patients with ER+ and HER2- advanced breast cancer who have failed endocrine therapy. The study was led by Professor Hu Xichun from Fudan University Shanghai Cancer Center.
In a 3+3 design, the trial evaluated the safety and tolerability from a daily dose of 50 mg to 1200 mg, with two dosage groups selected for expansion. [18F] Fluoroestradiol PET/CT imaging was used for PD study. All 44 enrolled subjects had previously undergone multiple lines of endocrine therapy. Specifically, 72.7% had received second-line therapy or higher. More than half had been treated with fulvestrant, a medication commonly used for hormone receptor-positive breast cancer. Also, over 50% had received advanced chemotherapy, and 40.9% had been treated with CDK4/6 inhibitors.
Maximum tolerated dose (MTD) was not reached in this study. Most adverse events are graded as mild to moderate (grade 1-2). The exposure of LX-039 increased along with the dose escalation, and no obvious accumulation after multiple doses. Inhibition of the ER pathway is observed in all subjects participating in the PD exploration. Four subjects achieved partial response, with an objective response rate of 10.8% and a clinical benefit rate at 24 weeks of 40%. LX-039 demonstrates good tolerability and PK/PD properties in ER+ and HER2- advanced breast cancer and shows preliminary anti-tumor activity. These encouraging results suggest that LX-039 holds great potential for further development. Consequently, a phase II study is under planning.
About 75% of breast cancer cases are classified as ER+. This subtype of breast cancer relies on the estrogen signaling pathway for its growth and progression. The primary therapeutic approach for ER+ breast cancer involves inhibiting the estrogen signaling pathway through various methods. Notably, drugs like tamoxifen and fulvestrant have been utilized in clinical settings to target the ER pathway. However, tamoxifen resistance and treatment non-compliance with fulvestrant have led to unmet clinical needs.
LX-039, an orally administered selective ER degrader (SERD) developed by Louxin Pharmaceutical, specifically focuses on modulating the estrogen signaling pathway. It antagonizes ER actions and promotes its ubiquitination and degradation within breast cancer cells, downregulating ER expression. LX-039 offers unique therapeutic benefits compared to selective ER modulators and aromatase inhibitors. Additionally, its oral formulation enhances patient convenience and compliance, as it eliminates the need for injections. There are currently no domestically available oral drugs with a similar mechanism of action to LX-039 in the market.
参考文献/References:
1. Wang Y, Ayres K L, Goldman D A, et al. 18F-fluoroestradiol PET/CT measurement of estrogen receptor suppression during a phase I trial of the novel estrogen receptor-targeted therapeutic GDC-0810: using an imaging biomarker to guide drug dosage in subsequent trials[J]. Clinical Cancer Research, 2017, 23(12): 3053-3060.
2. Patel H K, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment[J]. Pharmacology & therapeutics, 2018, 186: 1-24.
