山東羅欣藥業集團股份有限公司招標公告
10月20日至24日，2023年歐洲腫瘤內科學會（ESMO）大會在西班牙馬德里隆重召開。羅欣藥業集團股份有限公司（簡稱“羅欣藥業”）旗下抗腫瘤創新藥LX-039片I期臨床研究入選2023年ESMO年會壁報展示。
圖：ESMO官網頁面
ESMO作為全球最具影響力的腫瘤學會議之一，每年有來自150多個國家和地區的超過30000名專業人士參加會議。大會涵蓋了基礎研究、轉化研究以及最新臨床研究進展，為臨床診療、學術討論等提供了廣闊的交流學習平臺。
LX-039片是一種新型口服選擇性雌激素受體下調劑（SERD），此次入選的研究是LX-039片在內分泌治療失敗的雌激素受體陽性（ER+）、人表皮生長因子受體2陰性（HER2-）絕經后晚期乳腺癌患者中的劑量遞增與擴展I期臨床試驗。旨在探索其安全耐受性、藥代/藥效動力學（PK/PD）特征與初步抗腫瘤活性。復旦大學附屬腫瘤醫院胡夕春教授作為主要研究者牽頭開展。
該研究采用傳統“3+3”設計，探索了從50mg每日一次劑量組遞增至1200mg每日一次劑量組的安全耐受性，并選擇2個劑量組進行擴展。同時，使用18F-氟雌二醇PET/CT檢查進行藥效動力學探索。入組的44例患者均接受過多線抗腫瘤內分泌治療（72.7%≥2線），其中半數以上曾使用過氟維司群。亦有超過一半受試者接受了晚期化療，40.9%受試者曾使用過CDK4/6抑制劑。
該研究未探索到最大耐受劑量，同時與LX-039片相關的不良事件多數為1-2級。PK呈劑量線性，未見蓄積。所有參與PD探索的受試者均觀察到ER通路的抑制。共4例受試者達到部分緩解，客觀緩解率10.8%，24周臨床獲益率40%。LX-039片對ER+、HER2-晚期乳腺癌具有良好的耐受性和PK/PD特性，已經探索到初步抗腫瘤活性，具備進一步開發前景，目前正計劃進行II期臨床試驗。
ER+乳腺癌約占所有乳腺癌的75%，該類腫瘤對ER信號通路呈依賴性，主要治療策略為從各個途徑抑制ER信號通路。既往雖然已經有諸如他莫昔芬、氟維司群等作用于ER通路的藥物應用于臨床，但他莫昔芬的耐藥及氟維司群的用藥依從問題導致該領域仍有未被滿足的臨床需求。
LX-039片作為羅欣藥業自主研發的口服SERD，可直接作用于雌激素信號通路，不僅可拮抗雌激素受體，還可加速乳腺癌細胞內ER的泛素化降解，下調ER水平，相比選擇性雌激素受體調節劑和芳香化酶抑制劑表現出獨特的藥物優勢。另外，口服劑型能極大方便用藥，提高依從性，降低注射風險。目前國內尚無該機制口服藥物上市。
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.
參考文獻/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.
