PO.CTP01.03 · 进行中的临床试验
一项评估EP0031（lunbotinib，新一代选择性RET抑制剂）作为单药及联合化疗治疗晚期RET融合阳性NSCLC患者的I/II期研究
A phase I/II study to evaluate EP0031 (lunbotinib), a next-generation selective RET inhibitor, as monotherapy and in combination with chemotherapy, in patients with advanced RET -fusion-positive NSCLC
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摘要 Abstract
中文摘要
背景：EP0031（lunbotinib，A400）是一种同类首创的新一代选择性RET抑制剂（SRI），对包括耐药突变在内的常见RET变异具有广泛的效力，与第一代SRI相比，其具有更强的效力、抗肿瘤活性以及CNS穿透性/活性（1,2）。临床数据表明，EP0031在SRI初治或既往接受过SRI治疗的患者中均有活性，包括伴有脑转移和/或靶点RET耐药突变的患者，并具有可接受的耐受性（2,3,4）。对第一代SRI的耐药具有异质性，其特征为RET依赖性和非依赖性通路（4）。SRI+化疗可能是解决潜在疾病异质性的一种有前景的策略。越来越多的证据表明RET融合阳性NSCLC对以培美曲塞为基础的化疗敏感，且临床前证据证实EP0031与化疗之间具有强协同作用。这是首个评估该联合方案的研究。
研究设计与方法：这是一项正在进行的I/II期试验。基于剂量优化数据（4），选择了90 mg每日一次的单药RP2D。2期扩展队列正在招募晚期RET融合阳性NSCLC患者（NCT05443126），分为三个队列：（1）接受EP0031一线治疗的SRI初治患者（N=25）；（2）接受EP0031联合铂类-培美曲塞一线治疗的SRI初治患者（N=25）；（3）既往接受过第一代SRI治疗、接受EP0031联合铂类-培美曲塞二线治疗的患者（N=25）。主要入组标准包括年龄≥18岁，东部肿瘤协作组（ECOG）体能状态≤1，以及经RECIST v1.1可测量的RET融合阳性NSCLC，伴或不伴无症状、稳定的脑转移。EP0031口服给药，每日一次持续给药。在联合队列中，化疗双药以标准剂量每21天给药一次，共4个周期，随后进行培美曲塞维持治疗。每个联合队列在扩展至25例患者接受联合RP2D前均设有3+3安全性导入期。终点包括根据RECIST v1.1评估的肿瘤缓解、无进展生存期和总生存期。其他主要终点包括安全性（包括剂量限制性毒性和不良事件的发生率）和药代动力学参数。收集循环肿瘤DNA以评估靶点和脱靶突变的出现。该研究目前正在美国、欧洲和阿联酋招募患者。
参考文献 1. Zhou Q, et al. J Clin Oncol 2023:41:16_suppl, abstract 3007 2. Garralda E, et al. J Clin Oncol 2024:42:16_suppl, abstract 8556 3. Garralda E, et al. Ann Oncol 2024; 35: S824, abstract 1295P 4. Alonso G, et al. J Clin Oncol 2025: 43:16_suppl, 8598
查看英文原文 English abstract
Background: EP0031 (lunbotinib, A400), a first-in-class, next-generation selective RET inhibitor (SRI), has broad potency against common RET alterations, including resistance mutations, and has greater potency, antitumor activity, and CNS penetration/activity compared with first-generation SRIs (1,2). Clinical data indicates that EP0031 is active in patients who are SRI-naïve or have received prior SRI treatment, including those with brain metastases and/or on-target RET resistance mutations, and has acceptable tolerability (2,3,4). Resistance to first-generation SRIs is heterogeneous, characterized by RET -dependent and -independent pathways (4). SRI + chemotherapy may represent a promising strategy to address underlying disease heterogeneity. There is growing evidence that RET fusion-positive NSCLC is sensitive to pemetrexed-based chemotherapy and preclinical evidence confirms strong synergy between EP0031 and chemotherapy. This is the first study to evaluate this combination approach.
Study Design and Methods: This is an ongoing phase I/II trial. A monotherapy RP2D of 90 mg daily was selected based on dose optimization data (4). Phase II expansion cohorts are recruiting patients with advanced RET fusion-positive NSCLC (NCT05443126) across three cohorts: (1) SRI-naïve patients receiving first-line therapy with EP0031 (N=25); (2) SRI-naïve patients receiving first-line therapy with EP0031 in combination with platinum-pemetrexed (N=25); and (3) Patients previously treated with a first-generation SRI, receiving second-line treatment with EP0031 in combination with platinum-pemetrexed (N=25). Key inclusion criteria include age ≥ 18 years, an Eastern Cooperative Oncology Group performance status ≤ 1, and RET fusion-positive NSCLC measurable by RECIST v1.1, with or without asymptomatic, stable brain metastases. EP0031 is administered orally, continuously once daily. In combination cohorts, the chemotherapy doublet is administered every 21 days at standard doses for four cycles followed by pemetrexed maintenance. Each combination cohort has a 3+3 safety run-in before expansion in 25 patients at the combination RP2D. Endpoints include tumor response per RECIST v1.1, progression-free survival, and overall survival. Other key endpoints include safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetic parameters. Circulating tumor DNA is collected to evaluate the emergence of on- and off-target mutations. The study is currently recruiting across the US, Europe, and the UAE.
References 1. Zhou Q, et al. J Clin Oncol 2023:41:16_suppl, abstract 3007 2. Garralda E, et al. J Clin Oncol 2024:42:16_suppl, abstract 8556 3. Garralda E, et al. Ann Oncol 2024; 35: S824, abstract 1295P 4. Alonso G, et al. J Clin Oncol 2025: 43:16_suppl, 8598
利益披露 Disclosure
J. Rubio-Perez, None.
E. Garralda,
Novartis, Roche, AZ, Taiho, BeiGene, Janssen, BI, Seattle Genetics, Thermo Fisher, MabDiscovery, Anaveon, F-Star, Hengrui, Sanofi, Incyte, Medscape, Pfizer, Amgen; MSD, Roche, Thermo Fisher, Novartis ).
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S. Khan,
Roche, Serono, Eisai, Genmab, Kineto, Novartis, Merck, Threshold, Gilead, Bayer, Celldex, Abbvie ).
J. Wang,
Abbvie, Abdera Therapeutics, Accent Therapeutics, Accutar Biotech, Acrivon Therapeutics, Adagene, Allorion Therapeutics, Alterome Therapeutics, Apollo, Artios, Astellas Pharma, Avenzo, BeiGene, Bicyc ).
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Roche/Genentech, Lilly, Pfizer, BMS, MSD, AZ, PharmaMar, Novartis, Amgen, Sanofi, Bayer, Takeda, GSK, Janssen, BI, AbbVie, Gilead, BeOne, PharmaMar, Mirati, Regeneron, Astellas, Merck Serono, Daiichi ).
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S. Liu,
Roche, BMS, AZ, Takeda, Regeneron, Guardant, MSD, Jazz, Daiichi, Novartis, Gilead, Merus ).
M. Taylor,
Eisai, BMS, Exelexis, Merck, Pfizer, Moderna ).
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A. Gianoukakis,
Eisai ).
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Roche, AZ, GSK, Abbvie, Circle, Daiichi, MideX, Gatorade, Gilead, Medpace, Ottimo, Pyxis ).
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A. Drilon,
14ner/Elevation Oncology, Amgen, Abbvie, AnHeart Therapeutics, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, EcoR1 ), Honoraria.
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