Horinouchi H, Cho B C, Camidge D R, Goto K, Tomasini P, Li Y, Vasilopoulos A, Brunsdon P, Hoffman D, Shi W, Bolotin E, Blot V, Goldman J
National Cancer Center Hospital, Tokyo, Japan.
Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Ann Oncol. 2025 May;36(5):583-591. doi: 10.1016/j.annonc.2025.01.001. Epub 2025 Jan 11.
Osimertinib is the standard first-line treatment for advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, treatment resistance is inevitable and increased c-Met protein expression correlates with resistance. Telisotuzumab vedotin (Teliso-V) is an antibody-drug conjugate that targets c-Met protein overexpression. In this article, we report the results of a phase I/Ib trial evaluating Teliso-V plus osimertinib in patients with NSCLC after progression on osimertinib.
This multicenter, open-label study (NCT02099058) enrolled patients with advanced EGFR-mutated, c-Met protein-overexpressing, non-squamous NSCLC that had progressed on prior osimertinib. Patients received Teliso-V (intravenously, every 2 weeks) plus osimertinib (orally, 80 mg once daily). Teliso-V was evaluated at 1.6 mg/kg in a safety lead-in phase and escalated to 1.9 mg/kg. Dose expansion included both doses. Endpoints included safety and tolerability, pharmacokinetics, objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS).
A total of 38 patients received Teliso-V (1.6 mg/kg, n = 20; 1.9 mg/kg, n = 18) plus osimertinib and were included in this analysis. No dose-limiting toxicities were observed. Most frequent any-grade treatment-emergent adverse events (TEAEs) were peripheral sensory neuropathy (50%), peripheral edema (32%), and nausea (24%). Most common grade 3/4 TEAEs were anemia (11%) and pulmonary embolism (8%). Five TEAEs led to death; none were reported as being related to Teliso-V or osimertinib. The pharmacokinetic profile of Teliso-V plus osimertinib was similar to Teliso-V monotherapy. After a median follow-up of 7.4 months, the ORR was 50.0% per independent central review (ICR) (DOR not reached), and median PFS per ICR was 7.4 months (95% confidence interval 5.4 months-not reached).
Teliso-V plus osimertinib had promising activity and a manageable safety profile in patients with c-Met protein-overexpressing, EGFR-mutated non-squamous NSCLC after progression on osimertinib. This combination has the potential to address an unmet medical need in this patient population.
奥希替尼是晚期表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）的标准一线治疗药物。然而，治疗耐药不可避免，且c-Met蛋白表达增加与耐药相关。替雷利珠单抗（Teliso-V）是一种靶向c-Met蛋白过表达的抗体药物偶联物。在本文中，我们报告了一项I/Ib期试验的结果，该试验评估了替雷利珠单抗联合奥希替尼用于奥希替尼治疗后病情进展的NSCLC患者。
这项多中心、开放标签研究（NCT02099058）纳入了先前接受奥希替尼治疗后病情进展的晚期EGFR突变、c-Met蛋白过表达的非鳞状NSCLC患者。患者接受替雷利珠单抗（静脉注射，每2周一次）联合奥希替尼（口服，每日一次80mg）。在安全性导入期，替雷利珠单抗的剂量为1.6mg/kg，并逐步增加至1.9mg/kg。剂量扩展包括这两个剂量组。研究终点包括安全性和耐受性、药代动力学、客观缓解率（ORR）、缓解持续时间（DOR）和无进展生存期（PFS）。
共有38例患者接受了替雷利珠单抗（1.6mg/kg，n = 20；1.9mg/kg，n = 18）联合奥希替尼治疗，并纳入本分析。未观察到剂量限制性毒性。最常见的任何级别治疗期间出现的不良事件（TEAE）为周围感觉神经病变（50%）、周围水肿（32%）和恶心（24%）。最常见的3/4级TEAE为贫血（11%）和肺栓塞（8%）。5例TEAE导致死亡；均未报告与替雷利珠单抗或奥希替尼相关。替雷利珠单抗联合奥希替尼的药代动力学特征与替雷利珠单抗单药治疗相似。中位随访7.4个月后，根据独立中心审查（ICR），ORR为50.0%（DOR未达到），根据ICR的中位PFS为7.4个月（95%置信区间5.4个月 - 未达到）。
对于奥希替尼治疗后病情进展的c-Met蛋白过表达、EGFR突变的非鳞状NSCLC患者，替雷利珠单抗联合奥希替尼具有良好的活性和可控的安全性。这种联合治疗有可能满足该患者群体中未被满足的医疗需求。
