Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA.
University of Colorado Cancer Center, Denver, Colorado, USA.
Clin Transl Sci. 2024 Mar;17(3):e13766. doi: 10.1111/cts.13766.
Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations represent ~6%-12% of all EGFR-mutated non-small cell lung cancer (NSCLC) cases. First-, second-, and third-generation tyrosine kinase inhibitors (TKIs) have limited clinical activity against EGFR ex20ins mutations. Mobocertinib is a first-in-class oral EGFR TKI that selectively targets in-frame EGFR ex20ins mutations in NSCLC; accelerated approval in the United States was granted for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations whose disease has progressed on or after platinum-based chemotherapy. Accelerated approval was based on the results from the three-part, open-label, multicenter, pivotal phase I/II nonrandomized clinical trial (NCT02716116) that enrolled 114 patients with locally advanced or metastatic EGFR ex20ins mutation-positive NSCLC who were previously treated with platinum-based chemotherapy and received mobocertinib at the recommended dosage of 160 mg once daily. At the November 1, 2021, data cutoff date, the confirmed objective response rate per independent review committee (IRC) was 28%, median duration of response was 15.8 months, median progression-free survival per IRC was 7.3 months, and median overall survival was 20.2 months. The most common treatment-emergent adverse events were gastrointestinal- and skin-related. The phase III EXCLAIM-2 study evaluated mobocertinib versus chemotherapy as first-line therapy for locally advanced or metastatic EGFR ex20ins-positive NSCLC; however, the primary end point was not met, resulting in initiating voluntary withdrawal of mobocertinib worldwide. This mini-review article summarizes the mechanism of action, pharmacokinetic characteristics, key clinical trials, and clinical efficacy and safety data for mobocertinib.
表皮生长因子受体 (EGFR) 外显子 20 插入 (ex20ins) 突变占所有 EGFR 突变型非小细胞肺癌 (NSCLC) 病例的~6%-12%。第一代、第二代和第三代酪氨酸激酶抑制剂 (TKI) 对 EGFR ex20ins 突变的临床活性有限。莫博赛替尼是一种首创的口服 EGFR TKI，特异性针对 NSCLC 中的 EGFR ex20ins 突变；在美国，它被加速批准用于治疗 EGFR ex20ins 突变的局部晚期或转移性 NSCLC 成人患者，这些患者的疾病在铂类化疗后进展。加速批准基于三项、开放性、多中心、关键的 I/II 期非随机临床试验 (NCT02716116) 的结果，该试验招募了 114 名局部晚期或转移性 EGFR ex20ins 突变阳性 NSCLC 患者，这些患者先前接受过铂类化疗，并以 160mg 每日一次的推荐剂量接受莫博赛替尼治疗。在 2021 年 11 月 1 日的数据截止日期，IRC 确认的客观缓解率为 28%，IRC 中位缓解持续时间为 15.8 个月，IRC 中位无进展生存期为 7.3 个月，中位总生存期为 20.2 个月。最常见的治疗相关不良事件是胃肠道和皮肤相关的。III 期 EXCLAIM-2 研究评估了莫博赛替尼与化疗作为局部晚期或转移性 EGFR ex20ins 阳性 NSCLC 的一线治疗；然而，主要终点未达到，导致莫博赛替尼在全球范围内自愿撤回。本文对莫博赛替尼的作用机制、药代动力学特征、关键临床试验以及临床疗效和安全性数据进行了总结。
