简介：在非小细胞肺癌(NSCLC)中，EGFR外显子20插入(ex20ins)发生在EGFR突变的4%–10%中，约占NSCLC的2%。没有专门针对EGFR ex20ins+NSCLC的批准疗法。先前接受第一代，第二代或第三代EGFR酪氨酸激酶抑制剂(TKIs)治疗的患者的客观缓解率(ORR)<10%，中位无进展生存期(PFS)<4个月。Mobocertinib(TAK-788)是一种口服EGFR TKI，专门针对EGFR与ex20ins，为EGFR ex20ins+NSCLC患者提供突破性治疗名称，这些患者之前曾有过铂类化疗(在美国)，或之前接受过化疗(在中国)，基于初步的1/2期结果。

        Introduction:EGFRexon 20 insertions (ex20ins) occur in 4%–10% ofEGFRmutations in non–small cell lung cancer (NSCLC), accounting for ~2% of NSCLC. No approved therapies specifically forEGFRex20ins+ NSCLC are available. Objective response rates (ORRs) in previously treated patients receiving first-, second-, or third-generation EGFR tyrosine kinase inhibitors (TKIs) are <10%, with a median progression-free survival (PFS) <4 months. Mobocertinib (TAK-788), an oral EGFR TKI that specifically targetsEGFRwith ex20ins, holds Breakthrough Therapy Designation for patients withEGFRex20ins+ NSCLC who previously progressed on platinum-based chemotherapy (in the United States) or who had prior chemotherapy (in China), based on preliminary phase 1/2 results.

        方法：mobocertinib 1/2期开放标签多中心研究(NCT02716116)评估了一个剂量扩展EGFR ex20ins+转移性NSCLC队列，该队列在缓解或病情稳定后进展≥接受EGFR TKI治疗6个月。主要终点由研究者根据RECIST v1.1确认或评估。其他疗效终点包括疾病控制率(DCR)、反应持续时间(DoR)、PFS(根据独立审查委员会[IRC])和研究者，以及总生存率(OS)。患者口服mobocertinib 160 mg，每日一次。

        Methods:A phase 1/2, open-label, multicenter, study of mobocertinib (NCT02716116) evaluated a dose-expansionEGFRex20ins+ metastatic NSCLC cohort who progressed after response or stable disease for ≥6 months on any prior EGFR TKI therapy. The primary endpoint was confirmed ORR assessed by the investigator per RECIST v1.1. Other efficacy endpoints included disease control rate (DCR), duration of response (DoR), PFS (per Independent Review Committee [IRC]) and investigator, and overall survival (OS). Patients received mobocertinib 160 mg orally once daily.

        结果：入选20例曾接受EGFR TKI治疗的患者，中位年龄为61.0岁[范围：38–78]，东部肿瘤合作组的表现状态为0(35%)或1(65%);55%为女性。转移部位的中位数为3.5(范围：1-6);10名患者(50%)有基线脑转移。16名患者(80%)曾接受过铂类化疗，13名患者(65%)曾接受过免疫治疗。先前的EGFR TKIs包括波齐奥替尼(n=13)、厄洛替尼(n=5)、阿法替尼(n=4)和奥西米替尼(n=4);11/20患者(55%)接受EGFR TKIs作为最新的前期治疗。每名研究人员确认的ORR为20%，每名IRC确认的ORR为40%(表)，每名IRC 95%(19/20)的靶病变减少。观察到的治疗相关不良事件(TRAE)≥20%的患者为腹泻(90%)、恶心(35%)、瘙痒(30%)、皮疹(25%)、贫血(25%)、呕吐(20%)、痤疮样皮炎(20%)和疲劳(20%)。4例(20%)发生3/4级TRAEs。发生严重不良事件7例(35%)。两名患者因不良事件而停药(10%)。

        Results:Twenty patients previously treated with EGFR TKI were enrolled, with median age of 61.0 y [range: 38–78] and Eastern Cooperative Oncology Group performance status of 0 (35%) or 1 (65%); 55% female. Median number of metastatic sites was 3.5 (range: 1–6); 10 patients (50%) had baseline brain metastases. Sixteen patients (80%) received prior platinum-based chemotherapy and 13 patients (65%) received prior immunotherapy. Prior EGFR TKIs included poziotinib (n=13), erlotinib (n=5), afatinib (n=4), and osimertinib (n=4); 11/20 patients (55%) received EGFR TKIs as most recent prior treatment. Confirmed ORR was 20% per investigator and 40% per IRC () and 95% (19/20) had target lesion reduction per IRC. Treatment-related adverse events (TRAEs) observed in ≥20% of patients were diarrhea (90%), nausea (35%), pruritus (30%), rash (25%), anemia (25%), vomiting (20%), dermatitis acneiform (20%), and fatigue (20%). Grades 3/4 TRAEs occurred in 4 patients (20%). Serious AEs occurred in 7 patients (35%). Two patients discontinued due to AEs (10%).

        结论：Mobocertinib治疗EGFR ex20ins+转移性非小细胞肺癌合并肺癌患者具有临床意义≥在先前的EGFR TKI基础上进行6个月的疾病控制。安全性状况是可控的，与其他患者队列相似，并且与更广泛的EGFR TKI类别一致。

        Conclusion:Mobocertinib treatment had a clinically meaningful benefit for patients withEGFRex20ins+ metastatic NSCLC with ≥6-month disease control on prior EGFR TKI. The safety profile was manageable, similar to other patient cohorts, and consistent with the broader class of EGFR TKIs.