簡介：在非小細胞肺癌(NSCLC)中，EGFR外顯子20插入(ex20ins)發生在EGFR突變的4%–10%中，約占NSCLC的2%。沒有專門針對EGFR ex20ins+NSCLC的批準療法。先前接受第一代，第二代或第三代EGFR酪氨酸激酶抑製劑(TKIs)治療的患者的客觀緩解率(ORR)<10%，中位無進展生存期(PFS)<4個月。Mobocertinib(TAK-788)是一種口服EGFR TKI，專門針對EGFR與ex20ins，為EGFR ex20ins+NSCLC患者提供突破性治療名稱，這些患者之前曾有過鉑類化療(在美國)，或之前接受過化療(在中國)，基於初步的1/2期結果。

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期開放標簽多中心研究(NCT02716116)評估了一個劑量擴展EGFR ex20ins+轉移性NSCLC隊列，該隊列在緩解或病情穩定後進展≥接受EGFR TKI治療6個月。主要終點由研究者根據RECIST v1.1確認或評估。其他療效終點包括疾病控製率(DCR)、反應持續時間(DoR)、PFS(根據獨立審查委員會[IRC])和研究者，以及總生存率(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.

結果：入選20例曾接受EGFR TKI治療的患者，中位年齡為61.0歲[範圍：38–78]，東部腫瘤合作組的表現狀態為0(35%)或1(65%);55%為女性。轉移部位的中位數為3.5(範圍：1-6);10名患者(50%)有基線腦轉移。16名患者(80%)曾接受過鉑類化療，13名患者(65%)曾接受過免疫治療。先前的EGFR TKIs包括波齊奧替尼(n=13)、厄洛替尼(n=5)、阿法替尼(n=4)和奧西米替尼(n=4);11/20患者(55%)接受EGFR TKIs作為最新的前期治療。每名研究人員確認的ORR為20%，每名IRC確認的ORR為40%(表)，每名IRC 95%(19/20)的靶病變減少。觀察到的治療相關不良事件(TRAE)≥20%的患者為腹瀉(90%)、惡心(35%)、瘙癢(30%)、皮疹(25%)、貧血(25%)、嘔吐(20%)、痤瘡樣皮炎(20%)和疲勞(20%)。4例(20%)發生3/4級TRAEs。發生嚴重不良事件7例(35%)。兩名患者因不良事件而停藥(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%).

結論：Mobocertinib治療EGFR ex20ins+轉移性非小細胞肺癌合並肺癌患者具有臨床意義≥在先前的EGFR TKI基礎上進行6個月的疾病控製。安全性狀況是可控的，與其他患者隊列相似，並且與更廣泛的EGFR TKI類別一致。

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.