吡咯替尼治疗 HER2 突变型晚期肺腺癌的有效性和安全性：一项多中心、单臂、Ⅱ期临床试验。
Efficacy and safety of pyrotinib in advanced lung adenocarcinoma with HER2 mutations: a multicenter, single-arm, phase II trial.
机构信息
Department of Clinical Trial, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
Department of Respiratory Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
出版信息
BMC Med. 2022 Feb 1;20(1):42. doi: 10.1186/s12916-022-02245-z.
BACKGROUND
There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations.
METHODS
In this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored.
RESULTS
Seventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2-60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2-30.0), with median PFS of 5.6 months (95% CI, 2.8-8.4), and median OS of 10.5 months (95% CI, 8.7-12.3). The median duration of response was 9.9 months (95% CI, 6.2-13.6). All treatment-related adverse events (TRAEs) were grade 1-3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression.
CONCLUSIONS
Pyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR1800020262.
背景
目前，针对携带 HER2 突变的非小细胞肺癌（NSCLC）患者，缺乏有效的治疗方法。我们研究了泛 HER 抑制剂吡咯替尼在晚期携带 HER2 突变的 NSCLC 患者中的疗效和安全性，以及潜在的耐药机制。
方法
在这项多中心、单臂、II 期临床试验中，采用下一代测序技术确定存在 HER2 突变的 IIIB-IV 期 NSCLC 患者接受吡咯替尼治疗，剂量为 400mg/天。主要终点为 6 个月无进展生存期（PFS）率，次要终点为客观缓解率（ORR）、PFS、总生存期（OS）、疾病控制率（DCR）和安全性。还探讨了不同 HER2 突变类型对吡咯替尼敏感性的影响，以及利用循环肿瘤 DNA（ctDNA）突变谱预测疾病进展的潜力。
结果
78 例患者入组进行疗效和安全性分析。6 个月 PFS 率为 49.5%（95%置信区间[CI]，39.2-60.8）。吡咯替尼的 ORR 为 19.2%（95%CI，11.2-30.0），中位 PFS 为 5.6 个月（95%CI，2.8-8.4），中位 OS 为 10.5 个月（95%CI，8.7-12.3）。中位缓解持续时间为 9.9 个月（95%CI，6.2-13.6）。所有治疗相关不良事件（TRAEs）均为 1-3 级（均为 91.0%；3 级，20.5%），最常见的 TRAE 是腹泻（均为 85.9%；3 级，16.7%）。exon20 和非 exon20 HER2 突变患者的 ORR 分别为 17.7%和 25.0%。基线时有脑转移和先前接受过阿法替尼治疗与 ORR、PFS 或 OS 无关。疾病进展时检测到 HER2 突变丢失和 HER2 和 EGFR 扩增。
结论
吡咯替尼在携带 exon20 和非 exon20 HER2 突变的 NSCLC 患者中显示出良好的疗效和可接受的安全性，值得进一步研究。
试验注册
中国临床试验注册中心标识符：ChiCTR1800020262。
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