Zipalertinib在EGFR 20号外显子插入突变型非小细胞肺癌患者中的安全性、耐受性和抗肿瘤活性

SCI

7 July 2023

Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With Non–Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertions

（Journal of Clinical Oncology, IF: 45.3）

Piotrowska Z, Tan DS, Smit EF, Spira AI, Soo RA, Nguyen D, Lee VH, Yang JC, Velcheti V, Wrangle JM, Socinski MA, Koczywas M, Janik JE, Jones J, Yu HA.

CORRESPONDENCE TO: zofia. piotrowska@mgh.harvard.edu.

PURPOSE 研究目的

Although several agents targeting epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins- mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins- positive cell lines.

尽管最近FDA批准了几种针对EGFR20号外显子插入（ex20ins）的药物，但因抑制野生型（WT）EGFR相关的毒性在这些药物中很常见，并影响了整体耐受性。Zipalertinib（CLN-081，TAS6417）是一种口服的EGFR酪氨酸激酶抑制剂（TKI），具有新型的吡咯并嘧啶结构，相比EGFR野生型，对EGFR ex20ins-突变体的选择性增强，对EGFR ex20ins-阳性细胞系的细胞生长有强效抑制作用。

METHODS 研究方法

This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non–small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.

这项关于zipalertinib的1/2a期研究招募了曾接受过铂类化疗的复发性或转移性EGFR ex20ins突变的非小细胞肺癌（NSCLC）患者。

RESULTS 研究结果

Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day.

73名患者接受了zipalertinib治疗，剂量包括30、45、65、100和150毫克，每天两次口服。患者主要是女性（56%），中位年龄为64岁，并接受过多种方案治疗（之前接受过的治疗方案中位数为2，范围为1-9）。36%的患者以前接受过非EGFR ex20ins的TKIs，3/73（4.1%）患者以前接受过EGFR ex20ins的TKIs。最常报告的任何等级的药物相关不良事件包括皮疹（80%）、甲沟炎（32%）、腹泻（30%）和乏力（21%）。在100毫克一天两次或以下的剂量中，没有观察到3级或更高的药物相关皮疹或腹泻的病例。在试验中所有zipalertinib剂量都出现了OR，在28/73（38.4%）可评价病例中观察到PR。在100毫克每天两次的剂量下，16/39（41%）可评价病例中出现了PR。

CONCLUSION 结论

Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

Zipalertinib在接受过多种方案治疗的EGFR ex20ins突变的NSCLC患者中具有令人鼓舞的初步抗肿瘤活性，并具有可接受的安全性，包括低频率的重度腹泻和皮疹。

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