近日，美国德克萨斯大学安德森肿瘤中心John V. Heymach团队研究了Zongertinib在既往治疗的HER2突变型非小细胞肺癌中的疗效。该研究于2025年4月28日发表在《新英格兰医学杂志》上。

对于人表皮生长因子受体2 （HER2）突变的非小细胞肺癌（NSCLC）患者，创新的口服靶向治疗是有必要的。Zongertinib是一种口服、不可逆、HER2选择性酪氨酸激酶抑制剂，在一项i期研究中显示，该药物对HER2改变的晚期或转移性实体瘤患者有效。

研究组在一项涉及晚期或转移性HER2突变型NSCLC患者的多队列1a-1b期试验中评估了zongertinib。他们报告了先前接受过治疗的患者对zongertinib的初步分析：队列1肿瘤中含有酪氨酸激酶结构域突变，队列5肿瘤中含有酪氨酸激酶结构域突变，队列3肿瘤中含有非酪氨酸激酶结构域突变。在队列1中，患者最初被随机分配接受120 mg或240 mg剂量的zongertinib，每日一次。队列5和队列3的患者最初每天服用240毫克。在对队列1的数据进行中期分析后，随后所有队列的招募患者均接受了剂量为120mg的Zongertinib治疗。主要终点是通过盲法独立中心评价（队列1和5）或研究者评价（队列3）评估的客观缓解。次要终点包括反应持续时间和无进展生存期。

在队列1中，共有75名患者接受了剂量为120mg的zongertinib治疗。在数据截止日期（2024年11月29日），71%的患者有确定的客观缓解；中位缓解持续时间为14.1个月（95% CI， 6.9至不可评估），中位无进展生存期为12.4个月（95% CI， 8.2至不可评估）。13例（17%）患者发生3级或以上药物相关不良事件。在队列5（31例患者）中，48%的患者（95% CI, 32 ~ 65）有明确的客观缓解。3级及以上药物相关不良事件发生1例（3%）。在队列3（20例患者）中，30%的患者（95% CI, 15 ~ 52）有确认的客观缓解。5例患者（25%）发生3级或以上药物相关不良事件。在所有三个队列中，没有发生药物相关的间质性肺疾病病例。

研究结果表明，在先前接受过HER2突变型NSCLC治疗的患者中，zongertinib显示出主要低级别不良事件的临床获益。

附：英文原文

Title: Zongertinib in Previously Treated HER2-Mutant Non–Small-Cell Lung Cancer

Author: John V. Heymach, Gerrina Ruiter, Myung-Ju Ahn, Nicolas Girard, Egbert F. Smit, David Planchard, Yi-Long Wu, Byoung Chul Cho, Noboru Yamamoto, Joshua K. Sabari, Yanqiu Zhao, Hai-Yan Tu, Kiyotaka Yoh, Ernest Nadal, Behbood Sadrolhefazi, Maren Rohrbacher, Ute von Wangenheim, Sabina Eigenbrod-Giese, Jon Zugazagoitia

Issue&Volume: 2025-04-28

Abstract:

BACKGROUND

Innovative oral targeted therapies are warranted for patients with human epidermal growth factor receptor 2 (HER2)–mutant non–small-cell lung cancer (NSCLC). Zongertinib is an oral, irreversible, HER2-selective tyrosine kinase inhibitor that has been shown to have efficacy in persons with advanced or metastatic solid tumors with HER2 alterations in a phase 1 study.

METHODS

We evaluated zongertinib in a multicohort, phase 1a–1b trial involving patients with advanced or metastatic HER2-mutant NSCLC. Here we report the primary analysis of zongertinib in previously treated patients: those with tumors harboring a mutation in the tyrosine kinase domain (cohort 1), those with tumors harboring a mutation in the tyrosine kinase domain previously treated with a HER2-directed antibody–drug conjugate (cohort 5), and those with tumors harboring a non–tyrosine kinase domain mutation (cohort 3). In cohort 1, patients were initially randomly assigned to receive zongertinib at a dose of 120 mg or 240 mg once daily. Patients in cohorts 5 and 3 initially received 240 mg daily. After an interim analysis of data from cohort 1, subsequently recruited patients across all cohorts received zongertinib at a dose of 120 mg. The primary end point was an objective response assessed by blinded independent central review (cohorts 1 and 5) or by investigator review (cohort 3). Secondary end points included the duration of response and progression-free survival.

RESULTS

In cohort 1, a total of 75 patients received zongertinib at a dose of 120 mg. At the data cutoff (November 29, 2024), 71% of these patients (95% confidence interval [CI], 60 to 80; P<0.001 against a ≤30% benchmark) had a confirmed objective response; the median duration of response was 14.1 months (95% CI, 6.9 to not evaluable), and the median progression-free survival was 12.4 months (95% CI, 8.2 to not evaluable). Grade 3 or higher drug-related adverse events occurred in 13 patients (17%). In cohort 5 (31 patients), 48% of the patients (95% CI, 32 to 65) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 1 patient (3%). In cohort 3 (20 patients), 30% of the patients (95% CI, 15 to 52) had a confirmed objective response. Grade 3 or higher drug-related adverse events occurred in 5 patients (25%). Across all three cohorts, no cases of drug-related interstitial lung disease occurred.

CONCLUSIONS

Zongertinib showed clinical benefit with mainly low-grade adverse events in patients with previously treated HER2-mutant NSCLC.

DOI: NJ202504280000006

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2503704