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Xiuning Le, M.D., Ph.D. Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer. N Engl J Med. 2025; 393(18): 1819-1832. DOI: 10.1056/nejmoa2511065
SOHO-01研究显示， 在携带 HER2 突变的、局部晚期或转移性非小细胞肺癌（NSCLC） 患 者 中，sevabertinib显示出抗肿瘤活性，腹泻是其最常见的不良事件。
2%~4% 的 NSCLC 患 者 携 带 HER2 基因突变。sevabertinib 是一种口服的、可逆的酪氨酸激酶抑制剂，临床前模型显示其有靶向 HER2 的抗肿瘤活性。
为了评估 sevabertinib（20 mg bid）对携带 HER2 突变的、局部晚期或转移性 NSCLC 患者的疗效，该项开放标签的、多中心、多队列Ⅰ ~ Ⅱ期研究（SOHO-01）根据既往治疗情况定义了 3个队列：队列 D 包括未接受过抗 HER2 靶向治疗的但接受过其他治疗的患者，队列 E 包括接受过抗 HER2 抗体—药物偶联物治疗的患者，队列 F 包括未接受过治疗的患者。
主要终点为盲态独立中央评审委员会评估的客观缓解率（ORR）。次要终点为缓解持续时间和无进展生存期（PFS）。
结果显示， 截至 2025 年 6 月 27 日的数据截止日，共有 209 例患者接受了 sevabertinib 治疗。队列 D、队列 E、队列 F 的中位随访时间依次为 13.8 个月、11.7 个月和 9.9 个月，所纳入的患者依次为81 例、55 例和 73 例，客观缓解率依次为 64%（95%CI 53%~75%）、 38%（95%CI 25%~52%） 和 71%（95%CI 59%~81%），中位的缓解持续时间依次为 9.2 个月（95%CI
6.3~13.5 个月）、8.5 个月和 11.0个月，中位无进展生存期依次为8.3个月（95%CI 6.9~12.3 个月）、5.5个月和数据尚不成熟。
31% 的患者出现≥ 3 级的药物相关不良事件。最常见的不良事件为腹泻（ 发生率为 84%~91%），其中≥ 3 级腹泻发生率为5%~23%。 3% 的患者因药物相关不良事件停止治疗。
Sevabertinib的新型口服可逆酪氨酸激酶抑制剂在治疗局部晚期或转移性HER2突变非小细胞肺癌（NSCLC）患者中显示出显著的抗肿瘤活性。该研究是一项开放标签、多中心、多队列的1-2期临床试验，旨在评估每日两次、每次20毫克剂量的Sevabertinib的疗效和安全性。研究根据患者既往治疗情况分为三个队列：队列D为既往接受过治疗但未接受过HER2靶向治疗的患者；队列E为既往接受过HER2定向抗体-药物偶联物治疗的患者；队列F为未接受过任何既往治疗的患者。研究的主要终点是通过盲法独立中心评估的客观缓解率。
研究结果显示，截至2025年6月27日的数据截止日，共有209名患者接受了Sevabertinib治疗。在81名队列D患者中，客观缓解率达到64%，中位缓解持续时间为9.2个月，中位无进展生存期为8.3个月。在55名队列E患者中，客观缓解率为38%，中位缓解持续时间为8.5个月，中位无进展生存期为5.5个月。而在73名队列F（初治）患者中，客观缓解率高达71%，中位缓解持续时间达到11.0个月，无进展生存期数据尚未成熟。
在安全性方面，该研究报道31%的患者出现了3级或更高级别的药物相关不良事件。最常见的副作用是腹泻，发生率在84%至91%之间，其中3级或更高级别腹泻的发生率为5%至23%。仅有3%的患者因药物相关不良事件而停止治疗。
该研究得出结论，Sevabertinib在局部晚期或转移性HER2突变非小细胞肺癌患者中表现出显著的抗肿瘤活性，同时具有可管理的安全性特征。这些结果为HER2突变非小细胞肺癌患者提供了新的治疗选择，特别是对于未接受过既往治疗的患者群体显示出尤其 promising 的疗效。
Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.
BACKGROUND
HER2 gene mutations occur in 2 to 4% of patients with non–small-cell lung cancer (NSCLC). Sevabertinib is an oral, reversible tyrosine kinase inhibitor that has shown anti-HER2 activity in preclinical models.
METHODS
We conducted an open-label, multicenter, multicohort, phase 1–2 study to evaluate sevabertinib a twice-daily dose of 20 mg in patients with locally advanced or metastatic HER2-mutant NSCLC. Three cohorts were defined according to previous therapy: cohort D comprised previously treated patients who had not received HER2-targeted therapy; cohort E, patients who had previously received HER2-directed antibody–drug conjugates; and cohort F, patients who had not previously received treatment. The primary end point was an objective response, as assessed by blinded independent central review. Secondary end points were duration of response and progression-free survival.
RESULTS
A total of 209 patients received sevabertinib (as of June 27, 2025, the data-cutoff date); the median duration of follow-up was 13.8 months in cohort D, 11.7 months in cohort E, and 9.9 months in cohort F. Among 81 patients in cohort D, an objective response was observed in 64% (95% confidence interval [CI], 53 to 75); the median duration of response was 9.2 months (95% CI, 6.3 to 13.5), and the median progression-free survival was 8.3 months (95% CI, 6.9 to 12.3). Among 55 patients in cohort E, an objective response was observed in 38% (95% CI, 25 to 52); the median duration of response was 8.5 months, and the median progression-free survival was 5.5 months. Among 73 patients in cohort F, an objective response was observed in 71% (95% CI, 59 to 81), and the median duration of response was 11.0 months; data on progression-free survival were immature. Grade 3 or higher drug-related adverse events occurred in 31% of the patients. The most common adverse event was diarrhea (in 84 to 91%), with diarrhea of grade 3 or higher occurring in 5 to 23%. Treatment was discontinued by 3% of the patients owing to drug-related adverse events.
CONCLUSIONS
Sevabertinib showed antitumor activity in patients with locally advanced or metastatic HER2-mutant NSCLC. Diarrhea was the most common adverse event. (Funded by Bayer; SOHO-01 ClinicalTrials.gov number, NCT05099172.)
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