Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Author(s): Xiuning Le, M.D., Ph.D.¹; Tae Min Kim, M.D., Ph.D.²; Herbert H. Loong, M.B., B.S.^3,4; Arsela Prelaj, M.D., Ph.D.⁵; Boon Cher Goh, M.B., B.S.^6,7; Lin Li, M.D., Ph.D.^8,9; Yong Fang, M.D.¹⁰; Shun Lu, M.D., Ph.D.¹¹; Xiaorong Dong, M.D., Ph.D.¹²; Lin Wu, M.D.¹³; Yuki Shinno, M.D., Ph.D.¹⁴; Gennaro Daniele, M.D., Ph.D.¹⁵; Tsung-Ying Yang, M.D., Ph.D.¹⁶; Hye Ryun Kim, M.D., Ph.D.^17,18; Gerrina Ruiter, M.D., Ph.D.¹⁹; Jun Zhao, M.D.²⁰; Silvia Novello, M.D., Ph.D.²¹; Liyun Miao, Ph.D.²²; Pasi A. Jänne, M.D., Ph.D.²³; Koichi Goto, M.D., Ph.D.²⁴; Dominik Rüttinger, M.D., Ph.D.²⁵; Tine Descamps, Ph.D.²⁶; Jan Christoph Brase, Ph.D.²⁷; Weichao Bao, Ph.D.²⁸; Rui Li, M.S.²⁸; Nicoletta Brega, M.D.²⁷; Paolo Grassi, M.D.²⁹; Nicolas Girard, M.D., Ph.D.³⁰; Daniel Shao-Weng Tan, Ph.D., M.B., B.S.^31,32; the SOHO-01 Investigators*;

Source: DOI: 10.1056/NEJMoa2511065

Dr. Anjan Patel's Thoughts

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.)

Author Affiliations

¹M.D. Anderson Cancer Center, Houston; ²Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea; ³Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong; ⁴Phase 1 Clinical Trial Center, Chinese University of Hong Kong, Hong Kong; ⁵Oncologia Medica Toracica Dipartimento, Fondazione IRCCS–Istituto Nazionale dei Tumori, Milan; ⁶Department of Hematology–Oncology, National University Cancer Institute, Singapore; ⁷Cancer Science Institute of Singapore, National University of Singapore, Singapore; ⁸Department of Medical Oncology, Beijing Hospital, Beijing; ⁹National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing; ¹⁰Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; ¹¹Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; ¹²Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; ¹³Department of Thoracic Medical Oncology, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; ¹⁴National Cancer Center Hospital, Tokyo; ¹⁵Phase 1 Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome; ¹⁶Department of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; ¹⁷Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Seoul, South Korea; ¹⁸Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea; ¹⁹Departments of Clinical Pharmacology and Thoracic Oncology, Netherlands Cancer Institute, Amsterdam; ²⁰Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department I of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing; ²¹Department of Oncology, Azienda Ospedaliero–Universitaria San Luigi Gonzaga, Turin, Italy; ²²Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, China; ²³Lowe Center for Thoracic Oncology, Dana–Farber Cancer Institute, Boston; ²⁴National Cancer Center Hospital East, Kashiwa, Japan; ²⁵Bayer, Berlin; ²⁶Bayer, Reading, United Kingdom; ²⁷Bayer Consumer Care, Basel, Switzerland; ²⁸Bayer HealthCare Pharmaceuticals, Whippany, NJ; ²⁹Bayer, Milan; ³⁰Institut Curie, Paris; ³¹National Cancer Center Singapore, Singapore; ³²Duke–National University of Singapore Medical School, Singapore

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