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Sevabertinib in Advanced HER2-Mutant Non-Small-Cell Lung Cancer
Xiuning Le1, Tae Min Kim2, Herbert H Loong3,4
1M.D. Anderson Cancer Center, Houston.
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 at 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.).
Insights
Sevabertinib demonstrated significant antitumor activity in patients with HER2-mutant non-small-cell lung cancer (NSCLC). The most frequent side effect was diarrhea, but treatment was generally well-tolerated.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- HER2 gene mutations are found in 2-4% of non-small-cell lung cancer (NSCLC) patients.
- Sevabertinib is an investigational oral tyrosine kinase inhibitor targeting HER2 with demonstrated preclinical anti-tumor effects.
Purpose of the Study:
- To evaluate the safety and efficacy of sevabertinib in patients with locally advanced or metastatic HER2-mutant NSCLC.
- To assess objective response rate, duration of response, and progression-free survival in different patient cohorts.
Main Methods:
- An open-label, multicenter, phase 1-2 study enrolled 209 patients with HER2-mutant NSCLC.
- Patients received sevabertinib 20 mg twice daily in three cohorts based on prior therapy.
- Primary endpoint was objective response rate assessed by blinded independent central review.
Main Results:
- Objective response rates were 64% (previously treated, no HER2-targeted therapy), 38% (previously treated with antibody-drug conjugates), and 71% (treatment-naïve).
- Median duration of response ranged from 8.5 to 11.0 months across cohorts.
- Grade 3 or higher adverse events occurred in 31% of patients, with diarrhea being most common (5-23% grade 3+).
Conclusions:
- Sevabertinib exhibits significant antitumor activity in patients with locally advanced or metastatic HER2-mutant NSCLC.
- Diarrhea was the most common adverse event, and treatment discontinuation due to adverse events was low (3%).
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