A second oral HER2 lung-cancer drug clears FDA on tumour response, not survival
Hyrnuo (sevabertinib) is cleared for previously treated HER2-mutant NSCLC on response rate alone. The confirmatory trial that must justify it does not report until 2029.
The Food and Drug Administration granted accelerated approval on 19 November to Hyrnuo (sevabertinib) tablets for adults with locally advanced or metastatic non-squamous non-small-cell lung cancer whose tumours carry HER2 (ERBB2) tyrosine kinase domain activating mutations, detected by an FDA-approved test, and who have received a prior systemic therapy [s1][s4]. Bayer filed the application on 28 March 2025, and it was handled under priority review [s1][s4].
It is the second oral HER2-directed tyrosine kinase inhibitor cleared for this population this year. Zongertinib, marketed as Hernexeos, was approved on 8 August 2025, also under priority review [s4].
What accelerated approval means here
The approval was granted under section 506(c) of the Federal Food, Drug, and Cosmetic Act and 21 CFR 314.510, on the basis of objective response rate and duration of response [s1]. Under that pathway the agency accepts a measurement — tumours shrinking — as a stand-in for the outcomes patients care about, on condition that a confirmatory trial follows.
FDA required Bayer to complete SOHO-02, an ongoing multicentre randomised trial intended to verify and describe the clinical benefit of sevabertinib in patients with HER2 (ERBB2) tyrosine kinase domain activating mutations who have not received prior therapy for advanced disease [s1]. The timetable Bayer submitted on 23 October 2025 puts trial completion at April 2029 and the final report at October 2029 [s1].
Note the mismatch. The approved indication covers patients who have already had a prior systemic therapy [s1]. The confirmatory trial studies patients who have not [s1]. That is a common arrangement in oncology — the randomised trial is easier to run in the first-line setting — but it means the evidence that eventually justifies this approval will come from a different population than the one the label describes.
The trial behind it
SOHO-01 was an open-label, multicentre, multicohort phase 1–2 study of sevabertinib at 20 mg twice daily in patients with locally advanced or metastatic HER2-mutant NSCLC [s2]. HER2 gene mutations occur in 2 to 4% of patients with NSCLC [s2].
Three cohorts were defined by prior therapy: cohort D, 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 not previously treated [s2]. The primary endpoint was objective response by blinded independent central review [s2].
A total of 209 patients received sevabertinib as of the 27 June 2025 data cutoff [s2]. Median follow-up was 13.8 months in cohort D, 11.7 months in cohort E and 9.9 months in cohort F [s2].
Among the 81 patients in cohort D, an objective response was observed in 64% (95% CI, 53 to 75), with a median duration of response of 9.2 months (95% CI, 6.3 to 13.5) and median progression-free survival of 8.3 months (95% CI, 6.9 to 12.3) [s2]. In cohort E, 55 patients, response was 38% (95% CI, 25 to 52), median duration of response 8.5 months and median progression-free survival 5.5 months [s2]. In cohort F, 73 patients, response was 71% (95% CI, 59 to 81) with a median duration of response of 11.0 months; progression-free survival data were immature [s2].
Grade 3 or higher drug-related adverse events occurred in 31% of patients [s2]. The most common adverse event was diarrhoea, in 84 to 91% of patients depending on cohort, with grade 3 or higher diarrhoea in 5 to 23% [s2]. Three percent of patients discontinued treatment because of drug-related adverse events [s2].
Reading the two drugs side by side
Zongertinib's phase 1a–1b trial reported, in previously treated patients with tyrosine kinase domain mutations and no prior HER2 antibody-drug conjugate (cohort 1, 75 patients at the 120 mg dose), a confirmed objective response in 71% (95% CI, 60 to 80), median duration of response 14.1 months and median progression-free survival 12.4 months, with grade 3 or higher drug-related adverse events in 17% [s3]. In patients previously treated with a HER2-directed antibody-drug conjugate, 48% (95% CI, 32 to 65) had a confirmed response [s3].
Those numbers sit next to sevabertinib's, but they are not a head-to-head comparison and should not be read as one. Different trials, different cohort definitions, different follow-up durations, different response-assessment arrangements. What can be said is that two oral HER2 inhibitors now have accelerated approvals in overlapping populations, neither has randomised evidence of survival benefit, and clinicians have no trial telling them which to prefer.
Process notes
FDA did not refer the application to an advisory committee, stating that no significant efficacy or safety issues were identified during review that required external input, and that the application did not raise significant public health questions regarding the drug's role for the proposed indication [s1].
The 19 November approval letter was reissued in corrected form. FDA recorded two errors in the original: the carton and container labeling was not enclosed, and the indication statement duplicated the word "activating" before HER2 [s1]. The effective action date remains 19 November 2025 [s1]. The correction is administrative, but it is on the record, and the indication wording it fixes is the wording that defines who the drug is for.
Patient selection depends on an FDA-approved test for HER2 tyrosine kinase domain activating mutations [s1]. Without that testing infrastructure, the approval does not reach anyone.
What to watch
The gap between now and October 2029 [s1]. Accelerated approvals are provisional by design, and FDA may withdraw one if the required trials fail to verify clinical benefit or are not conducted with due diligence [s1]. Whether SOHO-02 delivers a survival benefit in the first-line setting — and what that implies for a label written for second-line use — is the question this approval defers.
This article describes a regulatory action and the trials behind it. It is not treatment advice.
Sources
- [s1] NDA 219972 Corrected Accelerated Approval Letter — Hyrnuo (sevabertinib) tablets, U.S. Food and Drug Administration, 19 November 2025. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/219972Orig1s000Correctedltr.pdf
- [s2] Sevabertinib in Advanced HER2-Mutant Non-Small-Cell Lung Cancer, The New England Journal of Medicine, 17 October 2025. https://doi.org/10.1056/NEJMoa2511065
- [s3] Zongertinib in Previously Treated HER2-Mutant Non-Small-Cell Lung Cancer, The New England Journal of Medicine, 28 April 2025. https://doi.org/10.1056/NEJMoa2503704
- [s4] Drugs@FDA: NDA 219972 (Hyrnuo) and NDA 219042 (Hernexeos) — approval records, U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=219972
Sources
- NDA 219972 Corrected Accelerated Approval Letter — Hyrnuo (sevabertinib) tablets — U.S. Food and Drug Administration , November 19, 2025
- Sevabertinib in Advanced HER2-Mutant Non-Small-Cell Lung Cancer — The New England Journal of Medicine , October 17, 2025
- Zongertinib in Previously Treated HER2-Mutant Non-Small-Cell Lung Cancer — The New England Journal of Medicine , April 28, 2025
- Drugs@FDA: NDA 219972 (Hyrnuo) and NDA 219042 (Hernexeos) — approval records — U.S. Food and Drug Administration , November 19, 2025
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