The robust efficacy of sevabertinib (Hyrnuo) observed across cohorts of pretreated patients with non–small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain (TKD) mutations marked a significant advance for this population, exemplifying the importance of leveraging precision medicine to tailor therapies to specific disease states, according to Xiuning Le, MD, PhD.
On November 19, 2025, the FDA granted accelerated approval to sevabertinib for the treatment of adult patients with locally advanced or metastatic, nonsquamous NSCLC with tumors harboring HER2 TKD activating mutations, as detected by an FDA-approved test, who have previously received 1 line of systemic therapy.1 This regulatory decision was backed by data in this patient subgroup from the phase 1/2 SOHO-01 trial (NCT05099172), in which the overall response rate (ORR) was 71% (95% CI, 59%-82%) among patients who had not previously received HER2-targeted therapy (n = 70). Among patients who had previously received HER2-targeted antibody-drug conjugates (ADCs; n = 52), the ORR was 38% (95% CI, 25%-53%).
Additional results presented at the 2025 ESMO Congress showed that at a median follow-up of 13.8 months (range, 1-32) for all previously treated patients (n = 81), the median duration of treatment was 9.9 months (range, 0-32), and 20% of patients had a treatment duration longer than 15 months.2
“The FDA approval of this oral medication brings another treatment option to the existing [paradigm] for patients,” Le said in an interview with OncLive®. “It’s great news worth celebrating.”
In the interview, Le discussed the significance of this approval, noted relevant aspects of the SOHO-01 clinical trial design, and highlighted efficacy findings across several subgroups of patients harboring HER2 TKD mutations who had received prior therapy, including chemotherapy and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu).
Le is an associate professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Internal Medicine at The University of Texas MD Anderson Cancer Center in Houston.
FDA Approval Highlights for Sevabertinib in Nonsquamous, HER2-Mutated NSCLC
- On November 19, 2025, the FDA granted accelerated approval to sevabertinib for adult patients with locally advanced or metastatic, nonsquamous NSCLC harboring HER2 TKD mutations.
- Clinical trial results showed that sevabertinib achieved a 71% (95% CI, 59%-82%) ORR in patients naive to HER2-targeted therapy and a 38% (95% CI, 25%-53%) ORR in patients who had previously received HER2-targeted ADCs.
- Sevabertinib is administered as a 20-mg oral dose twice daily with food and includes safety warnings for conditions such as diarrhea, hepatotoxicity, and interstitial lung disease.
OncLive: What are the clinical implications of the FDA approval of sevabertinib for patients with HER2 TKD–mutated NSCLC?
Le: This is an accelerated approval, but it means we have more treatment options for that patient population. This is great news. HER2-mutated NSCLC is an oncogene-defined subgroup of patients [that represents] only approximately 3% to 4% of all lung cancers.
What was the design of the pivotal SOHO-01 trial?
This was a phase 1 study, [and it was the first study that tested] this small molecule in humans. The first part of the study was to identify the appropriate dose for patients with lung cancer. The second part—dose expansion—was to identify efficacy and the most appropriate patient population. That’s why we had multiple cohorts. That’s part of precision oncology: matching a drug with the exact tumor alteration.
What efficacy findings from the SOHO-01 cohort of patients with HER2 TKD activating mutations supported the FDA approval of sevabertinib for HER2-mutated NSCLC?
In the initial dose-escalation part, we identified that 20 mg of sevabertinib twice per day is both efficacious and tolerable. Then we moved on to test the gene-molecular matching. HER2 mutations [typically occur] in the TKD. Those are the drivers [of the disease]. When patients with HER2 TKD[–mutated NSCLC] received sevabertinib, the ORR and duration of response were great. This was shown in multiple cohorts in SOHO-01.
The cohort with the most mature [data consisted of] patients who had received prior chemotherapy or other systemic therapy, [such as] immunotherapy. [Even in this cohort], sevabertinib elicited a 71% ORR, and additional patients had stable disease. This is impressive clinical efficacy when matching the target and drug appropriately.
What is the importance of showing the efficacy of sevabertinib in patients with HER2-mutated NSCLC who have received a prior HER2-directed ADC?
This is clinically important because for HER2-mutated NSCLC, [the FDA approval of sevabertinib] is the third precision oncology approval [in this space], with T-DXd already having received accelerated approval[in 2022, along with zongertinib (Hernexeos) receiving accelerated approval in August 2025]. Some of the patients [in SOHO-01] had previously received initial chemotherapy and then received T-DXd. The question we asked in cohort E was: Can patients still benefit from sevabertinib, even after multiple prior lines of therapy? The answer is yes. The response was a bit decreased [compared with in the overall population], but the duration was still robust, supporting that we should consider all different types of precision oncology treatments for patients, because their disease journeys will need different types of drugs to support them.
References
- FDA grants accelerated approval to sevabertinib for non-squamous non-small cell lung cancer. FDA. November 19, 2025. Accessed January 16, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sevabertinib-non-squamous-non-small-cell-lung-cancer
- Le X, Kim TM, Dong X, et al. Sevabertinib (BAY 2927088) in advanced HER2-mutant non-small cell lung cancer (NSCLC): results from the SOHO-01 study. Ann Oncol. 2025;36(suppl 2):S1617. doi:10.1016/j.annonc.2025.09.089
