Presenting Author: Katelyn Toeniskoetter, PharmD, BCOP, Dana-Farber Cancer Institute, Boston, MA
BACKGROUND: Mutations in HER2 occur in approximately 2% to 4% of patients with non–small-cell lung cancer (NSCLC) and are associated with unfavorable outcomes. Sevabertinib is a potent, oral, reversible HER2 tyrosine kinase inhibitor that has demonstrated durable responses and a manageable safety profile in patients with advanced NSCLC and HER2 mutations.1
OBJECTIVE: Our exploratory analysis sought to assess the impact of baseline clinical characteristics and molecular alterations on treatment outcomes.
METHODS: Patients from expansion cohort D of the SOHO-01 phase 1/2 study (NCT05099172) were included in this analysis. All patients had advanced NSCLC with a HER2-activating mutation and had disease progression after ≥1 systemic therapy, but were naïve to HER2-targeted therapy, and received treatment with sevabertinib 20 mg twice daily. Plasma ctDNA was assessed using the Thermo Fisher Scientific Oncomine Precision Assay. HER2 variant information and coalteration data were used to assess the correlation with investigator-assessed treatment response and outcomes.
RESULTS: Of the 44 patients who received treatment in expansion cohort D, 43 patients who had a postbaseline tumor assessment were included. At baseline, the median patient age was 62 years, 65.1% of the patients were female, 72.1% had never smoked, and 46.5% had received <2 previous lines of therapy. Treatment with <2 previous lines of therapy versus ≥2 previous lines was associated with a higher objective response rate (75% vs 69.6%, respectively), longer median duration of response (DOR; DOR, not reached vs 5.2 months, respectively), and improved median progression-free survival (PFS; PFS, not reached vs 6.7 months). TP53 mutations were the most frequently observed coalterations and were present in 13 of 37 patients (35.1%) with detectable HER2 ctDNA. The HER2 Y772_A775dup (YVMA) variant was associated with enhanced treatment efficacy, whereas the presence of a TP53 coalteration was not. Multivariate analysis indicated that TP53 and HER2 YVMA provide independent prognostic information. Patients lacking TP53 coalterations and having the YVMA variant showed favorable responses and outcomes, similar to those who had received only 1 previous therapy.
CONCLUSION: This exploratory analysis of clinical and molecular factors in patients with HER2 mutation–positive NSCLC indicates favorable DOR and PFS among those who received only 1 previous line of therapy or who had specific molecular characteristics. The findings underscore the importance of integrating clinical and molecular features to identify potential prognostic or predictive markers. As part of an ongoing study, these preliminary results emphasize the need for validation in a larger sample size to confirm these insights and further explore therapeutic strategies for patients with HER2-altered cancers.
- Girard N, Loong HHF, Goh BC, et al. 3O: phase I/II SOHO-01 study of BAY 2927088 in patients with previously treated HER2-mutant NSCLC: safety and efficacy results from 2 expansion cohorts. J Thorac Oncol. 2025;20(suppl 1):S5-S6.