HER2 mutations occur in approximately 2% to 4% of non−small cell lung cancer (NSCLC) cases and are linked to poor clinical outcomes, making them a challenging subset of advanced NSCLC to treat. Sevabertinib (BAY 2927088) is an oral, reversible HER2 tyrosine kinase inhibitor that has shown durable responses and manageable safety in patients with advanced HER2-mutant NSCLC. This exploratory analysis from the SOHO-01 phase 1/2 trial (NCT05099172) aimed to evaluate the relationship between baseline clinical and molecular characteristics and treatment outcomes in this population.

The study included patients with advanced HER2-mutant NSCLC enrolled in expansion cohort D. All patients had progressed after at least 1 prior systemic therapy but were HER2-targeted therapy-naïve. Participants received sevabertinib at 20 mg twice daily, and plasma circulating tumor DNA (ctDNA) was analyzed using the Oncomine™ Precision Assay to assess HER2 variants and co-alterations. Treatment response and clinical outcomes were investigator-assessed, with key endpoints including objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS).

As of October 14, 2024, of the 44 patients, 43 patients who had post-baseline tumor assessments were included in the analysis. At baseline, median age was 62.0 years, 65.1% were female, and 46.5% had received <2 prior lines of therapy. Patients with ECOG Performance Status (PS) 1 demonstrated favorable outcomes compared with ECOG PS 0, including higher ORR (79.2% vs 63.2%) and longer median PFS (9.6 months [95% confidence interval (CI), 4.1-not reached] vs 7.5 months [95% CI, 5.3-9.9]). Molecular analyses revealed TP53 mutations as the most frequent co-alteration, present in 35.1% of patients with detectable HER2 ctDNA. The HER2 Y772_A775dup (YVMA) variant was associated with enhanced treatment efficacy over other HER2 alterations with median PFS of 9.9 versus 3.9 months, ORR of 86.7% versus 30.8%, and median DOR of 9.7 versus 2.8 months. Patients without TP53 co-alterations had better outcomes than those with detectable TP53 (median PFS, 10.6 vs 6.7 months; ORR, 79.2% vs 69.2%; median DOR, not reached vs 5.3 months). Among patients with the HER2 YVMA variant, patients without TP53 co-alterations had superior outcomes over those with detectable TP53 (median PFS, not reached vs 6.7 months; ORR, 94.1% vs 80.0%; median DOR, not reached vs 5.3 months). In the multivariate analysis of PFS, significant associations were found for the HER2 mutation group (hazard ratio [HR], 7.1; P<.001) and TP53 mutation status (HR, 4.9; P=.003); ECOG PS and the number of prior treatment lines were not significantly associated (P=.43 and P=.28, respectively).

These findings underscore the clinical relevance of integrating molecular profiling into treatment decision-making for HER2-mutant NSCLC. Sevabertinib demonstrated promising efficacy and tolerability in this heavily pretreated population, with favorable outcomes in patients with specific molecular characteristics. While preliminary, this data highlights the importance of identifying predictive and prognostic biomarkers to optimize therapeutic strategies for HER2-altered NSCLC. Further validation in larger cohorts is warranted to confirm these observations and refine the role of sevabertinib in this setting.

Source: X Le, TM Kim, N Girard, et al. Factors associated with clinical outcomes in patients with HER2-mutant NSCLC treated with sevabertinib (BAY 2927088). Presented at: 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain.