Key Clinical Summary: 

• Design/Population: This exploratory analysis evaluated 43 patients with HER2-mutated advanced NSCLC treated with sevabertinib in the phase 1/2 SOHO-01 trial. Plasma ctDNA analysis was used to assess HER2 variants and co-occurring mutations.
• Key Outcomes: Patients treated earlier in the disease course demonstrated improved response rates, duration of response, and progression-free survival. The HER2 YVMA variant was associated with better outcomes, while TP53 co-alterations provided independent prognostic information.
• Clinical Relevance: Both clinical and molecular factors may influence response to HER2-targeted therapy in NSCLC. These findings support further validation of biomarker-driven approaches to optimize treatment selection in HER2-mutated disease.

Results from an exploratory analysis of the phase 1/2 SOHO-01 study suggest that clinical and molecular characteristics may influence treatment outcomes among patients with HER2-mutated non-small cell lung cancer (NSCLC) receiving sevabertinib therapy.

These results were presented at the Hematology/Oncology Pharmacy Association (HOPA) Annual Meeting in New Orleans, Louisiana, by Katelyn Toeniskoetter, PharmD, Dana-Farber Cancer Institute, Boston, Massachusetts.

“Mutations in HER2 occur in approximately 2% to 4% of patients with [NSCLC] and are associated with unfavorable outcomes,” stated Dr Toeniskoetter. “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.”

In expansion cohort D of this study, 43 patients who experienced disease progression after at least one prior line of systemic therapy and were naïve to HER2-targeted therapy received 20 mg of twice daily sevabertinib. Plasma circulating tumor DNA (ctDNA) was assessed using the Oncomine Precision Assay to evaluate HER2 variants and co-occurring genomic alterations. Key response end points included objective response rate (ORR), duration of response, and progression-free survival (PFS).

At analysis, the ORR was 75% in patients who received <2 prior lines of therapy and 69.6% in patients who received ≥ 2 prior lines of therapy. Duration of response was not reached in patients who received < 2 prior lines of therapy and was 5.2 months in patients who received ≥ 2 prior lines of therapy. 

Median PFS was not reached in patients who received < 2 prior lines of therapy, and was 6.7 months in patients who received ≥ 2 prior lines of therapy. 

The most frequently observed co-occurring alteration was TP53, identified in 35.1% of patients with detectable HER2 ctDNA. The HER2 Y772_A775dup (YVMA) variant was associated with improved efficacy, whereas TP53 co-alterations were not independently associated with poorer outcomes. Multivariable analysis indicated that HER2 YVMA and TP53 mutations provided independent prognostic information. Patients without TP53 co-alterations and with the YVMA variant experienced more favorable outcomes, similar to those treated earlier in the disease course. 

“The findings underscore the importance of integrating clinical and molecular features to identify potential prognostic or predictive markers,” concluded Dr Toeniskoetter. “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.” 

Source: 

Toeniskoetter K. Factors associated with clinical outcomes in patients with HER2 mutation-positive NSCLC who received sevabertinib (BAY 2927088). Presented at HOPA Annual Conference. March 25-27, 2026. CR17.