Sevabertinib (BAY 2927088), a potent and reversible HER2 tyrosine kinase inhibitor, has demonstrated manageable safety and antitumor activity in patients with HER2-mutant advanced non–small cell lung cancer (NSCLC). The ongoing phase I/II SOHO-01 trial (NCT05099172) is an open-label, multicenter study assessing the safety and efficacy of sevabertinib in this patient population. Here, we report updated data from 2 expansion cohorts: cohort D (patients pretreated with ≥1 systemic therapy, who were HER2-targeted therapy-naïve) and cohort F (patients who were untreated for advanced disease).

Patients received oral sevabertinib at 20 mg twice daily. Safety was the primary endpoint, assessed using MedDRA v27.1 and CTCAE v5.0, with antitumor activity (RECIST v1.1) as a key secondary endpoint. Cohort D included 81 patients, while cohort F enrolled 39. Median ages were 60 years (D) and 65 years (F), with a predominance of never-smokers (61.7% in D, 79.5% in F).

All 120 patients were evaluable for safety and efficacy. Investigator-assessed objective response rates (ORRs) were 59.3% (95% confidence interval [CI], 47.8-70.1) in cohort D, and 59.0% (95% CI, 42.1-74.4) in cohort F. The disease control rates, defined as confirmed response or stable disease for ≥12 weeks, were 84.0% (95% CI, 74.1-91.2) and 84.6% (95% CI, 69.5-94.1) in cohorts D and F, respectively. Notably, 1 patient in cohort D achieved a complete response.

Subgroup analysis from cohort D demonstrated consistent efficacy of sevabertinib across diverse patient populations with HER2-mutant NSCLC. Patients with baseline brain metastases had an ORR of 64.7%, and in patients with HER2 tyrosine kinase domain mutations, the ORR was 65.3%. Median follow-up was 7.3 months. Patients had a median treatment duration of 6.2 months, 50.6% were still on treatment, and 19.8% had a treatment duration of ≥12 months. The median duration of response (DoR) was 9.2 months (95% CI, 5.2-not estimable), with a 12-month DoR rate of 49.3%. In cohort F, the median follow-up was 5.6 months, with 82.1% of patients still on treatment at the data cutoff.

Sevabertinib demonstrated manageable safety and promising efficacy in both pretreated and first-line settings for HER2-mutant advanced NSCLC. In cohort D, treatment-related grade 3 diarrhea was observed in 24% of patients, with a median of 1 episode and a median time to onset of 1.3 months (interquartile range, 0.5-3.6). In cohort F, grade 3 diarrhea occurred in 3% of patients, and no cases of grade 4 diarrhea were reported. Across both cohorts, diarrhea was manageable and did not lead to significant treatment discontinuation. Four patients (4.9%) in cohort D and 1 patient (2.6%) in cohort F had treatment-related adverse events leading to treatment discontinuation. No cases of interstitial lung disease were reported. The results were consistent with previously reported efficacy responses and the safety profile for sevabertinib.

These findings support sevabertinib (BAY 2927088) as a well-tolerated and effective HER2-targeted therapy for patients with advanced NSCLC, regardless of prior treatment status.

Sources:

Loong HH, et al. SOHO-01: Safety and efficacy of sevabertinib (BAY 2927088) in patients with advanced HER2-mutant non-small cell lung cancer (NSCLC) who were pretreated but naïve to HER2-targeted therapy or had not received any treatment for advanced disease. Presented at: American Society of Clinical Oncology (ASCO) 2025 Annual Meeting. June 1, 2025; Chicago, IL. Oral presentation.