Early results from a single cohort in the first-in-human SOHO-01 Phase I/II study of BAY 2927088, an oral, reversible TKI, showed a rapid, substantial, and durable response in patients with HER2-mutated non-small cell lung cancer (NSCLC). The results were presented during the second of two Presidential Symposia at the 2024 World Conference on Lung Cancer.
Dr. Le presented preliminary safety and efficacy results from Cohort D of SOHO-01, a global dose escalation and dose expansion trial of BAY 2927088. Chemotherapy and antibody-drug conjugates are currently approved for HER2-mutated NSCLC, she said, but patients lack oral, targeted small-molecule therapies that can improve efficacy, convenience, and safety.
The cohort discussed included 44 patients with HER2-mutated NSCLC who had received prior chemotherapy or immunotherapy but no HER2-targeted therapy. The cohort was 64% female with a median age of 62 and 71% had no smoking history.
Investigators documented an objective response rate (ORR) of 72% and a disease control rate (DCR) of 84%.
“The majority of patients had tumor shrinkage regardless of their genetic alteration subtype, regardless of the presence or absence of brain metastases,” said Xiuning Le, MD, PhD, Assistant Professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center. “Those responses were observed early, usually at the first tumor assessment.”
These positive early results led to both the US Food and Drug Administration and the Chinese National Medical Products Administration granting Breakthrough Therapy Designations to BAY 2927088 for patients with unresectable or metastatic HER2-mutated NSCLC who have received previous treatment.
HER2 mutations occur in 1% to 7% of NSCLC patients, depending on their ancestry,1 and are associated with poor prognosis. The most common mutation is a YVMA insertion, which represents about 75% of all HER2-mutated lung cancers. BAY 2927088 inhibited activating HER2 mutations in preclinical models and showed encouraging preliminary anti-tumor activity in patients with HER2-mutated advanced NSCLC, Dr. Le said.
YVMA insertion was found in 71% of patients, and 18% of patients had brain metastases at baseline. About a third of patients (32%) had three or more previous therapies including 57% with both platinum-based chemotherapy and immunotherapy.
The primary endpoints were safety, tolerability, and pharmacokinetics. Secondary endpoints included ORR by investigator assessment, progression-free survival (PFS), duration of response (DoR), and DCR.
The median follow up was 11 months, and the median DoR was 7 months; 35% of patients were still on treatment at data cutoff and 32% remained on treatment longer than 12 months. Additionally, the median D0R and PFS were 9 and 8 months, respectively. Patients with brain metastases showed similar responses to the cohort as a whole.
Patients with a YVMA insertion did better, with an ORR of 90%, DCR of 97%, DoR of 10 months, and PFS of 10 months. Most patients (96%) had at least one treatment-related adverse event (TRAE). Diarrhea was the most common TRAE at 86%; 75% of these events were grade 1 or 2. About one-third of patients (32%) had dose reductions due to TRAEs, and 7% discontinued treatment due to TRAEs.
The overall safety profile of BAY 2927088 was consistent with previous reports, Dr. Le said, and the substantial response rates support further investigation of the compound. A phase III trial is already underway.
References
- 1. Ren S, Wang J, Ying J, et al. Consensus for HER2 alterations testing in non-small-cell lung cancer [published correction appears in ESMO Open. 2022 Jun;7(3):100482. doi: 10.1016/j.esmoop.2022.100482]. ESMO Open. 2022;7(1):100395. doi:10.1016/j.esmoop.2022.100395
