Zongertinib shows promise in Asians with advanced HER2-mutant NSCLC

Treatment with zongertinib in Asian patients with advanced HER2-mutant nonsmall cell lung cancer (NSCLC), who have received prior systemic therapy, delivers robust efficacy and elicits an acceptable safety profile, consistent with the overall global analysis, reports a China study.

“In this subset of Asian patients, zongertinib demonstrated clinically meaningful benefit consistent with the overall patient population in patients with previously treated advanced HER2-mutant NSCLC,” said lead study author Dr Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Southern Medical University, Guangzhou, China.

In the phase Ib (dose expansion of the Beamion LUNG-1) study, Wu and colleagues selected zongertinib 120 mg once daily following an interim analysis. They included 75 patients in cohort 1 (previously treated with TKD mutations), of whom 39 were Asians (China: n=18; Korea: n=12; Japan: n=9).

The Asian patients had a median age of 60 years, of whom 72 percent were female, 77 percent had no prior tobacco use, and 36 percent had baseline metastases. The cutoff data for the efficacy analyses was 29 November 2024. [ESMO Asia 2025, abstract 975MO]

The objective response rate (ORR) in all Asian NSCLC patients was 76.9 percent (95 percent confidence interval [CI], 61.7‒87.4), while the disease control rate (DCR) was 100 percent (95 percent CI, 91–100). The median duration of response (DoR) was 14.1 months (95 percent CI, 6.8‒not calculable [NC]), and the median progression-free survival (PFS) was 15.5 months (95 percent CI, 8.3‒NC).

In Chinese patients, the ORR and DCR were 83.3 percent (95 percent CI, 60.8‒94.2) and 100 percent (95 percent CI, 82.4‒100), respectively, while the corresponding median DoR and PFS were 14.1 (95 percent CI, 4.1‒14.1) and 15.5 (95 percent CI, 5.4‒NC) months.

Treatment-related adverse events (TRAEs) occurred in 92 percent of all Asian patients, while the incidence of grade ≥3 TRAEs stood at 18 percent. Diarrhoea (mainly grade 1) was the most common TRAE, occurring in 38 percent of Asian patients (28 percent in Chinese patients). Drug-related interstitial lung disease was not reported.

“The manageable safety profile of zongertinib in Asian patients was consistent with previously reported data, with a notably low incidence of grade ≥3 drug-related AEs, including those related to EGFR,” Wu said. Further data on zongertinib … are expected soon from local cohorts in Japan and China.”

HER2 mutation

An orally administered, irreversible tyrosine kinase inhibitor, zongertinib selectively obstructs HER2 while sparing wild-type EGFR, resulting in fewer related toxicities. [Cancer Discov 2025;15:119-138]

“HER2 mutations occur in approximately 2–4 percent of NSCLC patients and are associated with highly aggressive disease, a poor prognosis, female sex, a slightly younger age, and a high incidence of brain metastases,” Wu said. [Lung Cancer 2023;186:107385]

“Data from the phase Ib cohort 1 of Beamion LUNG-1 demonstrated meaningful clinical efficacy and a manageable safety profile with zongertinib in previously treated patients with HER2-mutant NSCLC, including in patients with brain metastases,” Wu added. [N Engl J Med 2025;392:2321-2333]

Recently, zongertinib was granted Breakthrough Therapy Designation by the FDA in the US and by the CDE in China for the first-line treatment of adult patients with unresectable/metastatic HER2-mutant NSCLC, according to Wu.