Updated Data Show Zongertinib Yields Responses in 71% With Previously Treated HER2-Mutated NSCLC

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Key Takeaways

Zongertinib achieved a 71% overall response rate in HER2-mutated NSCLC patients, with a disease control rate of 93%.
The study involved 75 patients, predominantly female and Asian, with a median age of 62 years.
Zongertinib's safety profile was favorable, with minimal dose reductions and discontinuations due to adverse events.
The drug has received FDA Fast Track and Breakthrough Therapy Designations, with a phase 3 study planned.

The investigational oral HER2-specific tyrosine kinase inhibitor would address an unmet need in non–small cell lung cancer.

Data presented December 6, 2024, show that zongertinib, an investigational oral HER2-specific tyrosine kinase inhibitor (TKI), produced responses in 71% of patients in a phase 1b study of previously treated patients with advanced non–small cell lung cancer (NSCLC).¹

Results for Beamion LUNG-1, presented at the ESMO Asia conference in Singapore, are updated from data seen at the World Congress on Lung Cancer in September.²

Zongertinib, being developed by Boehringer Ingelheim, is a highly selective oral TKI that promises potent responses with a favorable safety profile. The oral administration would fill an unmet need for patients with HER2-mutated NSCLC.

Noboru Yamamoto, MD, PhD | Image credit: Clinical Trials Network

In his presentation in Singapore, Noboru Yamamoto, MD, PhD, deputy director of the National Cancer Center Hospital of Japan and chief of the Department of Experimental Therapeutics, explained that HER2 mutations are seen in 2% to 4% of all patients with NSCLC, and these patients are more likely to have brain metastases and poor outcomes than other patients with the disease.

Approximately 48% of HER2 mutations are in exon 20, the active site of the tyrosine kinase domain, Yamamoto said. Zongertinib, he explained, is an irreversible TKI that selectively inhibits HER2 while sparing EGFR, “thereby avoiding associated toxicities.”

Zongertinib has been studied at doses of 120 mg and 240 mg per day. The results shared at ESMO Asia involve 75 patients who were given a 120-mg dose of zongertinib once daily. These patients had a median age of 62 years; 68% of the group was female, 53% were Asian, 32% were White, and investigators did not have a race recorded for 15%.¹

Among the patients, 35% were former or current smokers, while 65% had never smoked. A little more than half (56%) had 1 prior line of systemic therapy, 16% had 2 lines, and 28% had 3 or more lines of treatment.

Results were as follows¹:

Zongertinib at 120 mg per day yielded a confirmed overall response rate by central review of 71% (95% CI, 60%-80%; P < .0001), with a disease control rate of 93%.
At 6 months, the time-to-event data show progression-free survival (PFS) of 69% and duration of response at 73%, which investigators said suggest responses are durable. Data are not yet mature.
At the time of data cut-off, 55% of patients remained on treatment.

"This data update adds to the body of evidence indicating that zongertinib could be a future option for patients with non-small cell lung cancer who have activating HER2 mutations, a patient population for which targeted treatment options are currently severely limited," Yamamoto said in a statement.³“These data demonstrate the potential of zongertinib and support the long-term vision to change the benchmark for HER2 mutation-driven cancers.”

Safety data were highly favorable, with only 4 patients of the 75 (5%) requiring a dose reduction and only 2 patients (3%) stopping the drug due to adverse events (AEs). Most treatment-related AEs were manageable; only 1 patient had grade 3 diarrhea, and no patient had interstitial lung disease.

Zongertinib was granted FDA Fast Track Designation in 2023 and received Breakthrough Therapy Designation earlier this year.³ A phase 3 study, Beamion LUNG-2, plans to enroll 270 patients with unresectable or metastatic nonsquamous NSCLC harboring HER2 tyrosine kinase domain mutations to compare zongertinib with standard of care.

References

Yamamoto N, Tu H, Ahn M, et al. Zongertinib in patients with HER2-mutant NSCLC: updated analysis of Beamion LUNG-1. Ann Oncol. 2024;35(suppl_ 4):S1625-S1631. doi:10.1016/annonc/annonc1697
Ruiter G, Tu HY, Ahn MJ, et al. Primary phase Ib analysis of Beamion LUNG-1: zongertinib (BI 1810631) in patients with HER2 mutation-positive NSCLC. Presented at: 2024 World Conference on Lung Cancer; September 9, 2024; San Diego, CA.
Updated data from Beamion LUNG-1 study on zongertinib shows encouraging efficacy in previously treated HER2 mutated lung cancer patients. News release. Boehringer Ingelheim. December 6, 2024. Accessed December 12, 2024. https://www.boehringer-ingelheim.com/human-health/cancer/lung-cancer/zongertinib-efficacy-her2-lung-cancer-patients