FDA Grants Priority Review to Zongertinib for HER2-Mutant Advanced NSCLC

The FDA has granted priority review to the new drug application (NDA) seeking the approval of zongertinib (BI 1810631) for the treatment of adult patients with unresectable or metastatic non–small cell lung cancer (NSCLC) harboring HER2 mutations who have received prior systemic therapy.1

Zongertinib is an investigational, irreversible TKI that selectively inhibits HER2 and spares EGFR with the goal of limiting toxicities associated with EGFR inhibition.

The NDA is supported by data from the phase 1 Beamion LUNG-1 trial (NCT04886804), an open-label, dose-escalation and -expansion study evaluating zongertinib monotherapy in patients with advanced NSCLC harboring HER2 alterations. Findings from cohort 1 (n = 75) demonstrated an objective response rate (ORR) of 71%, with six-month progression-free survival (PFS) and duration of response (DOR) rates of 69% and 73%, respectively.

The NDA has been assigned a Prescription Drug User Fee Act target action date in the third quarter of 2025.1

“We believe zongertinib has the potential to transform the care of previously treated patients with HER2-mutant advanced NSCLC and are hopeful about the continued research in other tumor types and lines of therapy,” Shashank Deshpande, member of the Board of Managing Directors and head of Human Pharma at Boehringer Ingelheim, stated in a news release.1

Safety data from Beamion LUNG-1 showed that adverse effects (AEs) led to low rates of dose reductions (5%) and treatment discontinuations (3%). The majority of treatment-related AEs (TRAEs) were mild; the most common any-grade TRAEs were diarrhea (51%) and rash (27%). Only 1 patient experienced grade 3 or higher TRAEs. Notably, no treatment-related interstitial lung disease was reported.

Zongertinib is also under evaluation in the phase 3 Beamion LUNG-2 trial (NCT06151574), a randomized, active-controlled study comparing the agent with standard of care in patients with unresectable or metastatic nonsquamous NSCLC harboring HER2 mutations.

“Priority review illustrates the urgent need in this patient population and the possibility for zongertinib to be a groundbreaking innovation for patients with limited treatment options,” Deshpande added in the news release.

Study Design and Patient Enrollment Criteria of Beamion LUNG-1

Beamion LUNG-1 is a multicenter, open-label, phase 1 study evaluating the safety, tolerability, and preliminary efficacy of zongertinib in patients with unresectable or metastatic solid tumors harboring HER2 alterations.2

All enrolled patients had to be at least 18 years of age with histologically or cytologically confirmed advanced, unresectable, and/or metastatic non-hematologic malignancies with at least 1 measurable lesion per RECIST 1.1 criteria, an ECOG performance status of 0 or 1 (with ECOG 2 permitted only in Cohorts 6 and 7), and adequate organ function. Additionally, patients must have recovered from toxicities related to prior treatments.

Eligible patients must provide a tumor sample for HER2 mutation status confirmation, which may be via archival tissue obtained before enrollment.

Phase 1a allowed for patients with various tumor types harboring HER2 mutations; cohort 1 in phase 1b was designed specifically for patients with HER2-mutant nonsquamous NSCLC who received at least 1 prior line of therapy in the advanced setting.

In the dose-escalation phase, patients received escalating doses of zongertinib to determine the maximum tolerated dose and the recommended dose for expansion. In the dose-expansion phase, patients are receiving zongertinib at the optimal dose to further evaluate efficacy and safety.

The primary end points of phase 1a are the incidence of dose-limiting toxicities and to determine the MTD. ORR serves as the primary end point in phase 1b. Secondary objectives for phase 1b include disease control rate, DOR, PFS, overall survival, safety, and pharmacokinetics.

References

1. Boehringer’s zongertinib receives Priority Review from U.S. FDA for the treatment of HER2 (ERBB2)-mutant advanced non-small cell lung cancer. GlobeNewswire News Room. February 19, 2025. Accessed February 19, 2025. https://www.boehringer-ingelheim.com/us/zongertinib-granted-priority-review-us-fda
2. Beamion LUNG-1: a study to test different doses of zongertinib in people with different types of advanced cancer (solid tumours with changes in the HER2 gene). ClinicalTrials.gov. Updated February 10, 2025. Accessed February 19, 2025. https://clinicaltrials.gov/study/NCT04886804