Zongertinib Shows Antitumor Activity in Patients With HER2-Altered Tumors

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The HER2-selective TKI zongertinib was safe and elicited preliminary antitumor activity in patients with HER2-altered tumors, according to results from the ongoing phase 1a/1b Beamion LUNG-1 trial.^1,2

Results from phase 1a of the trial, which were recently published in the Journal of Clinical Oncology (JCO), showed that across all doses and tumor types, the confirmed investigator-assessed overall response rate (ORR) for zongertinib was 30% (95% CI, 23-40). The median duration of response was 12.7 months (95% CI, 6.9 to not reached). The ORR in patients who had prior HER2-directed treatment was 28%. Further, over half of the patients had NSCLC and the confirmed ORR in this subgroup was 35% (95% CI, 24-49).

The investigators also determined that zongertinib had a manageable safety profile. Overall, 82% experienced treatment-related adverse events (TRAEs) of any grade, and 10% of patients had a grade 3 or higher TRAE. The most frequently occurring TRAEs were diarrhea (50% any grade/1% grade ≥3), rash (16%/2%), anemia (10%/0%), decreased appetite (10%/1%), and increased alanine transaminase (10%/4%).

Based on the phase 1a efficacy and safety results, JCO Associate Editor Thomas E. Stinchcombe, MD, wrote in an accompanying commentary that, “Future development of zongertinib in solid tumors with HER2 alterations is warranted.”

Study Design and Patient Characteristics

Phase 1a of the first-in-human multicenter, multicohort phase 1a/1b Beamion LUNG-1 trial is enrolling patients with HER2-altered solid tumors. As of the cutoff date of May 23, 2024, 105 patients had been treated on the trial.

The median age of the 105 patients was 60 years (range, 31-81), 53% were female, 38% were White, and 51% were Asian. All patients had an ECOG performance status of 0 (40%) or 1 (60%). The primary tumor for over half of patients was NSCLC (51%), with other primary tumors being breast (11.4%), colorectal (13.3%), esophageal (4.8%), cervical (2.9%), endometrial (2.9%), gastrointestinal tract (2.9%), biliary tract (1.9%). One-fourth (25.7%) of patients had brain metastases at baseline. Patients had received a median of 4 prior lines (range, 1-17) of treatment, with over one-third (36%) having received at least 5 prior lines.

Patients in phase 1a received zongertinib either twice a day (15-150 mg) or once daily (60-360 mg). The maximum tolerated dose was not reached. The researchers selected 120 mg once daily and 240 mg once daily as the recommended doses for expansion.

Phase 1b and FDA Activity

Phase 1b of the Beamion LUNG-1 trial is already ongoing and data from Cohort 1 have been made available. Cohort 1 of phase 1b included 75 patients with previously treated HER2-positive advanced NSCLC. In these patients, treatment with zongertinib led to an ORR of 71%. The 6-month PFS rate with the TKI was 69%.

Based on the phase 1b data, the FDA granted a priority review to a new drug application for zongertinib for use in previously treated adult patients with unresectable or metastatic HER2 mutation–positive NSCLC. Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the NDA by the third quarter of this year.

References

1. Heymach JV, Opdam F, Barve M, et al. HER2-Selective Tyrosine Kinase Inhibitor, Zongertinib (BI 1810631), in Patients With Advanced/Metastatic Solid Tumors With HER2 Alterations: A Phase Ia Dose-Escalation Study [published online ahead of print March 3, 2025. J Clin Oncol. doi: 10.1200/JCO-24-01727

2. Boehringer’s zongertinib receives Priority Review from U.S. FDA for the treatment of HER2 (ERBB2)-mutant advanced non-small cell lung cancer. Published online February 19, 2025. Accessed March 26, 2025. https://www.boehringer-ingelheim.com/us/zongertinib-granted-priority-review-us-fda