Zongertinib is an irreversible tyrosine kinase inhibitor that selectively targets HER2 while minimizing effects on EGFR, thereby reducing related toxicities. The FDA has granted zongertinib Fast Track and Breakthrough Therapy designations for patients with advanced, unresectable, or metastatic NSCLC harboring activating HER2 mutations who have previously received systemic therapy. Beamion LUNG-1 (NCT04886804) is a phase 1a/1b trial evaluating the efficacy and safety of zongertinib in patients with HER2-positive advanced or metastatic NSCLC. The primary analysis of phase 1b, cohort 1 in May 2024 confirmed that the primary endpoint of objective response rate (ORR) by blinded independent central review (BICR) was achieved in pretreated patients with HER2-positive NSCLC involving the tyrosine kinase domain tyrosine kinase domain (TKD). Here, we highlight the previously unreported median duration of response and progression-free survival (PFS) for cohort 1, along with initial findings from cohorts 3 and 5.

Cohort 1 included patients with pretreated HER2-positive NSCLC with TKD mutations, randomized to receive zongertinib 120 mg or 240 mg once daily; 120 mg was selected as the recommended dose following interim analysis. Cohort 3 enrolled patients with pretreated HER2-positive NSCLC with either TKD or non-TKD mutations. Cohort 5 included patients with TKD mutations pretreated with a HER2-directed antibody–drug conjugate. Patients in cohorts 3 and 5 initially received 240 mg before transitioning to 120 mg. The primary endpoint was ORR (complete or partial response per RECIST v1.1), assessed by BICR (cohorts 1 and 5) or investigator review (cohort 3). Secondary endpoints included duration of response and PFS.

In cohort 1 (n=75), the ORR was 71% (95% confidence interval [CI], 60-80) and the disease control rate (DCR) was 96% (95% CI, 89-99). Median duration of response and PFS were 14.1 months (95% CI, 6.9-not evaluable [NE]) and 12.4 months (95% CI, 8.2-NE), respectively. The ORR in cohort 3 (n=20) was 30% (95% CI, 15-52); DCR was 65% (95% CI: 43–82). Duration of response and PFS data for cohort 3 were not yet mature. Patients in cohort 5 (n=31) demonstrated an ORR of 48% (95% CI, 32-65); DCR was 97% (95% CI, 84-99). Median duration of response and PFS were 5.3 months (95% CI, 2.8-NE) and 6.8 months (95% CI, 5.4-NE), respectively.

Drug-related adverse events of any grade occurred in 97% (grade ≥3, 17%) in cohort 1, 80% (grade ≥3, 25%) in cohort 3, and 77% (grade ≥3, 3%) in cohort 5, with diarrhea being the most common (primarily grade 1). No cases of drug-related interstitial lung disease were reported.

Building on these findings, the zongertinib clinical program has been expanded to include the Beamion LUNG-2 Phase 3 trial. This study will evaluate zongertinib in treatment-naïve patients with advanced or metastatic non-squamous NSCLC harboring TKD HER2 mutations. The trial will compare the efficacy and safety of zongertinib with the current standard of care: pembrolizumab plus platinum-based chemotherapy consisting of cisplatin/carboplatin and pemetrexed. The primary endpoint is PFS as assessed by RECIST v1.1 via BICR. Key secondary endpoints include overall survival, ORR, duration of response, and patient-reported outcomes.

Zongertinib demonstrated robust and clinically meaningful activity with a favorable safety profile in pretreated patients with HER2-positive advanced NSCLC, including those with prior HER2-directed therapy or non-TKD mutations.

Sources:

Heymach JV, et al. Zongertinib in patients with pretreated HER2-mutant advanced NSCLC: Beamion LUNG-1. Presented at: American Association for Cancer Research. April 28, 2025; Chicago, IL. Abstract CT050.

Yi-Long Wu, Frans Opdam, Noboru Yamamoto, et al. Beamion LUNG-1 and LUNG-2: The zongertinib clinical program in patients with advanced HER2-mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); April 25-30 2025; Chicago, IL. Philadelphia, PA: AACR; Cancer Res, 2025;85(8_Suppl_2):Abstract CT108.