Beamion LUNG-1: Zongertinib Shows ‘Significant’ Activity in Patients With NSCLC Harboring HER2 Mutations

Zongertinib demonstrated “significant” activity with a “manageable safety profile” in patients with pretreated advanced non–small cell lung cancer (NSCLC) who are harboring HER2 mutations, according to a study presented at the American Association for Cancer Research (AACR) Annual Meeting 2025.

John V. Heymach, MD, PhD, chair of Thoracic/Head and Neck Medical Oncology and the Ruth Legett Jones Distinguished Chair at The University of Texas MD Anderson Cancer Center, presented results from the phase Ia/Ib Beamion LUNG-1 trial during the AACR meeting.

“Zongertinib provided clinically meaningful activity in previously treated patients with advanced non-small cell lung cancer with HER2 mutations both inside and outside the tyrosine kinase domain, including in patients with brain metastases,” Dr. Heymach said during an AACR press conference held this morning.

Dr. Heymach explained why the results of Beamion LUNG-1 were meaningful for this population of patients.

“Activating HER2 mutations occur in roughly 2% to 4% of non-small cell lung cancer patients and lead to constitutive activation of the downstream signaling pathways,” Dr. Heymach said during the AACR press conference. “These patients harbor worse prognosis than the overall non-small cell lung cancer population, with higher rates of brain metastases.”

It was critical to evaluate this selective HER2-targeted therapy, as oral small-molecule inhibitors of HER2 have been approved for HER2-overexpressing breast cancer, but “these inhibitors are not as effective against HER2-mutated cancers and can also cause side effects related to cross-targeting of the epidermal growth factor (EGFR),” according to an AACR press release.  The irreversible tyrosine kinase inhibitor “selectively inhibits HER2 while sparing EGFR, thereby limiting associated toxicities,” according to the abstract presented at AACR.

“There remains a clear unmet need for an effective, easily tolerable, and convenient targeted therapy for patients with HER2-mutated NSCLC,” Dr. Heymach said in the AACR press release.

The phase Ia/Ib Beamion LUNG-1 trial previously met is primary end point, which was a confirmed response by blinded independent central review, in patients with pretreated NSCLC and a HER2 mutation within the tyrosine kinase domain. Dr. Heymach presented on the previously unreported median duration of response (DOR) and median progression-free survival (PFS) data from cohort 1 and on the first report of data from cohorts 3 and 5.

Cohort 1 included patients with pretreated NSCLC and a HER2 mutation within the tyrosine kinase domain. Study investigators initially randomized patients in cohort 1 to receive zongertinib 120 mg or 240 mg once daily but selected the 120-mg dose at the interim analysis.

The exploratory cohort 3 included patients with pretreated NSCLC and a HER2 mutation within or outside the tyrosine kinase domain. Cohort 5 included patients with NSCLC and a HER2 mutation within the tyrosine kinase domain who received previous treatment with a HER2-directed antibody-drug conjugate.

Patients in cohorts 3 and 5 initially received zongertinib 240 mg. However, after the 120-mg dose was selected for cohort 1, all newly recruited patients received zongertinib 120 mg. At the time of analysis, 75 patients in cohort 1, 20 patients with non–tyrosine kinase domain mutations in cohort 3, and 31 patients in cohort 5 had received zongertinib 120 mg.

The primary end point of Beamion LUNG-1 was objective response by blinded independent central review in cohort 5, and by investigator review in cohort 3. Secondary end points included DOR and PFS. The study investigators broke down results by cohort.

Cohort 1: The objective response rate (ORR) by blinded independent central review was 71% (95% CI, 60%-80%), with a disease control rate (DCR) of 96% (95% CI, 89%-99%). The median DOR was 14.1 months (6.9-not evaluable [NE]) with a median PFS of 12.4 months (8.2-NE).

Cohort 3: The ORR was 30% (95% CI, 15%-52%), with a DCR of 65% (95% CI, 43%-82%). The median DOR and PFS are “not yet mature” in cohort 3, the study investigators explained.

Cohort 5: The ORR was 48% (95% CI, 32%-65%) with a DCR of 97% (95% CI, 84%-99%). The median DOR was 5.3 months (2.8-NE) with a median PFS of 6.8 months (5.4-NE).

In the press release, Dr. Heymach explained that the results from cohort 3 suggest zongertinib may also target less common HER2 mutations outside the tyrosine kinase domain and that results from cohort 5 suggest the drug may benefit those who did not respond or experienced relapse after treatment with a HER2-targeted antibody-drug conjugate.

Drug-related adverse events were reported in 97% of patients in cohort 1, with 17% being grade 3 or higher. In cohort 3, drug-related adverse events were reported in 80% of patients, with 25% being grade 3 or higher. In cohort 5, drug-related adverse events were reported in 77% of patients, with 3% being grade 3 or higher. Diarrhea was the most common reported drug-related adverse event and was “mainly” grade 1, according to the study investigators. No cases of drug-related interstitial lung disease (ILD) were reported.

“The fact that we have not seen any significant ILD signals here tells us this is something that could be suitable for patients that do have underlying lung conditions,” Dr. Heymach said during the press conference.

Although the study is limited by its single-arm, open-label design, Dr. Heymach explained that these safety findings could be related to the selectivity to HER2.

“Zongertinib demonstrated a very favorable safety profile, with little or no significant rash, diarrhea, or pneumonitis—toxicities that were observed in prior therapies,” Heymach said in the news release. “These initial studies suggest that it may be more effective and less toxic than other available therapies for these patients.”

Zongertinib is currently under FDA review for Fast Track and Breakthrough Therapy designations for the indication evaluated in Beamion LUNG-1, officials said.

“Until recently, there were no effective targeted therapies for HER2-mutated NSCLC,” Dr. Heymach said in the news release. “This potentially practice-changing approval of zongertinib would provide access to a highly efficacious treatment option with a manageable safety profile and would be the first oral therapy and only tyrosine kinase inhibitor approved for patients with HER2-mutated NSCLC.”

During the press conference held at the AACR Annual Meeting, Dr. Heymach explained what the future could hold for clinical research on zongertinib.

“We want to continually move up the bar… We’re excited to see the performance of the monotherapy, but moving forward, I anticipate that combinations are going to play an important role,” Dr. Heymach said during the press conference.

Sources

American Association for Cancer Research. Accessed April 28, 2024. https://www.aacr.org/about-the-aacr/newsroom/news-releases/oral-her2-targeted-therapy-zongertinib-demonstrates-clinical-benefit-in-advanced-her2-mutated-lung-cancer/

American Association for Cancer Research Annual Meeting 2025. Abstract #CT050. https://www.abstractsonline.com/pp8/#!/20273/presentation/10423