First-Line Zongertinib Yields Strong Responses in Patients With Advanced HER2-Mutant NSCLC

On the heels of its recent accelerated approval for patients previously treated for advanced HER2-mutant non–small cell lung cancer (NSCLC),¹ the tyrosine kinase inhibitor (TKI) zongertinib demonstrated its potency in first-line treatment as well, with more phase 1b results for Beamion LUNG-1 (NCT04886804) presented Friday on the first day of the 2025 Congress of the European Society for Medical Oncology (ESMO),² being held in Berlin, Germany.

On August 8, the FDA approved zongertinib, sold as Hernexeos (Boehringer Ingelheim) for patients with unresectable or metastatic nonsquamous NSCLC with HER2 tyrosine kinase domain (TKD)–activating mutations, following systemic therapy and confirmation by an FDA-approved test.¹

Now, the oral, irreversible TKI inhibitor is showing strong results in more patients with these rare mutations in NSCLC, said Sanjay Popat, MD, of Royal Marsden Hospital in London.

"So, HER2 mutations, as you've heard, occur in up to 4% of patients with non-small cell lung cancer, and represent a highly aggressive disease, typically with poor prognosis and a high incidence of brain metastasis," Popat said. Right now, there are no approved targeted therapies for treatment-naive patients with this type of cancer, he said, so the standard of care is chemotherapy, with or without immunotherapy.

With nearly half of the responding patients still on therapy at data cutoff, zongertinib is a contender for these patients; the therapy has seen a rapid rise since gaining when phase 1b results for Beamion LUNG-1 were presented in September 2024 at the World Conference on Lung Cancer.³ The irreversible TKI inhibitor offered the promise of targeting HER2 while sparing EGFR, thus reducing toxicity seen in these patients when they were treated with antibody drug conjugates.

Previously, Beamion LUNG-1 investigator John Heymach, MD, PhD, of The University of Texas MD Anderson Cancer Center told The American Journal of Managed Care^® (AJMC^®) the therapy showed activity in patients with brain metastases, a common occurrence in this population.⁴

The Beamion LUNG-1 trial has multiple cohorts; data from 3 cohorts were presented during the American Association for Cancer Research in April 2025.⁵ Data from cohort 2 were presented at ESMO; these were adult patients who were treatment-naïve with nonsquamous advanced or metastatic HER2-mutant NSCLC with TKD mutation who received 120 mg of zongertinib once daily. Patients with stable/asymptomatic brain metastases were eligible.²

According to the abstract, the primary end point was objective response (OR), with secondary end points of duration of OR (DOR), disease control (DC), and progression-free survival (PFS). All end points were assessed by blinded independent central review (BICR). Results were as follows:²

• As of May 8, 2025, 74 patients had received zongertinib; the median patient age was 67 years (range, 35-88); 50% were female patients
• BICR confirmed the OR rate was 77% (95% CI, 66%-85%); with 6 patients (8%) having CR, 51 patients (69%) having partial response, and 14 patients (19%) having stable disease for a DC of 96% (95% CI, 89%-99%)
• The 6-month DOR and PFS rates (Kaplan-Meier estimates) were 80% (95% CI, 65%-89%) and 79% (95% CI, 68%-87%), respectively, with 47% of responding patients remaining on treatment at data cut-off
• Treatment-related adverse events (TRAEs) were reported in 91% of patients, and 18% of patients had grade 3 TRAEs. No patients had grade 4 or 5 TRAEs. The most common TRAEs were diarrhea (54% among all; 3% grade 3). Other common TRAEs were increased alanine aminotransferase (18%/4%), increased aspartate aminotransferase (16%/3%), and dysgeusia and nausea (both 16%/0%).

Although these data are “still early,” the results confirm the strong efficacy profile and very good tolerability profile reported in patient-reported outcome (PRO) results at the American Society of Clinical Oncology (ASCO),⁶ said Itziar Canamasas, PhD, global head of oncology for Boehringer Ingelheim, who spoke with AJMC ahead of ESMO.

“Anecdotally,” she said, “patients report being able to come back to feeling the way that they used to feel prior to having cancer.”

Joshua K. Sabari, MD, of NYU Langone Health, who was first author on the PROs abstract at ASCO, agreed. He told AJMC at the time, “Zongertinib is a very clean medicine. It’s selective for HER2 and spares EGFR, so we don’t see significant diarrhea, we don’t see significant rash. And there was really no interstitial lung disease. It’s a very well-tolerated oral therapy.”⁷

Although zongertinib offers better tolerability than some other options, rates diarrhea concern Popat. "I want to know more," he said.

Zongertinib has a breakthrough therapy designation in the first-line indication,⁸ Canamasas noted. The phase 3 Beamion LUNG-2 is under way, and commentator Anne-Marie C. Dingemans, MD, PhD, of Erasmus MC University Medical Center of the Netherlands said she could envision standing ovations at future conferences for competing phase 3 trials addressing unmet needs in this rare lung cancer.

References

1. Caffrey M, McCormick B. Zongertinib granted accelerated approval in nonsquamous NSCLC for HER2 TKD-activating mutations. AJMC. August 8, 2025. Accessed October 17, 2025. https://www.ajmc.com/view/zongertinib-granted-accelerated-approval-in-nonsquamous-nsclc-for-her2-tkd-activating-mutations
2. Popat S, Yamamoto N, Girard N, et al. Zongertinib as first-line treatment in patients with advanced HER2-mutant NSCLC: Beamion LUNG-1. Presented at: 50th Congress of the European Society for Medical Oncology; October 17-21, 2025 Berlin, Germany. Abstract LBA74.
3. Boehringer Ingelheim to unveil groundbreaking oncology research at WCLC, demonstrating strength of portfolio. News release. Boehringer Ingelheim. August 27, 2024. Accessed October 17, 2025. https://www.boehringer-ingelheim.com/human-health/cancer/lung-cancer/groundbreaking-oncology-research-zongertinib
4. Heymach J, McCormick B. Zongertinib shows benefit across subgroups in HER2-mutated NSCLC: John Heymach, MD, PhD. AJMC. April 28, 2025. Accessed October 17, 2025. https://www.ajmc.com/view/zongertinib-shows-benefit-across-subgroups-in-her2-mutated-nsclc-john-heymach-md-phd
5. Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in previously treated HER2-Mutant non–small-cell lung cancer. N Engl J Med. 2025;392(23):2321-2333. doi:10.1056/NEJMoa2503704
6. Sabari JK, Nadal E, Hendriks L, et al. Patient-reported outcomes (PRO) evaluating physical functioning and symptoms in patients with pretreated HER2-mutant advanced non-small cell lung cancer (NSCLC): results from the Beamion LUNG-1 trial. J Clin Oncol. 2025;43(suppl 16):8620. doi:10.1200/JCO.2025.43.16_suppl.8620
7. Sabari JK, Caffrey M. PROs affirm zongertinib’s combination of strong response rates with low toxicity. AJMC. July 1, 2025. Accessed October 17, 2025. https://www.ajmc.com/view/pros-affirm-zongertinib-s-combination-of-strong-response-rates-with-low-toxicity
8. FDA grants Hernexeos breakthrough therapy designation for first line use in HER2 (ERBB2)-mutant advanced NSCLC. News release. Boehringer Ingelheim. September 8, 2025. Accessed October 17, 2025. https://www.boehringer-ingelheim.com/us/human-health/cancer/lung-cancer/fda-grants-boehringer-breakthrough-therapy-designation