Frontline Zongertinib Shows Systemic and Intracranial Activity in Advanced HER2-Mutant NSCLC

Zongertinib (Hernexeos) elicited responses in patients with advanced HER2-mutant non–small cell lung cancer (NSCLC), with intracranial efficacy observed in those with active brain metastases, according to data from cohorts 2 and 4 of the phase 1b Beamion LUNG-1 study (NCT04886804) presented during the 2026 European Lung Cancer Congress.¹

In treatment-naive patients enrolled in cohort 2 (n = 74), the confirmed objective response rate (ORR) with the agent was 76% by blinded independent central review (BICR), which comprised a complete response (CR) rate of 11% and a partial response (PR) rate of 65% (Figure). The disease control rate was 96%, with 20% of patients achieving stable disease (SD); 1 patient experienced disease progression. The median time to response was 1.4 months (95% CI, 1.1-6.9), and the median duration of response (DOR) was 15.2 months (95% CI, 9.8-not evaluable [NE]). In this group, zongertinib showcased clinical benefit in all patients, regardless of HER2 mutation type. The median progression-free survival (PFS) with the agent was 14.4 months (95% CI, 11.1-NE).

In those with active brain metastases who were included in cohort 4 (n = 30), the confirmed intracranial ORR by BICR and RANO-BM criteria was 47%; this comprised CR and PR rates of 7% and 40%, respectively. The disease control rate (DCR) was 87%, with 40% of patients having SD. The median DOR was 6.9 months (95% CI, 2.9-NE) and the median PFS was 8.2 months (95% CI, 4.1-11.3). In those without prior brain radiotherapy and confirmed measurable intracranial disease who were also enrolled in cohort 4 (n = 17), the confirmed intracranial ORR was 59%, with a CR rate of 6% and a PR rate of 53%. The DCR was 94%; 35% of patients had SD. The median DOR and PFS in this group were 6.2 months (95% CI, 2.7-NE) and NE, respectively.

“Zongertinib demonstrated clinically meaningful benefit in patients with advanced HER2-mutant NSCLC, including in patients with active brain metastases, with a manageable safety profile and notably few grade 3 or higher treatment-emergent adverse effects [TEAEs],” John V. Heymach, MD, PhD, said in a presentation of the data. Heymach is the chair of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

How might zongertinib serve an unmet need in HER2-mutated NSCLC?

Heymach noted that HER2 mutations emerge in approximately 2% to 4% of all cases of NSCLC, a disease that is linked with poor prognosis and a high incidence of brain metastases. The irreversible TKI selectively inhibits HER2 and spares wild-type EGFR, which leads to fewer toxicities such as rash and diarrhea.

Under the National Priority Review Voucher pilot program, in February 2026, the FDA granted accelerated approval to zongertinib for use in adult patients with unresectable or metastatic, nonsquamous NSCLC whose tumors harbor HER2 TKD activating mutations based on findings from Beamion LUNG-1.² In a previous interview with OncLive®, Balazs Halmos, MD, MS, of Montefiore Health System and Albert Einstein College of Medicine, shed light on the evolving treatment landscape for this population following this regulatory decision.³

The expanded indication followed the accelerated approval of the agent for use in adult patients with unresectable or metastatic nonsquamous NSCLC harboring HER2 TKD activating mutations who had previously received systemic treatment, which happened in August 2025.⁴ “Prior to zongertinib, there was no approved HER2-targeted first-line therapy, a major unmet clinical need,” Heymach noted.¹

What was the design of Beamion LUNG-1?

The single-arm, open-label, multicenter, multicohort trial enrolled patients with unresectable or metastatic NSCLC harboring HER2 mutations.⁵ The trial comprises 5 cohorts: previously treated patients with TKD mutations (cohort 1), treatment-naive patients with TKD mutations (cohort 2), previously treated patients with non-TKD mutations (cohort 3), treatment-naive or previously treated patients with TKD mutations and active baseline brain metastases (cohort 4), and patients with TKD mutations and prior exposure to HER2-directed antibody-drug conjugates (cohort 5).¹

In the phase 1a portion of the research, the maximum tolerated dose was not reached at 360 mg once daily. In the phase 1b portion, following an interim futility analysis, a dose of 120 mg once daily was selected. Patients received zongertinib at this dose until disease progression or intolerable toxicity.⁵

At the meeting, Heymach shared data from cohorts 2 and 4, which had respective primary end points of ORR by BICR and RECIST 1.1 criteria and ORR in central nervous system lesions by BICR.¹

What were the key patient and disease characteristics in cohorts 2 and 4 of Beamion LUNG-1?

In cohort 2, the median patient age was 67 years (range, 35-88), with 41% of patients falling between the ages of 65 and 75 years. Half of patients were female, 46% of patients were Asian, 54% of patients had an ECOG performance status of 1, 34% were former smokers, and 30% had brain metastases at baseline. In cohort 4, the median patient age was 59 (range, 38-77), with 20% of patients between the ages of 65 and 75 years. More than half of patients were female (63%), half were Asian (50%), 57% had an ECOG performance status of 1, and 33% had a history of tobacco exposure. Twenty-seven percent of patients in this cohort were treatment naive.

What was the toxicity profile of zongertinib in patients with treatment-naive HER2-mutant NSCLC?

In cohort 2, treatment-related adverse effects (TRAEs) occurred in 91% of patients, with 19% experiencing effects that were grade 3 or higher. The most common TRAEs reported with zongertinib in these patients were diarrhea (all, 55%; grade 3, 3%), rash (24%; 0%), increased alanine aminotransferase levels (18%; 4%), dysgeusia (18%; 0%), nausea (18%; 0%), increased aspartate aminotransferase levels (16%; 3%), paronychia (14%; 1%), dry skin (14%; 0%), pruritus (14%; 0%), fatigue (12%; 0%), anemia (11%; 3%), and stomatitis (11%; 0%).

Toxicities led to dose reductions for 16% of patients who received the agent and to discontinuation for 9% of patients, Heymach noted.

What additional trials are examining zongertinib in HER2-mutant NSCLC?

The phase 3 Beamion LUNG-2 (NCT06151574) is comparing zongertinib with standard of care (SOC) in the first-line treatment of patients with unresectable, locally advanced, or metastatic HER2-mutant NSCLC.⁶ “Target enrollment has been reached,” Heymach reported. Moreover, adjuvant zongertinib is also being compared with SOC in patients with early-stage, resectable HER2-mutant NSCLC as part of the ongoing, randomized, phase 3 Beamion LUNG-3 study (NCT07195695).⁷

Disclosures: Heymach disclosed serving in a consulting or advisory role for AbbVie, Amgen, AnHeart Therapeutics, ArriVent BioPharma, AstraZeneca, BioNTech SE, Boehringer Ingelheim, Bristol Myers Squibb, Curio Science, DAVA Oncology, Eli Lilly and Company, EMD Serono, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Mirati Therapeutics, Moffitt Cancer Center, ModeX Therapeutics, Novartis Pharmaceuticals, OncoCyte, Pfizer, Sanofi, Spectrum Pharmaceuticals, and Takeda Pharmaceutical. Research funding was provided by AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Mirati Therapeutics, Takeda Pharmaceutical, and Taiho Pharmaceutical.

References

1. Heymach JV, Yamamoto N, Girard N, et al. Zongertinib in treatment-naive patients with HER2-mutant NSCLC, including those with active brain metastases: Beamion LUNG-1. Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Abstract 6MO.
2. FDA grants accelerated approval to zongertinib for unresectable or metastatic non-squamous non-small cell lung cancer. FDA. February 26, 2026. Accessed March 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-unresectable-or-metastatic-non-squamous-non-small-cell
3. Halmos B. Dr Halmos on the FDA approval of zongertinib in HER2 TKD-mutated NSCLC. OncLive.com. February 26, 2026. Accessed March 26, 2026. https://www.onclive.com/view/dr-halmos-on-the-fda-approval-of-zongertinib-in-her2-tkd-mutated-nsclc
4. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. FDA. August 8, 2025. Accessed March 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations
5. Hernexeos. Prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc; 2026. Accessed March 26, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219042s000lbl.pdf
6. Beamion LUNG-2: A study to test whether zongertinib (BI 1810631) helps people with advanced non-small cell lung cancer with HER2 mutations compared with standard treatment. ClinicalTrials.gov. Updated March 18, 2026. Accessed March 26, 2026. https://clinicaltrials.gov/study/NCT06151574
7. Beamion LUNG-3: A study to test whether zongertinib helps people with surgically removed, non-small cell lung cancer with HER2 mutations compared with standard treatment. ClinicalTrials.gov. Updated March 18, 2026. Accessed March 26, 2026. https://clinicaltrials.gov/study/NCT07195695