Zongertinib shows antitumour activity in previously treated HER2-mutant NSCLC

The oral, irreversible, HER2-selective tyrosine kinase inhibitor (TKI) zongertinib confers clinically meaningful benefit to patients with previously treated HER2-mutant nonsmall cell lung cancer (NSCLC), including those with brain metastases, while having a manageable safety profile, according to the phase 1A/1B Beamion LUNG-1 trial.

Among patients with tumours harbouring HER2 mutations within the tyrosine kinase domain (TKD) who had not received a prior HER2-directed antibody–drug conjugate (ADC) treatment (cohort 1, n=75), the objective response rate (ORR) was 71 percent (95 percent confidence interval [CI], 60–80), of which 7 percent were complete responses and 64 percent were partial responses. The majority of patients (96 percent) achieved disease control, and the median best percentage change from baseline in target lesions was –43 percent. [AACR 2025, abstract CT050]

At the data cutoff of November 2024, 44 percent of patients remained on therapy. The median time to objective response was 1.4 months, and the median duration of response was 14.1 months. The median progression-free survival was 12.4 months.

“The responses to zongertinib were durable, and the majority were observed at the first assessment,” reported first study author Dr John Heymach from the University of Texas M.D. Anderson Cancer Center in Houston, Texas, US.

Meanwhile, in the subset of 27 patients in cohort 1 who had intracranial metastasis that could be assessed by the RANO-BM criteria, the ORR was 41 percent (95 percent CI, 25–59), of which 15 percent were complete responses and 26 percent were partial responses. Heymach pointed out that in one patient, one of the multiple brain metastases disappeared with zongertinib treatment.

“The drug demonstrated clear intracranial activity in patients with brain metastases, with 81 percent achieving disease control,” he added.

In terms of safety, drug-related adverse events (AEs) occurred in 97 percent of patients in cohort 1, and most of these events were grade 1 or 2 and manageable, according to Heymach. The most common was diarrhoea, which was largely grade 1. Other drug-related AEs included rash, nausea, dry skin, and pruritus.

Grade 3 drug-related AEs were observed in 17 percent of patients. These included elevations in AST and ALT in 5 percent and 8 percent of patients, respectively, and diarrhoea and decreased neutrophil count in 1 percent each.

AEs led to dose reduction in 7 percent of patients and to treatment discontinuation in 3 percent.

“Zongertinib had a manageable safety profile, with notably low incidence of grade ≥3 drug-related AEs or dose reductions,” Heymach said. “[This drug] is a potent, covalent TKI that inhibits HER2 while sparing EGFR wild-type, thereby potentially limiting associated toxicities.”

Other patient cohorts

In preclinical studies, zongertinib showed clinical activity in trastuzumab deruxtecan-resistant tumour models and against HER2 mutations both within and outside the TKD. As such, Heymach and colleagues assessed tumour responses in other cohorts of patients—those with tumours harbouring HER2 mutations within the TKD who did receive prior HER2-directed ADC treatment (cohort 5, n=31) and those with tumours harbouring a non–TKD mutation (cohort 3, n=20). [Cancer Discov 2025;15:119-138; AACR 2024, abstract 5857]

In cohort 5, the ORR was 48 percent (95 percent CI, 32–65), with 3 percent being complete responses and 45 percent being partial responses. Disease control was achieved in 97 percent of patients. Additionally, in the subset of 22 patients who had specifically received prior trastuzumab deruxtecan treatment, the ORR was 41 percent (95 percent CI, 23–61).

In cohort 3, on the other hand, the ORR was 30 percent (95 percent CI, 15–52), all of which were partial responses. A total of 65 percent of patients achieved disease control.

Heymach pointed out that among the patients in cohort 3, 17 had known activating mutations and three had mutations of uncertain function. The ORR in this subset of patients with non-TKD mutations that were known to be activating was 35 percent.

These data demonstrate the clinical activity of zongertinib in patients previously treated with HER2-directed ADCs and those with non-TKD HER2 mutations, Heymach said. The safety profile of the drug in cohorts 5 and 3 was similar to that in cohort 1, and there were no reported cases of drug-related interstitial lung disease.

Beamion LUNG-1

Beamion LUNG-1 was conducted in two phases. In phase 1a, zongertinib was evaluated in patients with HER2-altered advanced solid tumours. These patients received escalating doses of zongertinib either once or twice per day in 3-week cycles. The maximum tolerated dose was not reached with either dose schedule, but an interim futility analysis led to the selection of 120-mg once-per-day dose for evaluation in phase 1b.

Phase 1b included five cohorts of patients with NSCLC. The present analysis included the efficacy and safety data with zongertinib 120 mg daily in cohort 1 (median age 62 years, 68 percent female, 53 percent Asian, 39 percent had ≥2 lines of prior systemic anticancer treatment), cohort 3 (median age 61 years, 68 percent female, 35 percent Asian, 84 percent had ≥2 lines of prior systemic anticancer treatment), and cohort 5 (median age 65 years, 45 percent female, 45 percent Asian, 60 percent had ≥2 lines of prior systemic anticancer treatment).

Data for cohort 2—consisting of patients with treatment-naïve disease harbouring HER2 mutations within the TKD—and cohort 4—comprising those with HER2 mutations within the TKD and active brain metastases—are not yet available.

The primary endpoint of ORR per RECIST 1.1 criteria was assessed by blinded independent central review in cohorts 1 and 5 and by investigator review in cohort 3.

Heymach said that a phase III randomized study, Beamion LUNG-2, will evaluate zongertinib against standard of care in patients with unresectable, locally advanced or metastatic HER2-mutant NSCLC, adding that those with mutations within the TKD are currently being enrolled exclusively.

TKIs gain an edge

Study discussant Dr Charles Rudin, deputy director of Memorial Sloan Kettering Cancer Center in New York, New York, US, congratulated Heymach and colleagues for completing what he described as “a very important” study.

“An effective, well-tolerated, orally bioavailable therapy for patients with HER2-driven lung cancers has been a major unmet need. Zongertinib, in my opinion, satisfies the primary criteria we would want to see for a drug in this class,” Rudin said.

Looking at the treatment landscape for HER2-driven lung cancers, next-generation TKIs, such as zongertinib, and ADCs, such as trastuzumab deruxtecan, have higher response rates and greater durability than chemotherapy or chemotherapy plus immunotherapy regimens, according to Rudin. However, he emphasized that ADCs, despite showing remarkable efficacy in the DESTINY Lung01 and -02 studies, are accompanied by toxicities including chemotherapy-like side effects (eg, bone marrow suppression, fatigue, nausea), which can lead to dose reductions or treatment discontinuations. [N Engl J Med 2022;386:241-251; J Clin Oncol 2023;41:4852-4863]

So, when considering which to give in the first-line setting, Rudin said he would give an “edge” to the TKIs based on the tolerability and high response rate. Furthermore, there are other exciting highly selective TKIs aside from zongertinib, and brain efficacy may end up as an important discriminant between these agents.

In closing, Rudin highlighted that HER2-mutant NSCLC is a highly competitive space. This reinforces the basic oncologic principle of giving the best available therapies first, which ultimately benefits patients.