Patients Report Early, Sustained Functional Gains With First-Line Zongertinib in HER2-Mutant NSCLC

Patients with treatment-naive HER2-mutant advanced non–small cell lung cancer (NSCLC) who received zongertinib (Hernexeos; Boehringer Ingelheim) reported improvements in physical functioning within 1 week of starting therapy, according to patient-reported outcome (PRO) data from the phase 1b Beamion LUNG-1 trial (NCT04886804).^1,2 Presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, improvements in physical functioning and NSCLC-related symptoms were observed to be sustained over time, and patients reported a low overall adverse effect (AE) burden.²

Beamion LUNG-1 is an open-label, multicenter, multicohort phase 1a/1b study, and this analysis included 71 adult patients unresectable or metastatic nonsquamous NSCLC harboring HER2 tyrosine kinase domain (TKD) mutations who had not received systemic therapy for advanced disease and who were treated with zongertinib 120 mg once daily.^1,3-5

In a news release, Joshua K. Sabari, MD, of NYU Langone Health's Perlmutter Cancer Center, noted that, for this population, understanding how treatment affects how patients “feel and function in daily life” is especially important, and that the findings further support zongertinib’s use in the first-line setting.²

Measuring the Patient Experience and AEs

In this analysis, the investigators assessed 4 PRO domains using validated instruments: physical functioning, the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) physical functioning scale, scored 0 to 100, with higher scores indicating better functioning; disease-related symptoms, the NSCLC Symptom Assessment Questionnaire (NSCLC-SAQ), a 7-item measure of cough, pain, dyspnea, fatigue, and appetite, with total scores ranging from 0 to 20 and lower scores indicating fewer symptoms; and both overall AE burden and symptomatic AEs.^1,2

The NSCLC-SAQ total score and EORTC QLQ-C30 physical functioning score are also secondary end points in the ongoing randomized phase 3 Beamion LUNG-2 trial (NCT06151574)⁶, which compares first-line zongertinib with standard treatment.

Physical functioning, as measured by the EORTC QLQ-C30, improved from baseline within the first week of treatment, and disease-related symptoms, as measured by the NSCLC-SAQ total score, also improved from baseline. Both improvements were sustained over the course of treatment.^1,2

Tolerability findings were consistent with the drug’s selective mechanism. Patients reported a low overall AE burden on the EORTC IL46/Q168, and most PRO-CTCAE–assessed symptomatic AEs were mild and in line with zongertinib's published safety data. Symptomatic AE Incidence was considered low.^1,2

Efficacy Behind the First-Line Approval

The PRO data build on efficacy results from the same cohort that supported the FDA's February 26, 2026, accelerated approval of zongertinib for adults with unresectable or metastatic nonsquamous NSCLC whose tumors have HER2 TKD-activating mutations, as detected by an FDA-authorized test.³ The expanded indication removed the prior requirement for previous systemic therapy.⁷

In the FDA efficacy population of 72 treatment-naive patients, the confirmed objective response rate (ORR) was approximately 76% (95% CI, 65%-85%). Additionally, 64% of responders had a duration of response (DOR) of at least 6 months, and 44% had a DOR of at least 12 months.³ In the published analysis of 74 patients from the first-line cohort, the confirmed ORR was also 76%, with a median DOR of 15.2 months and a median progression-free survival (PFS) of 14.4 months.⁵

The drug also demonstrated central nervous system activity. In a separate cohort of 30 patients with active brain metastases, the confirmed intracranial response rate was approximately 47%.⁵ Results in the first-line setting were consistent with earlier findings in previously treated disease, in which 75 patients who had not received a prior HER2-directed TKI had a confirmed ORR of 71%, a median DOR of about 14.1 months, and a median PFS of 12.4 months.⁷

For the approval, ORR and DOR were assessed by blinded independent central review per RECIST version 1.1. The review used the Real-Time Oncology Review pilot program, and the application was part of the FDA Commissioner’s National Priority Voucher pilot program, and it also received priority review and breakthrough therapy designation.³

Zongertinib is an oral, irreversible tyrosine kinase inhibitor designed to inhibit mutant HER2 while sparing wild-type EGFR, a selectivity that may limit the EGFR-associated diarrhea and rash seen with earlier pan-HER inhibitors.⁷ The recommended dose is weight-based and may be administered with or without food: Patients who weigh less than 90 kg are recommended to receive 120 mg once daily, and those weighing 90 kg or more may receive 180 mg once daily.³

Implications for Pharmacists

The PRO findings give pharmacists concrete information for counseling patients starting zongertinib, including the expectation that functional improvement may come early and that most symptomatic adverse effects are mild. They also reinforce the importance of encouraging patients to report symptoms promptly rather than wait for scheduled visits.^1,8

Low patient-reported burden does not reduce the need for laboratory and clinical monitoring. The prescribing information includes warnings for hepatotoxicity, left ventricular dysfunction, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.³

Pharmacists should verify that the pathology or next-generation sequencing report identifies a HER2 TKD-activating mutation, not HER2 protein overexpression or amplification alone; confirm the weight-based dose at each fill; monitor liver function tests at baseline (every 2 weeks for the first 12 weeks, and monthly thereafter as clinically indicated); counsel patients to report new cough, dyspnea, or fever, which warrant evaluation for interstitial lung disease/pneumonitis; establish an antidiarrheal plan at initiation; and screen for strong CYP3A inducers and breast cancer resistance protein substrates during medication reconciliation.⁷

REFERENCES

1. Sabari JK, et al. PRO results from the Beamion LUNG-1 trial in treatment-naive patients with HER2-mutant advanced NSCLC. J Clin Oncol. 2026;44(suppl 16):8616. doi:10.1200/JCO.2026.44.16_suppl.8616

2. Boehringer Ingelheim’s oncology portfolio shows strong promise across multiple cancers at ASCO 2026. News release. Boehringer Ingelheim. May 21, 2026. Accessed October 8, 2026. https://www.boehringer-ingelheim.com/us/human-health/cancer/across-cancer-types/boehringer-presents-data-across-oncology-portfolio-asco

3. FDA grants accelerated approval to zongertinib for unresectable or metastatic non-squamous non-small cell lung cancer. News release. FDA. February 26, 2026. Accessed October 8, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-unresectable-or-metastatic-non-squamous-non-small-cell

4. Beamion LUNG-1: a study to test different doses of zongertinib in people with different types of advanced cancer (solid tumours with changes in the HER2 gene). ClinicalTrials.gov identifier: NCT04886804. Updated October 5, 2026. Accessed October 8, 2026. https://clinicaltrials.gov/study/NCT04886804

5. Heymach JV, Yamamoto N, Girard N, et al. First-line zongertinib in advanced HER2-mutant non-small-cell lung cancer. N Engl J Med. 2026;394(17):1675-1684. doi:10.1056/NEJMoa2516969

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 identifier: NCT06151574. Updated October 1, 2026. Accessed October 8, 2026. https://clinicaltrials.gov/study/NCT06151574

7. Valletti D. Beyond the approval: operationalizing zongertinib for HER2-mutant lung cancer. Pharmacy Times. August 5, 2026. Accessed October 8, 2026. https://www.pharmacytimes.com/view/beyond-the-approval-operationalizing-zongertinib-for-her2-mutant-lung-cancer

8. 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