Patient-Reported Outcomes Highlight Favorable Tolerability of Zongertinib in HER2-Mutant NSCLC: Insights From the Beamion LUNG-1 Trial

Zongertinib, an irreversible tyrosine kinase inhibitor, selectively targets HER2 while sparing EGFR, thereby limiting associated toxicities. The phase Ia/IIb Beamion LUNG-1 trial (NCT04886804) assessed the safety and efficacy of zongertinib in HER2-mutant advanced non–small cell lung cancer (NSCLC). Quality of life was also evaluated in this study through patient-reported outcomes (PROs) from phase Ib, cohort 1, including physical functioning, NSCLC-related symptoms, and side effect burden.

The PRO analysis included 30 patients from cohort 1 who were previously treated (antibody–drug conjugates not permitted), had HER2-mutant NSCLC, and who received 120 mg zongertinib once daily. PROs were assessed using multiple instruments: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) physical functioning scale, the Non–Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ), the EORTC IL46/Q168, and 9 items from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events including mouth/throat sores, taste changes, nausea, vomiting, diarrhea, rash, skin dryness, itching, and numbness/tingling. Assessments were conducted at multiple time points during the 3-week cycles, including cycle 1 (days 1, 8, and 15) and day 1 of the subsequent cycles (cycles 2, 3, 5, 7, and 9).

Longitudinal analysis demonstrated significant and sustained improvements in physical functioning and symptom burden. From baseline to cycle 5, the least-square (LS) mean changes were 9.6 (95% confidence interval [CI], 6.3-12.9) and to cycle 9, 7.8 (95% CI, 3.2-12.5) on the EORTC QLQ-C30 physical functioning scale, where higher scores indicate better functioning. Most patients showed rapid improvement or maintained stable physical functioning compared with baseline. Peak improvement was observed at cycle 5, where 53.3% of patients experienced meaningful improvement. Forty percent of patients showed overall improvement, over two-thirds remained stable or improved, and only a small proportion experienced a deterioration.

The LS mean change in the NSCLC-SAQ total score from baseline was –3.9 (95% CI, –4.8- –2.9), where lower scores reflect symptom reduction. Overall, one-third of patients showed improved total scores across all post-baseline visits, with the highest improvement observed at cycle 5. At cycle 5, 60% of patients experienced meaningful symptom relief, consistent with the mixed model for repeated measures analysis results. Over 50% of patients reported "no coughing at all" at cycles 5 and 9, doubling baseline levels. Dyspnea responses showed a 30% and 10% increase in patients reporting "never/rarely" at cycles 5 and 9, respectively.

Patients reported a low overall side effect burden with zongertinib, as assessed by the EORTC IL46, with 80 to 90% of patients indicating "not at all" or "a little" trouble with side effects throughout the treatment period. The proportion of patients reporting side effects as “quite a bit” or “very much” remained low, with only a transient increase to 10% at cycle 1, day 15. The PRO-CTCAE analysis showed that 50% of patients reported "never" experiencing diarrhea after starting treatment (post-baseline), compared with 83.3% at baseline. Among those reporting diarrhea, the majority classified it as "rarely" or "occasionally," reflecting expected toxicity profiles. Few patients reported high severity or interference from any adverse events, consistent with zongertinib's favorable tolerability profile.

These findings indicate that zongertinib provides a favorable tolerability profile in HER2-mutant advanced NSCLC. Patients experienced rapid and sustained improvements in physical functioning and symptom burden, while side effect severity and burden remained low. These patient-reported outcomes further underscore the clinical potential of zongertinib as a HER2-targeted therapy.

Sources:

Sabari JK, 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. Presented at: 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. May 3, 2025; Chicago, IL. Poster presentation.