Effects of zongertinib on physical functioning and symptoms for patients with pretreated HER2-mutant advanced non-small cell lung cancer (NSCLC): Results from the Beamion LUNG-1 trial.

385 Background: Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing EGFR, thereby limiting associated toxicities. Beamion LUNG-1 (NCT04886804) is a Phase Ia/Ib first-in-human study evaluating safety and efficacy of zongertinib in patients with HER2-mutant advanced NSCLC (Phase Ib). We report PRO data on NSCLC-related symptoms, physical functioning, symptomatic adverse events (AEs) and their burden from Phase Ib Cohort 1. The PRO analysis included those with previously treated HER2-mutant NSCLC who received 120mg QD zongertinib. Methods: EORTC QLQ-C30 physical functioning, NSCLC-SAQ (cough, dyspnea, pain, fatigue and poor appetite), EORTC IL46/Q168 (side effect burden) and 9 PRO-CTCAE items (mouth and/or throat sores, taste changes, nausea, vomiting, diarrhea, rash, skin dryness, itching and numbness/tingling) were collected at days 1, 8, 15 (cycle [C] 1) and day 1 (C2, C3, C5, C7, C9). Change from baseline (CFB) to C5 in EORTC QLQ-C30 physical functioning (0-100, higher = better) and NSCLC-SAQ total score (0-20, lower = fewer symptoms) were analyzed using mixed model repeated measures. EORTC IL46 and PRO-CTCAE were analyzed descriptively. Results: The PRO analysis set comprised 30 patients. Completion rates exceeded 86% across PROs and visits. EORTC QLQ-C30 physical functioning and NSCLC-SAQ total scores improved rapidly and were maintained to C9; CFB to C5: LS means 9.6 (95% CI: 6.3, 12.9) and -3.9 (95%CI: -4.8, -2.9), respectively. Improvements in NSCLC-SAQ total score were observed for patients with objective response (complete/partial response) and for patients with stable disease as the best overall response. NSCLC-SAQ item scores improved: 3% reported often/always fatigue at C9, reduced from 43% at baseline (BL); 53% reported no coughing at C9, improved from 27% at BL and no patient reported severe coughing after C5; 3% reported often/always shortness of breath at C9, reduced from 23% at BL. Patients generally reported low overall side effect (SE) burden (EORTC IL46): 7% (BL), 3% (C5) and 0% (C9) were troubled with SE quite a bit/very much. Patient-reported AE frequency/severity (PRO-CTCAE items) reflected the known safety profile for zongertinib, with mostly mild/moderate severity and no/minimal interference. Diarrhea was the most common patient-reported symptomatic AE; reported as the lower categories rare/occasional for 13% (BL), 40% (C5), and 33% (C9). Rash occurred for 13% at BL, 37% at C5, and 10% at C9. Most dry skin AEs were mild/moderate (BL, 60%; C5, 57%; C9, 50%). Conclusions: Zongertinib-treated patients reported rapid improvement followed by stability in physical functioning and NSCLC-SAQ total score. Frequency and severity of patient-reported symptomatic AEs and overall side effect burden demonstrated favorable tolerability of zongertinib. Clinical trial information: NCT04886804 .