Phase Ia/Ib trial of zongertinib (BI 1810631), a HER2-specific tyrosine kinase inhibitor (TKI), in patients (pts) with HER2 aberration-positive solid tumors: Updated Phase Ia data from Beamion LUNG-1, including progression-free survival (PFS) data.

8514 Background: Zongertinib, a novel HER2-specific TKI, binds selectively and covalently to the HER2 tyrosine kinase domain while sparing wild-type epidermal growth factor receptor. Beamion LUNG-1 (NCT04886804), a Phase Ia/Ib, first-in-human, open-label trial, is evaluating the safety and efficacy of zongertinib in pts with HER2 aberration-positive solid tumors (Phase Ia) and HER2 mutation-positive (m+) NSCLC (Phase Ib). We present updated Phase Ia data, including PFS data, and data from Phase Ib Cohort 1. Methods: Phase Ia enrolled pts with confirmed HER2 aberration-positive (gene mutations, rearrangements, amplification, or overexpression) advanced/unresectable/metastatic solid tumors, refractory to/unsuitable for standard treatment. Pts received escalating doses of zongertinib orally twice daily (BID; ≥15 mg) or once daily (QD; ≥60 mg), guided by a Bayesian model with overdose control. Phase Ib is recruiting pts with HER2 m+ advanced/metastatic NSCLC. Primary endpoint: MTD based on DLTs (Phase Ia), number of pts with DLTs during the MTD evaluation period (Phase Ia) and ORR (Phase Ib). Prespecified futility analysis was passed. Results: At data cut-off (Sept 15, 2023), 61 pts in Phase Ia received zongertinib at 15/30/60/100/150 mg BID (n = 3/3/4/4/3) and 60/120/180/240/300/360 mg QD (n = 5/4/9/12/10/4). Median treatment duration: 4.8 months (mos; range, < 1─18.7 mos). Treatment was ongoing in 35 pts at cut-off. Two DLTs were reported during the MTD evaluation period (grade G 3 decreased platelets 360 mg QD, G3 diarrhea 240 mg QD); the MTD was not reached for BID/QD schedules. Doses taken into optimization: 240/120 mg QD. TRAEs (all/G3/G4/G5): 72/10/0/0% of pts. One pt (2%) had serious TRAEs (G3 increased AST/ALT). In 53 evaluable pts, the ORR/DCR were 49/91%. ORR/DCR were 62/97% and 33/83% in evaluable pts with (n = 29) or without (n = 24) HER2 mutations. In 36 evaluable pts with NSCLC, the ORR/DCR were 58/97%. Overall median duration of response: 12.7 mos (95% CI: 4.2–12.7 mos). In all treated pts, median PFS was 8.7 mos (95% CI: 5.5 mos─not evaluable NE). In 36 evaluable pts with NSCLC, median PFS was NE (95% CI: 7.6 mos─NE). In a prespecified interim analysis of Phase Ib (July 31, 2023), 42 pts were treated in Cohort 1 (pretreated HER2 m+ NSCLC randomized to 120/240 mg QD). TRAEs (all/G3/G4/G5): 67/5/5/0%, most commonly diarrhea (G1/G2/G≥3; 24/5/0%). Serious TRAEs: 5% (n = 2; G4 decreased neutrophils, G4 immune thrombocytopenia). No AEs led to treatment discontinuation. ORR/DCR (n = 23): 73.9/91.3%. All responding pts remained on treatment at data cut-off. Conclusions: Zongertinib was well tolerated and demonstrated promising efficacy in pts with HER2 aberration-positive solid tumors, showing particular effectiveness in those with HER2-mutated NSCLC. Clinical trial information: NCT04886804 .