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.

John Heymach Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center,, Houston, TX info_outline John Heymach, Frans Opdam, Minal A. Barve, Hai-Yan Tu, Yi-Long Wu, David Berz, Maren Rohrbacher, Behbood Sadrolhefazi, Josep Serra, Kiyotaka Yoh, Noboru Yamamoto

Authors John Heymach Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center,, Houston, TX info_outline John Heymach, Frans Opdam, Minal A. Barve, Hai-Yan Tu, Yi-Long Wu, David Berz, Maren Rohrbacher, Behbood Sadrolhefazi, Josep Serra, Kiyotaka Yoh, Noboru Yamamoto Organizations Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center,, Houston, TX, Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands, Mary Crowley Cancer Research Center, Dallas, TX, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China, Valkyrie Clinical Trials, Inc, Los Angeles, CA, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an Der Riss, Germany, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, Boehringer Ingelheim España S.A., Barcelona, Spain, National Cancer Center Hospital East, Kashiwa, Japan, Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan Abstract Disclosures Research Funding Boehringer Ingelheim 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 .