3025 Background: Safety and efficacy of HER2 tyrosine kinase inhibitor (TKI) and anti-HER2 antibody-drug conjugate (ADC) in HER2-mutant solid tumors have not been investigated. Methods: Mobocertinib, a potent HER2 TKI plus T-DM1, an anti-HER2 ADC was evaluated in this phase I study. In a dose-finding cohort (phase Ia, pIa), the maximum tolerated dose was estimated in patients (pts) irrespective of HER2 mutational status. To further establish safety and evaluate preliminary efficacy, additional pts with HER2 mutations were enrolled in a dose-expansion cohort (phase Ib, pIb). Mobocertinib of 80, 120 to 160 mg was orally administered with intravenous T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint was to determine the recommended dose (RD) (pIa), and to evaluate the confirmed objective response rate (ORR) (pIb). Results: Between Nov 2022 and Jun 2023, a total of 28 pts, 6 in the pIa and 22 in the pIb were enrolled to this study (14 NSCLC; 4 cervical; 2 duodenal papilla; 2 pancreatic, median follow-up, 6.4 mo [range, 1.9 to 12.9 mo]). The median age was 54 (range, 40-84) years, 17 pts were female. Among 27 pts with HER2-mutant tumors, mutations in kinase domain were most common (66.7%). In the pIa cohort, 3 DLTs were observed with mobocertinib 120 mg, including grade 3 thrombocytopenia, grade 4 acute kidney injury, and drug withdrawal due to nausea and anorexia, while there was no DLT with 80 mg. The RD was therefore determined to be mobocertinib 80 mg plus T-DM1 3.6 mg/kg. Among 22 pts in the pIb, grade ≥ 3 AE occurred in 72.7% of pts; the common events (>5%) being thrombocytopenia (50.0%), diarrhea (13.6%), and anorexia (13.6%). No interstitial lung disease/pneumonitis was observed. The ORR was 28.6%, the disease control rate (DCR) was 71.4%, and median progression-free survival (mPFS) was 3.2 mo (95% CI 1.6, 6.1) in the pIb. In 27 pts with HER2 mutations across all cohorts, the ORR was 42.3%, the DCR was 76.9%, and mPFS was 4.3 mo (95% CI 2.7, 6.7). Additionally, in 13 pts with HER2-mutant NSCLC including those who had developed resistance to trastuzumab deruxtecan, the ORR was 53.8%, the DCR was 84.6%, and mPFS was 6.1 mo (95% CI 2.9, 6.3). Conclusions: The RD of this study treatment is mobocertinib 80 mg plus T-DM1 3.6 mg. Combination therapy of HER2 TKI and HER2 ADC demonstrated feasibility and potential efficacy for HER2-mutant solid tumors. Clinical trial information: 2051220070 .