Background: Currently, limited targeted therapies are available for HER2 mutant NSCLC patients. Previous studies have shown the antitumor activity of pyrotinib in advanced NSCLC patients with HER2 mutations. Inetetamab is a recombinant humanized anti-HER2 monoclonal antibody. Whether inetetamab combined with pyrotinib could show manageable safety and more active antitumor activity remains unknown. This study was designed to evaluate the safety and efficacy of inetetamab in combination with pyrotinib in HER2 mutant patients with advanced NSCLC. Methods: This study was an open-label, phase Ib study. The HER2 mutant patients with locally advanced or metastatic NSCLC were assigned to receive inetetamab combined with pyrotinib. The study consisted of dose-escalation part and dose-expansion part. During dose-escalation period, the parallel "3+3" dose-escalation design was used to determine the dose-limiting toxicity (DLT). Inetetamab was administered every 3 weeks (8 mg/kg loading dose for cycle 1, followed by 6 mg/kg in subsequent cycles) with pyrotinib (dose-escalation part, 240mg QD, 320mg QD; dose-expansion part, 320mg QD). Primary endpoint of the study was DLT dosage and safety. The DLT was assessed during the 21-day DLT evaluation period after the first dose. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression free survival and overall survival. Results: Between August 6, 2021, and August 25, 2022, 48 patients were enrolled. No DLT occurred during pyrotinib 240mg and 320mg escalation period. Therefore, pyrotinib 320mg was chosen as expansion dose. The most common treatment-related adverse events (TRAEs) were diarrhea (66.7% [2/3] in pyrotinib 240mg group, 95.6% [43/45] in pyrotinib 320mg group), rash (66.7% [2/3] in pyrotinib 240mg group, 22.2% [10/45] in pyrotinib 320mg group) and vomiting (0 in pyrotinib 240mg group, 24.4% [11/45] in pyrotinib 320mg group). TRAEs were generally Grade (G) 1-2. Only 7 patients reported G3 TRAE (1 in pyrotinib 240mg group, 6 in pyrotinib 320mg group). The preliminary efficacy was shown in the table below. The ORR and DCR of group receiving inetetamab with pyrotinib 240mg were 0% and 66.7%, respectively. The ORR and DCR of inetetamab with pyrotinib 320mg group were 36.6% and 85.4% respectively. The relationship between different mutation subtypes or co-mutations and efficacy will be updated during the conference reports. Conclusions: The preliminary data of inetetamab in combination with pyrotinib showed manageable safety and compelling antitumor activity in advanced NSCLC patients harboring HER2 mutations. Clinical trial information: NCT05016544.