Abstract 7197: Targeting FAK exhibits therapeutic effects on interstitial lung disease induced by trastuzumab deruxtecan

Abstract Interstitial lung disease (ILD) is a common pulmonary complication associated with cancer therapy. Several antibody-drug conjugates (ADCs), including trastuzumab deruxtecan (Enhertu), have been implicated in the induction of ILD, thereby limiting their clinical application. Treatment with ADCs must be permanently discontinued if grade 2 or higher ILD-related adverse effects occur. The standard approach for managing Enhertu-induced ILD involves the use of corticosteroids, which can exacerbate the toxicities faced by cancer patients. Our previous studies demonstrated that targeting focal adhesion kinase (FAK) enhances the efficacy of Enhertu and other ADCs in solid tumor treatment. Notably, we have now identified that FAK inhibition by the small molecule inhibitor Ifebemtinib (aka IN10018, Ifebe) can mitigate Enhertu-induced ILD. In an animal model of Enhertu-induced ILD, Ifebe showed recovery trends comparable to those observed with corticosteroids across multiple physiological parameters of mouse respiration. Both inflammatory and ILD injury biomarkers which were activated by Enhertu were significantly reduced with Ifebe monotherapy. Collectively, the combination of FAK inhibition and Enhertu may offer improved therapeutic efficacy while mitigating ILD-related toxicities. These findings warrant further clinical investigation. Citation Format: Baoyuan Zhang, Ran Pang, Jingwen Cheng, Jiaming Gao, Natasha Qin, Leo Liu, Zaiqi Wang. Targeting FAK exhibits therapeutic effects on interstitial lung disease induced by trastuzumab deruxtecan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7197.