A Phase 2, Multicenter, Open-Label Study Evaluating Trastuzumab Deruxtecan (T-Dxd) for the Treatment of Solid Tumors Harboring Specific HER2-activating Mutations (Destiny-Pantumor01).

TPS3162 Background: There are substantial data suggesting that a subset of human epidermal growth factor receptor 2 (HER2)–activating mutations induce ligand-independent constitutive HER2 signaling and promote oncogenesis. Direct therapeutic targeting of HER2 has transformed the treatment of patients with HER2-overexpressing breast and gastric cancers. However, currently no targeted treatments are approved for patients with tumors harboring HER2-activating mutations. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload that may be selectively internalized in tumors with HER2 mutations (Li BT, et al. Cancer Discov. 2020;10:674-687). In a phase 1 study (DS8201-A-J101), T-DXd demonstrated preliminary antitumor activity in patients with tumors harboring HER2 mutations, with confirmed responses observed in 9 of 19 patients (47.4%) (Tsurutani J, et al. Cancer Discov. 2020;10:688-701). Here we describe the DESTINY-PanTumor01 trial (NCT04639219). Methods: DESTINY-PanTumor01 is an open-label, multicenter, single-arm, phase 2 study evaluating T-DXd for the treatment of patients with unresectable and/or metastatic solid tumors (excluding non-small cell lung cancer) harboring prespecified HER2-activating mutations. Patients (N≈100) are required to have progressed following prior treatment for advanced or metastatic disease or have no satisfactory alternative treatment options. Prior HER2-targeting therapy is allowed. HER2 mutation status will be determined locally using next-generation sequencing or a validated nucleic acid–based methodology. The primary endpoint is confirmed objective response rate according to independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include duration of response, disease control rate, progression-free survival, investigator-assessed confirmed objective response rate, overall survival, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT04639219.