Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial

Purpose: Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small cell lung cancer. Treatments are limited for other HER2-expressing solid tumors. Patients and methods: This open-label phase II study evaluated T-DXd (5.4 mg/kg Q3W) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment, or without alternative treatments. Primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included safety, duration of response (DOR), progression-free (PFS), and overall survival (OS). Results: primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Median follow-up was 12.75 months. In all patients: ORR, 37.1% (n=99; 95% CI, 31.3-43.2) with responses in all cohorts; median DOR, 11.3 months (95% CI, 9.6-17.8); median PFS, 6.9 months (95% CI, 5.6-8.0); median OS, 13.4 months (95% CI, 11.9-15.5). In patients with central HER2 IHC 3+ expression (n=75): ORR, 61.3% (95% CI, 49.4-72.4); median DOR, 22.1 months (95% CI, 9.6-not reached); median PFS, 11.9 months (95% CI, 8.2-13.0); median OS, 21.1 months (95% CI, 15.3-29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths. Conclusion: Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pre-treated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.