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. METHODS: This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) 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. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 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 pretreated 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.

Cancer Research Institute Seoul National University College of Medicine

Department of Investigational Cancer Therapeutics University of Texas MD Anderson Cancer Center Houston TX

Department of Medical Oncology Hospital Universitario 12 de Octubre Madrid Spain

Department of Medicine Weill Cornell Medical College New York NY

Department of Obstetrics and Gynecology Yonsei University College of Medicine Seoul South Korea

Department of Oncology Asan Medical Center University of Ulsan College of Medicine Seoul South Korea

Department of Oncology Palacký University Medical School and University Hospital Olomouc Czech Republic

Early Phase Clinical Trials Unit and Department of Soft Tissue Bone Sarcoma and Melanoma Maria Skłodowska Curie National Research Institute of Oncology Warsaw Poland

Experimental Therapeutics in Cancer Department of Medical Oncology Hospital Clínico San Carlos Madrid Spain

Gynaecologic Cancer Programme Vall d'Hebron Institute of Oncology Hospital Universitari Vall d'Hebron Vall d'Hebron Barcelona Hospital Campus Barcelona Spain

Gynaecology Unit The Royal Marsden NHS Foundation Trust and Institute of Cancer Research London United Kingdom

Gynecologic Medical Oncology Service Memorial Sloan Kettering Cancer Center New York NY

Healthcare Department Moscow City Oncology Hospital No 62 Moscow Russia

Integrated Major in Innovative Medical Science Seoul National University Graduate School Seoul South Korea

Medical Oncology Department and Programme in Solid Tumours CIMA Cancer Center Clínica Universidad de Navarra Madrid Spain

Niguarda Cancer Center Grande Ospedale Metropolitano Niguarda and the Department of Oncology and Hemato Oncology Università degli Studi di Milano Piazza dell'Ospedale Maggiore Milan Italy

Oncology R and D AstraZeneca Cambridge United Kingdom

Oncology R and D AstraZeneca Gaithersburg MD

Seoul National University Hospital

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