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.

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

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; Cancer Research Institute Seoul National University College of Medicine; Integrated Major in Innovative Medical Science Seoul National University Graduate School Seoul South Korea

Cancer Discov. 2023 Dec 12;13(12):OF10. doi: 10.1158/2159-8290.CD-ND2023-0013. PubMed

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Najjar MK, Manore SG, Regua AT, et al. : Antibody-drug conjugates for the treatment of HER2-positive breast cancer. Genes (Basel) 13:2065, 2022 PubMed PMC

Yan M, Schwaederle M, Arguello D, et al. : HER2 expression status in diverse cancers: Review of results from 37,992 patients. Cancer Metastasis Rev 34:157-164, 2015 PubMed PMC

Slamon DJ, Clark GM, Wong SG, et al. : Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-182, 1987 PubMed

Xing F, Gao H, Chen G, et al. : CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer. Mol Cancer 22:6, 2023 PubMed PMC

Oh D-Y, Bang Y-J: HER2-targeted therapies – a role beyond breast cancer. Nat Rev Clin Oncol 17:33-48, 2020 PubMed

Owen DH, Singh N, Ismaila N, et al. : Therapy for stage IV non–small-cell lung cancer with driver alterations: ASCO living guideline, version 2022.2. J Clin Oncol 41:e10-e20, 2023 PubMed

Shah MA, Kennedy EB, Alarcon-Rozas AE, et al. : Immunotherapy and targeted therapy for advanced gastroesophageal cancer: ASCO guideline. J Clin Oncol 41:1470-1491, 2023 PubMed

Giordano SH, Franzoi MA, Temin S, et al. : Systemic therapy for advanced human epidermal growth factor receptor 2–positive breast cancer: ASCO guideline update. J Clin Oncol 40:2612-2635, 2022 PubMed

Cervantes A, Adam R, Roselló S, et al. : Metastatic colorectal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 34:10-32, 2023 PubMed

Diver E J, Foster R, Rueda BR, et al. : The therapeutic challenge of targeting HER2 in endometrial cancer. Oncologist 20:1058-1068, 2015 PubMed PMC

Gadducci A, Cosio S: Pharmacological treatment of patients with metastatic, recurrent or persistent cervical cancer not amenable by surgery or radiotherapy: State of art and perspectives of clinical research. Cancers (Basel) 12:2678, 2020 PubMed PMC

Siegel RL, Miller KD, Fuchs HE, et al. : Cancer statistics, 2022. CA Cancer J Clin 72:7-33, 2022 PubMed

Tariq NU, McNamara MG, Valle JW: Biliary tract cancers: Current knowledge, clinical candidates and future challenges. Cancer Manag Res 11:2623-2642, 2019 PubMed PMC

Ogitani Y, Aida T, Hagihara K, et al. : DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res 22:5097-5108, 2016 PubMed

US Food and Drug Administration (FDA) : ENHERTU (fam-trastuzumab deruxtecan-nxki): Highlights of prescribing information (PI). 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761139s024lbl.pdf

European Medicines Agency (EMA) : ENHERTU (trastuzumab deruxtecan): Summary of product characteristics (SmPC) [Internet]. 2023. https://www.ema.europa.eu/en/documents/product-information/enhertu-epar-product-information_en.pdf

Daiichi Sankyo : Press release. ENHERTU® approved in Japan as first HER2 directed therapy for patients with HER2 mutant metastatic non-small cell lung cancer. 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202308/20230823_E.pdf

Tsurutani J, Iwata H, Krop I, et al. : Targeting HER2 with trastuzumab deruxtecan: A dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov 10:688-701, 2020 PubMed PMC

Daiichi Sankyo : Press release. ENHERTU® granted two breakthrough therapy designations in U.S. for patients across multiple HER2 expressing cancers. 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202308/20230831_E2.pdf

Oken MM, Creech RH, Tormey DC, et al. : Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-656, 1982 PubMed

Bartley AN, Washington MK, Ventura CB, et al. : HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: Guideline from the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med 140:1345-1363, 2016 PubMed

Schwartz LH, Litière S, de Vries E, et al. : RECIST 1.1—Update and clarification: From the RECIST committee. Eur J Cancer 62:132-137, 2016 PubMed PMC

Omar N, Yan B, Salto-Tellez M: HER2: An emerging biomarker in non-breast and non-gastric cancers. Pathogenesis 2:1-9, 2015

Stinchcombe T, Monk BJ, Okines AF, et al. : SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations (trial in progress). J Clin Oncol 39, 2021. (suppl 15; abstr TPS3151)

Taniguchi H, Yagisawa M, Satoh T, et al. : Tissue-agnostic efficacy of trastuzumab deruxtecan (T-DXd) in advanced solid tumors with HER2 amplification identified by plasma cell-free DNA (cfDNA) testing: Results from a phase 2 basket trial (HERALD/EPOC1806). J Clin Oncol 41, 2023. (suppl 16; abstr 3014) PubMed PMC

Erickson BK, Zeybek B, Santin AD, et al. : Targeting human epidermal growth factor receptor 2 (HER2) in gynecologic malignancies. Curr Opin Obstet Gynecol 32:57-64, 2020 PubMed PMC

Lamarca A, Palmer DH, Wasan HS, et al. : Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): A phase 3, open-label, randomised, controlled trial. Lancet Oncol 22:690-701, 2021 PubMed PMC

Ohba A, Morizane C, Kawamoto Y, et al. : Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): An investigator-initiated multicenter phase 2 study (HERB trial). J Clin Oncol 40, 2022. (suppl 16; abstr 4006) PubMed

Swain SM, Nishino M, Lancaster LH, et al. : Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis—Focus on proactive monitoring, diagnosis, and management. Cancer Treat Rev 106:102378, 2022 PubMed

Rugo HS, Bianchini G, Cortes J, et al. : Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer. ESMO Open 7:100553, 2022 PubMed PMC

Powell CA, Modi S, Iwata H, et al. : Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open 7:100554, 2022 PubMed PMC

Tateo V, Marchese PV, Mollica V, et al. : Agnostic approvals in oncology: Getting the right drug to the right patient with the right genomics. Pharmaceuticals (Basel) 16:614, 2023 PubMed PMC

Incidental germline findings during comprehensive genomic profiling of pancreatic and colorectal cancer: single-centre, molecular tumour board experience

Expanding horizons in a new era for pathology: perspectives from the ASCO meeting

Efficacy of Trastuzumab Deruxtecan in HER2-Expressing Solid Tumors by Enrollment HER2 IHC Status: Post Hoc Analysis of DESTINY-PanTumor02

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