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Opportunities and Challenges for a Histology-Agnostic Utilization of Trastuzumab Deruxtecan

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Abstract

Purpose of Review

This review delves into the prospects and challenges offered by a potential pan-histological utilization of trastuzumab deruxtecan (T-DXd) in patients with advanced solid tumors.

Recent Findings

The HER2-targeted antibody-drug conjugate (ADC) T-DXd has shown broad activity across cancer types, with current indications for patients with biomarker-selected breast, gastric, and non-small-cell lung cancer and relevant activity observed in multiple histology-specific trials. Moreover, two recently reported phase 2 trials (DESTINY-Pantumor02 and HERALD) have supported the potential for a pan-cancer utilization of this ADC in patients with advanced cancers expressing HER2 or with HER2 amplifications.

Summary

By improving the delivery of cytotoxic chemotherapy, ADCs have allowed for meaningful clinical advantages in broad populations of cancer patients, often leading to survival advantages over conventional chemotherapy. Notably, the broad spectrum of activity of certain ADCs has led to the hypothesis of a histology-agnostic utilization based on detecting specific biomarkers, similar to what is already established for certain targeted treatments and immunotherapy. To date, T-DXd has shown the broadest activity across cancer types, with current approvals in breast, gastric, and lung cancer, and relevant antitumor activity observed in a multiplicity of additional cancer types. The optimization of the drug dose, identification of predictive biomarkers, and clarification of mechanisms of resistance will be critical steps in view of a pan-histological expansion in the use of T-DXd.

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Authors and Affiliations

  1. Rochester General Hospital, Rochester, NY, USA

    Niraj Neupane

  2. Westchester Medical Center, New York Medical College, New York, NY, USA

    Sangharsha Thapa

  3. Institute of Medicine, Tribhuvan University, Kathmandu, Nepal

    Abhinav Bhattarai

  4. Medical Database, Irvine, CA, USA

    Abhinav Bhattarai

  5. Internal Medicine, John H Stroger Hospital of Cook County, Chicago, IL, USA

    Kriti Ahuja

  6. Division of Hematology and Oncology, Tufts Medical Center, Boston, MA, USA

    Ilana Schlam

  7. Tufts University, Boston, MA, USA

    Ilana Schlam

  8. Health Sciences North, Northern Ontario School of Medicine, Sudbury, ON, Canada

    Abhenil Mittal

  9. Breast Oncology Program, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    Sara M. Tolaney & Paolo Tarantino

  10. Harvard Medical School, Boston, MA, USA

    Sara M. Tolaney & Paolo Tarantino

  11. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Paolo Tarantino

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Conflict of Interest

SMT has served as an advisor/consultant to Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, Odonate Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, Certara, Chugai Pharma, Ellipses Pharma, Infinity, 4D Pharma, OncoSec Medical Inc., BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, and ARC Therapeutics, and has received institutional research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Odonate Therapeutics, Sanofi, and Seattle Genetics. PT served as advisor/consultant for AstraZeneca, Daiichi Sankyo, Gilead, Genentech, Roche, and Eli Lilly. All other authors report no conflicts of interest to disclose.

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Neupane, N., Thapa, S., Bhattarai, A. et al. Opportunities and Challenges for a Histology-Agnostic Utilization of Trastuzumab Deruxtecan. Curr Oncol Rep 25, 1467–1482 (2023). https://doi.org/10.1007/s11912-023-01469-3

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