Trastuzumab-deruxtecan in solid tumors with HER2 alterations: from early phase development to the first agnostic approval of an antibody–drug conjugate

ABSTRACT

Introduction

Antibody–drug conjugates (ADCs) represent a revolutionary approach in the systemic treatment for both solid and hematologic tumors. Constituted by an antibody, a cytotoxic payload, and a linker, ADCs aim to selectively deliver cytotoxic agents to tumors while sparing normal tissues. Various ADCs have been tested and approved for multiple solid tumors so far, but if there is one that had a major impact on clinical practice, this is Trastuzumab-deruxtecan (T-DXd). Notably, T-DXd was approved for HER2-positive and HER2-low metastatic breast cancer (MBC), HER2-positive gastric cancer (GC), HER2-mutant non-small cell lung cancer (NSCLC) and HER2 3+ solid tumors. Moreover, it received Breakthrough Therapy Designation for HER2-positive colorectal cancer (CRC).

Areas covered

We review preclinical and clinical data of T-DXd, focusing on early-phase ongoing trials exploring combination therapies to enhance the activity of T-DXd in HER2-expressing solid tumors.

Expert opinion

The clinical use of T-DXd still raises questions about selection of patients, treatment duration, prioritization over other approved ADCs, and management of resistance. Concerns regarding the toxicity of T-DXd remain, particularly with combinations involving potentially toxic drugs. Advancements in biomarker identification and combination therapies offer promising avenues to enhance efficacy and overcome resistance to T-DXd, ultimately improving outcomes for patients with cancer.

KEYWORDS:

• HER2
• trastuzumab-deruxtecan
• clinical trial
• drug development
• antibody–drug conjugates
• agnostic treatment
• precision oncology
• breast cancer

Article highlights

• Antibody–drug conjugates are redefining the treatment paradigm of solid tumors.

• Trastuzumab-Deruxtecan is the first antibody–drug conjugate to obtain agnostic approval for HER2+ tumors.

• Combining Trastuzumab-Deruxtecan with other anticancer agents is gaining a great deal of interest.

• Questions about patients selection, treatment duration, prioritization, and management of resistance remain.

• Efforts are still required to optimize the use of Trastuzumab-Deruxtecan in clinical practice.

Declaration of interest

G Curigliano reports personal fees from Daichii Sanlyo, Astra Zeneca, Gilead, Lilly, Pfizer, Novartis, Menarini, Roche, Exact Sciences, and BluePrint outside the submitted work. E Crimini is supported by Fondazione IEO-Monzino. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors thank all the supporters of European Institute of Oncology through the 5 × 1000 financing.

Additional information

Funding

This paper was not funded.