Toxicity Profiles of Antibody–Drug Conjugates: Synthesis and Graphical Insights to Optimize Patient-Centered Treatment Strategies for HER2-Negative Metastatic Breast Cancer

TL;DR

This paper compares the toxicity profiles of two antibody-drug conjugates for HER2-negative metastatic breast cancer to help guide patient-centered treatment decisions.

Contribution

The study provides a graphical synthesis of toxicity data from pivotal trials to support shared decision-making in ADC treatment selection.

Findings

T-DXd showed high rates of nausea, fatigue, and neutropenia, with pneumonitis occurring in 10.7% of cases.

SG had higher rates of neutropenia and diarrhea, with grade ≥ 3 neutropenia in 51.3% of patients.

Graphical tools were developed to compare adverse events and support patient-centered treatment strategies.

Abstract

The advent of antibody–drug conjugates (ADCs) has reshaped the treatment landscape for HER2-negative metastatic breast cancer through their targeted cytotoxic delivery. Trastuzumab deruxtecan (T-DXd) and Sacituzumab govitecan (SG) have shown their efficacy but come with distinct toxicity profiles, including conventional adverse events, such as hematologic and digestive toxicity, and ADC-specific adverse events like pneumonitis for T-DXd. With a growing pipeline of ADCs and limited head-to-head or sequencing data, treatment choices may become increasingly complex. In clinical scenarios where both T-DXd and SG are treatment options, understanding and comparing their safety profiles is key to guiding shared decision-making. Decision-support tools synthesizing efficacy and toxicity data are essential to help oncologists and patients select the most appropriate ADC for each clinical situation.

Background: The treatment options for HER2-negative metastatic breast cancer include targeted therapies, cytotoxic chemotherapies, and immunotherapy. However, limited specificity and inevitable resistance highlight the need for novel agents. Antibody–drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), represent a breakthrough by selectively delivering cytotoxic agents to tumor cells, potentially improving the therapeutic index. Despite demonstrated efficacy, ADCs present toxicity profiles similar to conventional chemotherapy, alongside unique adverse events. In clinical practice, oncologists may face scenarios where both T-DXd and SG are treatment options in HER2-negative mBC. To enable shared decision-making, it is crucial to present a comprehensive overview that includes both efficacy data and detailed toxicity profiles. Our objective was to provide a pooled and informative synthesis of toxicities from pivotal studies, including graphical representations, to support informed, patient-centered medical decisions. Methods: We reviewed safety data from phase 3 clinical trials in HER2-negative mBC: DESTINY-Breast04/DESTINY-Breast06 for T-DXd and ASCENT/TROPICS-02 for SG. Adverse event (AE) profiles, including frequency and severity, were extracted, and weighted means were calculated. Emerging ADCs such as datopotamab deruxtecan and patritumab deruxtecan were considered to contextualize future therapeutic decisions. Results: Tables, bar plots and radar plots were generated. T-DXd demonstrated high rates of nausea (69.2%), fatigue (47.2%), and neutropenia (35.6%), with 52.7% experiencing grade ≥ 3 AEs. Notably, pneumonitis occurred in 10.7%, with grade ≥ 3 in 2.6%. SG showed a distinct AE profile, with higher incidences of neutropenia (67.1%), with grade ≥ 3 in 51.3%, and diarrhea (60.8%). Conclusions: The choice between ADCs in HER2-negative metastatic BC when both T-DXd and SG are treatment options should consider toxicity profiles to optimize patient-centered treatment strategies. Tailoring ADC selection based on individual tolerance and preferences is critical for shared decision-making, and future research should focus on assessing the utility and acceptability of such clinical tools to guide treatment selection.

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