Comparing ADCs in HR+/HER2– Breast Cancer Without Head-to-Head Trials

The advent of multiple antibody-drug conjugates (ADCs) has significantly altered the therapeutic landscape for patients with metastatic hormone receptor–positive, HER2-negative breast cancer. Agents such as sacituzumab govitecan-hziy (Trodelvy), fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), and the recently approved datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) have demonstrated promising efficacy in this setting. However, a critical challenge facing clinicians is the lack of direct comparative data between these agents, making treatment sequencing decisions complex.

In a recent interview with CancerNetwork®, Kit Yu Lu, MD, an oncology/hematology oncologist who specializes in breast cancer at the University of Pittsburgh Medical Center, addressed the difficulties in comparing the efficacy and safety profiles of these 3 ADCs based on available trial data.

Lu highlighted the fundamental issue of the absence of head-to-head clinical trials directly comparing sacituzumab govitecan, T-DXd, and Dato-DXd in the HR-positive/HER2-negative metastatic breast cancer population. This lack of direct comparison makes it challenging to extrapolate and perform cross-trial comparisons to definitively rank their efficacy. As Lu noted, this represents a significant dilemma in the current clinical practice.

Regarding standard indications, T-DXd gained approval for use in the first-line setting based on the phase 3 DESTINY-Breast04 trial (NCT03734029), while sacituzumab govitecan and dato-DXd, supported by the phase 3 TROPiCS-02 trial (NCT03901339) and the phase 3 TROPION-Breast01 (NCT05104866), respectively, are indicated for subsequent lines of therapy. The optimal sequencing and relative efficacy of these agents in different lines of treatment remain areas of ongoing investigation.

Lu pointed out that sacituzumab govitecan, T-DXd, and dato-DXd each have distinct adverse effect (AE) profiles, tolerability considerations, and infusion schedules. Therefore, a comprehensive assessment of these factors is crucial when determining which ADC to initiate and how to sequence them in subsequent lines of therapy.

Transcript:

We do not have head-to-head comparisons between the 3 [agents], so it’s hard to extrapolate and do cross-trial comparisons. This is the current dilemma in our field today. In terms of the standard indications, we now have an indication for T-DXd approved for the first-line setting, and then we have sacituzumab govitecan and dato-DXd for subsequent lines of therapy.1-3 The sequencing and efficacy of the data remain unknown. However, most of us in the field continue to try to give our patients the best treatment possible. We certainly have offered additional ADCs. In terms of how we choose which ADC to initiate, some of that has to do with what the current guidelines dictate, and the lines of therapy the patients had. In addition, AE profiles will be important. All these ADC agents have different AE profiles, tolerability, and scheduling of infusion, so we take all of that into consideration when we think about which ADC to prescribe first and then [for] subsequent lines of therapy.

References

1. Enhertu approved in the US as first HER2-directed therapy for patients with HER2-low or HER2-ultralow metastatic breast cancer following disease progression after one or more endocrine therapies. News release. FDA. January 27, 2025. Accessed May 19, 2024. https://tinyurl.com/5n8ab8sk
2. U.S FDA approves Trodelvy in pre-treated HR+/HER2- metastatic breast cancer. News release. Gilead. February 3, 2023. Accessed May 19, 2025. https://bwnews.pr/3Y0bftX
3. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic HR-positive, HER2-negative breast cancer. News release. FDA. January 17, 2025. Accessed May 19, 2025. https://tinyurl.com/3t5xbjnr