ADC Innovations With T-DXd/Sacituzumab Govitecan in Breast Cancer

Kit Yu Lu, MD, discusses the applications of T-DXd and sacituzumab govitecan for patients with breast cancer.

The landscape of breast cancer treatment is undergoing a significant evolution marked by the emergence of sophisticated targeted therapies. Among these options, antibody-drug conjugates (ADCs) like fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and sacituzumab govitecan-hziy (Trodelvy) are demonstrating remarkable efficacy in challenging subtypes such as hormone receptor (HR)–positive and HER2-negative disease.

To gain a deeper understanding of the clinical implications and optimal utilization of these ADCs, CancerNetwork® spoke with Kit Yu Lu, MD, about the impact of agents like T-DXd across various lines of therapy while exploring the data that underscore their place in the field.

Furthermore, Lu highlighted the significant role of sacituzumab govitecan. She also shed light on the unique mechanism of action and the pivotal trial results that have established the value of ADCs for patients with limited prior treatment options.

Lu is an oncology/hematology oncologist and specializes in breast cancer at the University of Pittsburgh Medical Center.

CancerNetwork: What specific patient characteristics or disease progression patterns might prompt earlier consideration of T-DXd or sacituzumab govitecan?

For our patients with HR-positive, HER2-negative metastatic breast cancer, I would consider sacituzumab govitecan appropriate for those who have progressed through their endocrine therapy, targeted therapy, and 1 to 2 lines of standard chemotherapy.

How should clinicians interpret and act upon somatic BRCA mutations identified through liquid biopsies in the context of treatment selection for this patient population?

There are limited data regarding the use of the PARP inhibitors in somatic BRCA mutations. In smaller studies, there’s been some effectiveness in using PARP inhibitors, but most of our data are on germline mutations. I typically recommend discussing the risks and benefits with patients and following our standard guidelines in regards to PARP inhibitor use in the context of clinical trials.

How do the efficacy and safety profiles of sacituzumab govitecan, T-DXd, and datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) compare in the treatment of HR–positive/HER2-negative breast cancer based on recent trial data?

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, adverse effect [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.

Considering the phase 3 TROPiCS-02 (NCT03901339) and the phase 3 DESTINY-Breast06 (NCT04494425) trial data, what are the key takeaways regarding the sequencing of ADCs?

Destiny-Breast06 has now shown that you can use T-DXd in the first-line setting after a patient has become endocrine refractory. In that trial, it showed that T-DXd was better in terms of progression-free survival compared with standard first-line chemotherapy. What we don’t know is how that will fare if it’s compared head-to-head with sacituzumab govitecan. The current guidelines and standards are that we can utilize T-DXd in the first-line setting. Whereas in TROPiCS-02, [treatment] was after endocrine therapy progression and 1 to 2 lines of chemotherapy. Unfortunately, right now, the only indication we have is at least 1 [prior] line of chemotherapy for sacituzumab govitecan.

For patients progressing on CDK4/6 inhibitors, what factors influence the decision-making process on utilizing T-DXd vs sacituzumab?

Some of that could [depend on] the level of estrogen receptor [ER] expression. If we have high ER-positive [expression], most of us will probably follow the standard algorithm of endocrine therapy, CDK4/6 inhibitor, targeted therapy, and then continue to chemotherapy and our ADCs. In very low ER-expressing subtypes, potentially, we tend to treat this more like a triple-negative disease. HER2 expression also factors in when we decide T-DXd vs sacituzumab govitecan. T-DXd is now indicated for patients with HER2-low and HER2-ultralow [disease]. For sacituzumab govitecan, it’s [indicated] for all HER2-negative [disease], including HER2-low and HER2 [score of] 0. Some of those factors are taken into consideration.

Looking ahead, what are the next steps for this patient population?

We need to know the sequencing data and the effectiveness of ADC after ADC. It would also be interesting to see combination therapy with these ADCs and perhaps immunotherapy or other targeted agents. [We should also] look into more novel types of ADCs with different antibodies or chemotherapy backbones.

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 14, 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 14, 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 14, 2025. https://tinyurl.com/3t5xbjnr