Beyond HER2: The Rise of Antibody-Drug Conjugates in Breast Cancer Treatment

Tanya Gupta, MD

The current landscape of antibody-drug conjugates (ADCs) for breast cancer is expanding beyond just in HER2-positive disease.

Currently approved ADCs in this space include ado-trastuzumab emtansine (T-DM1; Kadcyla) in HER2-positive disease, which was the first to be approved in 2013; fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), which gained accelerated approval from the FDA for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who had received 2 or more prior HER2-targeted therapies in the metastatic setting; and sacituzumab govitecan (Trodelvy), which is approved for both patients with advanced triple-negative breast cancer who have received 2 or more prior systemic therapies, at least 1 of which was in the metastatic setting, and in hormone receptor (HR)-positive/HER2-negative advanced disease given prior endocrine therapy and at least 2 additional systemic therapies.

While T-DM1 remains a mainstay for HER2-positive settings, these newer ADCs like T-DXd and sacituzumab govitecan have shown to have immense improvements in outcomes for patients. Further, a new ADC, datopotamab deruxtecan (Dato-DXd; DS-1062a), is showing promise for those with HR-positive, HER2-advanced disease who had received 1 to 2 prior lines of chemotherapy, as well as in other disease states.

“The field of ADCs in breast cancer is a very exciting area,” Tanya Gupta, MD, told Targeted Oncology^TM in an interview. “In particular, we are very excited to see more about Dato-DXd in the near future. If Dato-DXd gains approval, there will be a lot of discussion about sequencing of therapies, because you can certainly imagine that there will be patients who are candidates for multiple ADCs.”

In the interview, Gupta, medical oncologist in the Stanford University Department of Medicine, Division of Medical Oncology, highlighted the approved indications for these ADCs in breast cancer, the efficacy data supporting their approvals, and ongoing studies to advance the space further.

3D rendered medically accurate illustration of a breast cancer: © SciePro - stock.adobe.com

Targeted Oncology: Can you discuss the current landscape of antibody-drug conjugates for breast cancer subtypes beyond HER2-positive disease?

Gupta: There are multiple antibody-drug conjugates that have now been approved, as well as multiple antibody-drug conjugates that are being studied in the field of breast oncology. The currently approved antibody-drug conjugates are trastuzumab emtansine, also known as T-DM1; trastuzumab deruxtecan, also known as T-DXd; [and] sacituzumab govitecan.

T-DXd and sacituzumab have indications outside of conventionally defined HER2-positive disease. Specifically, T-DXd is used in HER2-low disease, which is a disease where the immunohistochemistry result is 1+ or 2+ IHC result that is negative. Sacituzumab is indicated both in triple negative breast cancer and hormone receptor-positive, HER2-negative breast cancer, both in the advanced setting.

Please walk us through the currently approved ADCs in the breast cancer space.

T-DM1 is indicated for both adjuvant HER2-positive disease and metastatic HER2-positive disease in the adjuvant setting. It is specifically indicated for patients who have been treated neoadjuvantly and then have residual disease at the time of surgery based on the results of the KATHERINE study [NCT01772472]. This study demonstrated that adjuvant T-DM1 is associated with an improved median overall survival and invasive disease-free survival as compared with adjuvant trastuzumab. In the metastatic setting, T-DM1 has been shown to be more efficacious than capecitabine and lapatinib [Tykerb], as based on the EMILIA trial [NCT00829166]. For some time, T-DM1 was our favored second-line therapy for metastatic HER2-positive disease. T-DXd is now the favored second-line therapy.

T-DXd is a monoclonal antibody that has the same amino acid sequence as trastuzumab, and it is bound by a linker to a cytotoxic payload, which is a topoisomerase 1 inhibitor. This drug appears to use the bystander effect whereby the payload can permeate to neighboring tumor cells. DESTINY-Breast01 [NCT03248492] first demonstrated the efficacy of this drug...In this study, patients had received a median of 6 prior lines of therapy, and yet, still had a remarkable overall response rate of just under 61%. DESTINY-Breast02 [NCT03523585] was then the confirmatory phase 3 study, and then DESTINY-Breast03 [NCT03529110] compared T-DXd to T-DM1. It was this study that then established T-DXd as generally our second-line therapy of choice for advanced HER2-positive disease. Specifically, in this study, T-DXd had a quadrupling of the median progression-free survival as compared with T-DM1. The median progression-free survival with T-DXd was just under 29 months as compared with being just under 7 months with T-DM1, which is a really extraordinary increase in median progression-free survival. Finally, T-DXd has been studied in HER2-low disease in DESTINY-Breast04 [NCT03734029]. When compared in that study to physicians' choice of chemotherapy, T-DXd is associated with a significant improvement in median progression-free survival and overall survival.

Sacituzumab govitecan is a Trop2-directed ADC and it comprises a monoclonal antibody that binds Trop2, which is a cell surface antigen that is expressed in greater than 80% of breast cancers. [It is] currently approved for patients with advanced triple-negative breast cancer who have received 2 or more prior systemic therapies, at least 1 of which was in the metastatic setting, but it is also approved for patients with hormone receptor-positive, HER2-negative advanced disease among patients who have received endocrine therapy and at least 2 additional systemic therapies.

The ASCENT clinical study [NCT02574455] evaluated sacituzumab as compared to physicians' choice of chemotherapy in patients with advanced triple-negative breast cancer and in that setting, sacituzumab was associated with an improvement and median progression-free survival, as well as overall survival. Sacituzumab has also been studied for hormone receptor-positive, HER2-negative advanced breast cancer. This was in the TROPiCS-02 study [NCT03901339] where sacituzumab was associated with an improvement in median [progression-free survival), along with median [overall survival] as compared with physicians’ choice of chemotherapy.

What are some of the antibody-drug conjugates currently in development?

One antibody-drug conjugate to highlight is datopotamab deruxtecan, often called Dato-DXd. This is a Trop2-directed antibody-drug conjugate. This was studied in the phase 3 TROPION-Breast01trial [NCT05104866], which was a global study that enrolled patients with hormone receptor-positive, HER2-advanced disease who had received 1 to 2 prior lines of chemotherapy. In this study, patients treated with Dato-DXd had a median progression-free survival of 6.9 months as compared with the median progression-free survival of 4.9 months among those treated with physicians' choice of chemotherapy. Dato-DXd is given on day 1 of a 3-week cycle, and we are very excited to see what comes of Dato-DXd.

What options are there to address the challenges of resistance and tumor heterogeneity genetically when using ADCs in breast cancer treatment?

For most patients with hormone receptor-positive, HER2-negative metastatic breast cancer, endocrine resistance does eventually develop, and ADCs present an opportunity to use a more targeted therapy prior to using chemotherapy in this setting where there is endocrine resistance. One example of a strategy that can help overcome tumor heterogeneity is that some ADCs use the bystander effect whereby the cytotoxic payload can permeate to nearby cells. This can be a strategy to potentially overcome tumor or receptor heterogeneity.

Are there any specific biomarkers that can guide treatment decisions with ADCs?

T-DM1 is used specifically for HER2-positive disease. T-DXd is currently used for HER2-positive disease and HER2-low disease. We define HER2-low disease as immunohistochemistry results 1+ or 2+ with an ISH result that is negative. Sacituzumab does not require any specific biomarkers. Specifically, it does not require Trop2 expression. The vast majority of breast cancers, greater than 80% of breast cancers, will express Trop2. Sacituzumab can be effective regardless of Trop2 expression.

Is there a role for combining ADCs with other treatment modalities? Can you discuss any of the ongoing clinical trials investigating such combinations?

This is certainly an area under investigation and under exploration currently when it comes to combining ADCs with other therapies. ASCENT-04 [NCT05382286] is a phase 3 study in the frontline metastatic triple-negative breast cancer space in which patients who have PD-L1-positive disease who are randomized to receive sacituzumab with pembrolizumab [Keytruda] as compared with treatment of physicians’ choice [of chemotherapy] with pembrolizumab. This comparator arm, the noninvestigational arm in this study, derives from the current standard of care in which patients who have PD-L1-positive disease are given chemotherapy with pembrolizumab, based on the prior KEYNOTE-355 [NCT02819518] data.

What are the most critical adverse effects associated with ADCs used in breast cancer? How can these be effectively managed?

I'll focus primarily on trastuzumab deruxtecan and sacituzumab. T-DXd can be associated with interstitial lung disease or pneumonitis. Depending on the study that you look at, this rate can be anywhere from approximately 10% to 15%. In select cases or in rare cases, the toxicity can be quite severe. It is important for the treating provider along with the patient to be aware of this potential adverse effect, so that patients can notify their team immediately if they are developing a new cough, shortness of breath, or any other pulmonary symptoms. The best way to manage suspected interstitial lung disease or pneumonitis is to promptly stop the drug, evaluate the patient with a high resolution chest CT, if needed, involve pulmonary colleagues, if there is uncertainty about whether there could be an infectious etiology of some of the pulmonary symptoms, or potentially the CT chest findings to potentially also involve infectious disease colleagues. A cornerstone of treatment of interstitial lung disease from T-DXd is starting high-dose steroids promptly.

Sacituzumab can be associated with diarrhea and neutropenia. Given the neutropenia, if patients are developing issues with their counts, then growth factor can be used if it was not already being used. Dose reductions may sometimes be required. The diarrhea with sacituzumab can be addressed with antidiarrheal agents such as loperamide. But additionally, patients can be advised on dietary modifications and hydrating well. As needed, the drug may need to be paused and sometimes dose reductions are merited.

What is the future outlook for ADCs in breast cancer treatment? What are some of the exciting developments on the horizon?

The field of ADCs in breast cancer is a very exciting area. In particular, we are very excited to see more about Dato-DXd in the near future. If Dato-DXd gains approval, there will be a lot of discussion about sequencing of therapies, because you can certainly imagine that there will be patients who are candidates for multiple ADCs. Certainly, more to come and more discussion to be had in this space of sequencing.