Dr Foldi on T-DXd and Sacituzumab Govitecan in Metastatic Breast Cancer

Julia Foldi, MD, PhD, assistant professor of medicine, Hematology/Oncology, Department of Medicine, University of Pittsburg Medical Center (UPMC), breast medical oncologist, UPMC Hillman Cancer Center, discusses the utility of of antibody-drug conjugates (ADCs), such as fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) and sacituzumab govitecan-hziy (Trodelvy), in the treatment of patients with metastatic HER2-low and triple-negative breast cancer (TNBC).

In both the HER2-low triple-negative and hormone receptor (HR)–positive metastatic breast cancer settings, there are notable data from the phase 3 DESTINY-Breast04 trial (NCT03734029)demonstrating the efficacy of T-DXd following 1 line of chemotherapy, Foldi begins. Based on the findings from this randomized, 2-arm, open-label, multicenter trial 

 for patients with unresectable or metastatic HER2-low breast cancer, in August 2022. It was noted that the study enrolled patients irrespective of HR status.

Furthermore, Foldi continues by stating that 

the data readout of the phase 3 DESTINY-Breast06 trial

 was highly anticipated. Findings from the trial may support the replacement of chemotherapy with T-DXd in patients with endocrine-resistant HR-positive metastatic breast cancer. At the meeting, investigators reported that treatment with T-DXd elicited a statistically significant and clinically meaningful improvement in progression-free survival vs chemotherapy in pretreated patients with HR-positive, HER2-low metastatic breast cancer. Despite the risk of interstitial lung disease (ILD) that may occur with T-DXd treatment, an increase in surveillance and patient education can help minimize the risk of pulmonary toxicity.

Similarly, for treatment with sacituzumab govitecan, there are data to suggest that this ADC is better than the single-agent sequential chemotherapy for patients with TNBC who have progressed on first-line chemotherapy, Foldi expands. Although toxicities with these agents may present a challenge, they can also be managed. Foldi concludes by stating that oncologists are getting increasingly better at treating these events, ensuring that patients can stay on schedule with their treatments.

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Julia Foldi, MD, PhD, discusses the utility of of T-DXd and sacituzumab govitecan in the treatment of metastatic HER2-low and triple-negative breast cancer.

Dr Foldi on the Evolving Treatment Landscape of ADCs in HER2+ Breast Cancer

Julia Foldi, MD, PhD, assistant professor of medicine, Hematology/Oncology, Department of Medicine, University of Pittsburg Medical Center (UPMC), University of Pittsburg Medical Center, breast medical oncologist, discusses the evolving role of antibody-drug conjugates (ADCs) in the treatment paradigm for metastatic HER2-positive breast cancer.

In multiple large, randomized phase 3 clinical trials, including the series of DESTINY-Breast trials, both fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) and sacituzumab govitecan-hziy (Trodelvy) have demonstrated superior outcomes compared with standard chemotherapy drugs commonly used in patients, Foldi begins. These ADCs consistently outperform conventional chemotherapy in all evaluated outcomes, indicating a significant advancement in targeting chemotherapy more effectively, she explains, noting that these drugs deliver more targeted versions of traditional cytotoxic chemotherapy.

Given these findings, Foldi recommends incorporating ADCs in second-line and subsequent treatment settings across all three subtypes of metastatic breast cancer. For HER2-positive breast cancer, an overwhelming amount of data supports the use of T-DXd in the second-line setting, she continues. However, this treatment space was previously dominated by the use of ado-trastuzumab emtansine (Kadcyla; T-DM1) as the standard of care, Foldi explains. However, the question remains whether there is still a role for T-DM1 following the establishment of T-DXd in this setting.

This paradigm shift underscores the importance of utilizing more targeted chemotherapy approaches to improve patient outcomes in metastatic breast cancer treatment, Foldi expands, noting that this approach could potentially extend survival rates and improve the quality of life for patients with HER2-positive metastatic breast cancer. Therefore, integrating ADCs like T-DXd and sacituzumab govitecan into treatment regimens could significantly enhance the care provided to patients with metastatic HER2-positive breast cancer, she concludes.

Julia Foldi, MD, PhD, discusses the evolving role of antibody-drug conjugates in the treatment paradigm for metastatic HER2-positive breast cancer.


Dr Foldi on the Impact of ILD in HER2+ Breast Cancer Treatment

Julia Foldi, MD, PhD, assistant professor, medicine, Hematology/Oncology, Department of Medicine, University of Pittsburg Medical Center (UPMC), breast medical oncologist, UPMC Hillman Cancer Center, discusses interstitial lung disease (ILD) associated with the use of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in patients with HER2-positive breast cancer.

The most concerning toxicity associated with T-DXd is ILD, Foldi begins, saying that in early clinical trials, before this adverse effect (AE) was fully understood, some deaths resulted from ILD. Consequently, oncologists have become highly attuned to the risk of this AE in this patient population, she emphasizes. In more recent trials, there has been significant emphasis on imaging surveillance to detect ILD, with oncologists typically increasing surveillance frequency with CT chest scans, Foldi says. Many oncologists now have increased this frequency, she notes, adding that she personally images patients approximately every 9 weeks to ensure that any asymptomatic ILD is detected early.

The reason for this increased surveillance is that if ILD is identified on imaging when still asymptomatic, it can be treated with steroids, Foldi continues. It also may be possible to rechallenge patients with T-DXd once the ILD has been resolved on imaging. However, if ILD progresses to a higher grade and becomes symptomatic, T-DXd rechallenge is not possible, even if symptoms and imaging findings resolve, according to the package insert and oncologists’ understanding of this toxicity, she elucidates.

For many patients, T-DXd is a highly effective treatment, so it is crucial to ensure patients remain on therapy for as long as possible, Foldi expands. Thus, increased ILD surveillance is essential. With this imaging approach, Foldi says she has become comfortable treating patients using T-DXd. It is also crucial to ask patients whether they are experiencing pulmonary symptoms, especially during the winter season, according to Foldi. Symptoms of ILD, such as a cough or shortness of breath, could be attributed to other causes, but any pulmonary symptom should be taken seriously in this context, and imaging should be done immediately, she concludes.

Julia Foldi, MD, PhD, discusses interstitial lung disease associated with the use of T-DXd in HER2+ breast cancer.

Julia Foldi, MD, PhD, discusses the evolving role of treatment with T-DXd in metastatic HER2-positive breast cancer.

Dr Foldi on the Evolving Role of T-DXd in HER2+ Breast Cancer  

Julia Foldi, MD, PhD, assistant professor of medicine, Hematology/Oncology, Department of Medicine, University of Pittsburg Medical Center (UPMC), University of Pittsburg Medical Center, breast medical oncologist, UPMC Hillman Cancer Center, discusses the evolving role of fam-trastuzumab deruxtecan-nxki (Enthertu; T-DXd) in the treatment of metastatic HER2-positive breast cancer.

Within the HER2-positive setting there is also the HER2-low setting, which can make treatment navigation even more complicated, Foldi begins. In HER2-positive disease, T-DXd is the current standard of care (SOC) in the second-line setting following progression on standard, first-line pertuzumab (Verzenio), trastuzumab (Herceptin), and docetaxel, Foldi begins. In the phase 3 DESTINY-Breast03 trial (NCT03529110), T-DXd demonstrated a significant progression-free survival (PFS) and overall survival (OS) benefit over the prior SOC, ado-trastuzumab emtansine (Kadcyla; T-DM1), and was accordingly established as the preferred second-line treatment option, Foldi reports.

Prior trials such as the phase 2 DESTINY-Breast01 (NCT03248492) and phase 3 DESTINY-Breast02 (NCT03523585) studies had already positioned T-DXd as an effective treatment in later lines of therapy, demonstrating its efficacy and tolerability in more advanced stages of the disease, Foldi explains. IN DESTINY-Breast01, T-DXd generated superior response rates in a heavily pretreated patient population; T-DXd also produced superior efficacy vs physician's choice of chemotherapy in the third-line and beyond in the DESTINY-Breast02 trial, she says. Foldi emphasizes that the DESTINY-Breast03 trial expanded on these findings by confirming T-DXd's role in earlier lines of therapy.

Ongoing research is exploring the potential use of T-DXd in earlier treatment lines, including the first-line setting, Foldi continues. An ongoing trial will compare T-DXd with taxane-based chemotherapy and HER2-targeting antibody combinations. This approach reflects a broader effort to optimize treatment strategies and leverage the benefits of T-DXd across different stages of HER2-positive breast cancer, Foldi explains.

Overall, T-DXd's emergence represents a significant advancement in the therapeutic landscape, improving outcomes for patients with HER2-positive breast cancer, especially those facing disease progression after initial therapies.

Julia Foldi, MD, PhD

Articles

Dr Foldi on T-DXd and Sacituzumab Govitecan in Metastatic Breast Cancer

Dr Foldi on the Evolving Treatment Landscape of ADCs in HER2+ Breast Cancer

Dr Foldi on the Impact of ILD in HER2+ Breast Cancer Treatment

Dr Foldi on the Evolving Role of T-DXd in HER2+ Breast Cancer