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Hi there. I'm Dr. Sara Hurvitz from UCLA, and I'm speaking about what factors impact the use of antibody drug conjugates in special patient populations with metastatic triple-negative breast cancer.
First, I'd like to talk about the use of sacituzumab govitecan, the TROP2-targeted antibody drug conjugate that is available for patients with metastatic triple-negative breast cancer based on the phase 3 randomized ASCENT trial, in which sacituzumab govitecan was compared to single-agent chemotherapy of physician’s choice. The overall study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival and overall survival for the intent-to-treat population. These practice-changing data did lead to the regulatory approval of this agent in patients who'd received at least two prior lines of systemic chemo for metastatic or locally advanced breast cancer.
So a question is begged, when we are treating patients in the real world, are all patients likely to derive similar benefits from the use of this drug? And to help address this question, we can reflect on the subgroup analyses that were reported from the ASCENT clinical trial. If you look at the forest plots from the ASCENT clinical trial, you can see that patients derive benefit from sacituzumab more than chemotherapy, regardless of their age group, regardless of their race, or the number of prior therapies received, regardless of whether they were enrolled or treated in North America or rest of world, regardless of their tumor PD-L1 status, location of their tumor, including liver metastases or not, and regardless of whether or not their tumor was initially diagnosed as triple-negative breast cancer. So these data are really important and give us reassurance that these patient groups would derive some benefit from this treatment.
There was actually also an analysis done looking at the ASCENT trial outcomes in patients who had brain metastases. And we saw that patients with or without brain metastases both derive benefit from sacituzumab, the median PFS in the small number of patients who had brain metastases treated with sacituzumab was 2.8 months which compared favorably to those treated with treatment a physician's choice at 1.6 months. In addition, patients derive benefit from sacituzumab regardless of whether they were younger than 65 years of age, or 65 years of age or older.
We also have another ADC available, trastuzumab deruxtecan, for patients with HER2-low triple-negative breast cancer. And analysis of the DESTINY-Breast04 clinical trial looking at outcomes based on age, indicated that patients treated with T-DXd had a similar PFS improvement compared to chemotherapy alone, regardless of whether they are less than 65 years of age or 65 years of age or older. One caveat of this subgroup analysis is that it included patients who had ER-positive HER2-low breast cancer, which was the majority of patients enrolled in the trial, as well as triple-negative HER2-low breast cancer. So that's important to keep in mind.
Another thing to keep in mind is the differing toxicity profiles between these two agents with T-DXd from the DESTINY-Breast04 trial having higher risk of interstitial lung disease and nausea, and with sacituzumab govitecan having a higher risk of febrile neutropenia, as well as diarrhea. The risk factors for ILD have been analyzed in several pooled analyses. One analysis indicated that patients who are older or who had baseline poor renal function or an O2 saturation at baseline of less than 95% may be a particularly high risk of the development of ILD and may not be suitable patients for the treatment with T-DXd.
In summary, we have two ADCs available, sacituzumab govitecan and trastuzumab deruxtecan, for our patients with triple-negative breast cancer, the latter being available for HER2-low triple-negative breast cancer. A variety of analyses have been done showing benefits of these two agents in various subgroups. The safety profiles of these agents are slightly different and may impact our choice between these two agents.
Thank you so much.
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