Double Trouble for Breast Cancer: Are Two ADCs Better Than One?

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

Trastuzumab deruxtecan (T-DXd; Enhertu) and sacituzumab govitecan (Trodelvy) are both mainstays of treatment for HER2-low metastatic breast cancer, but research has not yet focused on the sequential use of these antibody-drug conjugates (ADCs) in this setting.

A retrospective cohort study sought to investigate the effectiveness of using these agents one after another in this patient population. Researchers looked at data from 84 patients who received both drugs at some point in their treatment.

Overall, the first drug seemed to be more effective than the second drug in terms of delaying disease progression, regardless of the order the drugs were given or other factors like age or presence of visceral disease.

For patients with hormone receptor (HR)-negative, HER2-low metastatic breast cancer, those with central nervous system (CNS) involvement had a shorter progression-free survival (PFS) and overall survival when on the first drug compared to those without CNS involvement. The use of additional treatments between the 2 drugs did not seem to affect the effectiveness of the second drug.

In an interview with Targeted Oncology^TM, Laura Huppert, MD, assistant professor of medicine at the University of California San Francisco, discussed this study and its implications for using sequential ADCs in this population.

Laura Huppert, MD

Targeted Oncology: What was the background or rationale for this study?

Huppert: There are 2 antibody-drug conjugates that are currently approved for patients with metastatic hormone receptor-positive, HER2-negativeand triple-negative metastatic breast cancer: sacituzumab govitecan and trastuzumab deruxtecan. One important question in clinical practice relates to the efficacy of these agents in a real-world setting, including in sequence.

What were the goals of this study?

To address this question, we conducted a retrospective, multi-institutional cohort study at 5 academic centers. Wei dentified patients with HER2-low metastatic breast cancer who had received both sacituzumab govitecan and T-DXd in either order, per standard of care or on a clinical trial with 1 of these agents as monotherapy. We identified 84 patients who had received both ADCs, including 56 who had hormone receptor-positive HER2-low disease, and 28 patients who were hormone receptor-negative, HER2-low. Most patients were female; it was a somewhat more diverse patient population than in most of the phase three clinical trials. Most of these patients were later lines of therapy; most of them had visceral disease. What we did was then we looked at the real-world progression-free survival and the real-world overall survival of using each of these agents in either order.

Could you summarize your findings? Were there any patient subgroups with a marked difference?

In the hormone receptor-positive, HER2-low cohort, 43% of patients received sacituzumab govitecan prior to T-DXd, and 57% of patients received T-DXd prior to sacituzumab govitecan. In the triple-negative cohort, most patients received sacituzumab govitecan prior to T-DXd. In general, we found that the real-world progression-free survival was longer for the first ADC than the second ADC, regardless of the hormone receptor status and the sequence.

Importantly, there were exceptions. There were some patients that had a shorter real-world [PFS] with a first ADC and a longer real-world [PFS] with a second ADC, which suggests that it is worth trying both ADCs since you might be lucky and have one of those patients that has a longer response with the second. We also looked at whether the use of an intervening therapy mattered. For example, if you did T-DXd first, whether you put a chemo[therapy] in the middle before sacituzumab govitecan or not, did that make a difference? we found that the use of an intervening therapy did not seem to affect outcomes.

What would you consider to be the major implications of this research?

In this retrospective, real-world study, I think we learned that these ADCs are effective in sequence. In general, patients have a longer duration of response on their first ADC than their second. But there are exceptions with patients having a longer on their second than their first. It did not seem that the use of an intervening therapy seems to matter. I think prospective data is needed to validate and better understand these findings, though, and identifying mechanisms of response and resistance to ADCs, so that we can better sequence patients and choose the right order and the right therapies for each individual patient.

What do you see as the next steps of this research?

I think the prospective work is really what is exciting, because then you can collect blood and tissue and look at the mechanisms of response and resistance in more detail. In a randomized study, you would be able to make a better comment on whether the order seems to matter. In terms of these retrospective data, though, [there are] a few additional analyses that we are hoping to do. We are collecting [next-generation sequencing] data on the patients in our cohort to see if there are any differences in response by mutation subtypes. Then, we have also been analyzing the safety data from this cohort and plan to present that.

REFERENCE:

Huppert L, Mahtani R, Fisch SC, et al. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumabgovitecan (SG) in patients with HER2-low metastatic breast cancer (MBC): Updated data and subgroup analyses by age, sites of disease, and use of intervening therapies.J Clin Oncol.2024;42(suppl 16):abstr 1083.doi:10.1200/JCO.2024.42.16_suppl.1083