Sacituzumab Govitecan, Trastuzumab Deruxtecan Highlight Expanding Role of ADCs in TNBC

Sacituzumab govitecan-hziy (Trodelvy) has a well-established role in second-line treatment of patients with triple-negative breast cancer (TNBC). However, data from a subgroup of those with TNBC treated with fam-trastuzumab deruxtecan-nxki (Enhertu) in the phase 3 DESTINY-Breast04 trial (NCT03734029) has added questions about the sequencing of antibody-drug conjugates (ADCs) in this patient population.

“After the big shakeup of DESTINY-Breast04, how does this affect our management of TNBC?” said Nour Abuhadra, MD, who made a presentation on the ADCs during the 40th Annual Chemotherapy Foundation Symposium^®. “For all intents and purposes, at this time, I would say second-line therapy remains sacituzumab govitecan, and third-line [therapy] is trastuzumab deruxtecan for HER2-low patients.

In an interview with OncLive^®, Abuhadra discussed what the data from DESTINY-Breast04 means for trastuzumab deruxtecan in the TNBC space, cross resistance mechanisms for different ADCs, and future areas of research for ADCs in TNBC. Abuhadra is the director of the Rare Breast Cancer Program in the Department of Medicine and the co-section head of the Triple Negative Breast Cancer Clinical Research Program in the Department of Medicine at the Memorial Sloan Kettering Cancer Center.

OncLive^®: Could you provide an overview of your presentation on the use of ADCs in TNBC?

Abuhadra: I reviewed recent updates in metastatic TNBC, [specifically looking] at first-line data with immunotherapy and PARP inhibitors. However, the focus of the talk was how ADCs are shifting [therapies in the] second line and beyond, particularly with sacituzumab govitecan and trastuzumab deruxtecan and how we ought to sequence them.

What has the regular approval of sazcituzumab govitecan in April 2021 meant in terms of adding another treatment option this population?

Whenever we add an agent that’s not a chemotherapy to our armamentarium in TNBC, we're very happy about that. The other thing that came with the 2021 FDA approval was that it [was approved for patients with] 2 prior lines of therapy, with at least 1 in the metastatic setting. That allowed us to move sacituzumab govitecan into the second-line setting for our patients, getting it to them sooner.

How have recent data for trastuzumab deruxtecan in HER2-positive and -low breast cancer changed the agent’s potential role for patients with TNBC?

Although the data were in such a small subset of patients on the [phase 3] DESTINY-Breast04 trial [NCT03734029], it was compelling enough that [the ADC] fits into our algorithm beautifully. The only concern that we have is that on DESTINY-Breast04, it was such a small subset of patients. There were only 58 patients with TNBC, [including] 40 who received trastuzumab deruxtecan. As promising as those results are, they are premature.

On the other hand, sacituzumab govitecan has a phase 3, TNBC-specific study [the ASCENT trial (NCT02574455)] to back it with a confirmed OS benefit. Until we see more on trastuzumab deruxtecan in TNBC, we would recommend second-line sacituzumab govitecan, then sequence trastuzumab deruxtecan in the HER2-low patients.

What are some other areas of research for ADCs in TNBC right now?

The big topic of interest as it pertains to ADCs is moving them up even sooner. There’s a first-line study that is now open looking at datopotamab deruxtecan [DS-1062a] in patients who are PD-L1 negative. Could [datopotamab deruxtecan] come into our first-line setting for PD-L1–negative patients?

Moreover, moving these ADCs up into the early-stage setting is a big area of interest. Looking at those high-risk patients who have residual disease after neoadjuvant chemotherapy or even giving these ADCs in the neoadjuvant setting themselves [are potential areas of exploration].

What are the unmet needs in this patient population?

An area of unmet need where we don’t have a lot of information is cross resistance amongst ADCs. As ADCs are increasingly crowding the [TNBC] space, the question of sequencing becomes even more critical.

Sacituzumab govitecan and trastuzumab deruxtecan both have the same cytotoxic payload. Are we going to see cross resistance? Is it better to start with one before the other? Should we not be sequencing them at all if a patient progresses on an ADC that has a topoisomerase I payload?

[Something that] applies to all breast cancers [is that treatment options in] later lines are still dwindling, and we are coming back down to those traditional chemotherapies. We need more drugs that can help. One of the big issues is that the mechanisms of resistance we’re generating now with immunotherapy, PARP inhibitors, and ADCs are completely new territory. [These mechanisms of resistance] highlight the importance of the correlative analyses that are being done on a lot of these studies.

Editor’s Note: This interview was conducted prior to the 2022 San Antonio Breast Cancer Symposium.