Ongoing Research Aims to Bring Novel TROP-2–Directed ADCs to Metastatic TNBC

Currently, sacituzumab govitecan-hziy (Trodelvy) is the only TROP-2–targeted antibody-drug conjugate (ADC) approved for the treatment of patients with triple-negative breast cancer (TNBC), with the agent currently indicated for patients with unresectable locally advanced or metastatic disease who have previously received 2 or more systemic therapies, including at least 1 in the metastatic setting. However, research involving other novel TROP-2–directed ADCs, such as datopotamab deruxtecan (Dato-DXd), could provide additional options for this patient population, according to Sara M. Tolaney, MD, MPH.

In an interview with OncLive®, Tolaney concludeda 3-part discussion, where she detailed the impact of ADCs in TNBC, raised questions surrounding sequential ADC treatment, and highlighted future strategies for this treatment paradigm.

Tolaney is the chief of the Division of Breast Oncology, and associate director for the Susan F. Smith Center for Women's Cancers; serves as a senior physician at the Dana-Farber Cancer Institute; as well an associate professor of medicine at the Harvard Medical School, in Boston, Massachusetts.

OncLive: Beyond sacituzumab govitecan, how could TROP-2–directed ADCs continue to affect the treatment paradigm in breast cancer?

Tolaney: I would say that there is not just sacituzumab govitecan as a TROP-2–targeted ADC. [Sacituzumab govitecan] is the only currently approved [agent from this class]; however, there are other TROP-2–directed ADCs that are very promising.

There's Dato-DXd, [which] is being studied in metastatic TNBC in the first-line setting [in] the phase 3 TROPION-Breast02 trial [NCT05374512], comparing Dato-DXd to standard chemotherapy. There is also the phase 3 TROPION-Breast05 trial [NCT06103864] comparing Dato-DXd [with or without] durvalumab [Imfinzi] to chemotherapy plus pembrolizumab [Keytruda] in the PD-L1–positive first-line setting [for patients with advanced TNBC]. We are awaiting data from those 2 trials to know if Dato-DXd will have a role in [the treatment of] metastatic TNBC.

There is also sacituzumab tirumotecan [MK-2870/SKB264], another TROP-2–directed ADC. This targets TROP-2 and has a belotecan[-derivative topoisomerase I inhibitor] payload. [Sacituzumab tirumotecan] is also being studied in metastatic TNBC, and we saw some data at the 2024 ASCO Annual Meeting [from] the phase 3 [OptiTROP-Breast01] trial [NCT05347134] conducted in China, comparing sacituzumab tirumotecan to chemotherapy in a similar fashion to how [the phase 3 ASCENT trial (NCT02574455) evaluated sacituzumab govitecan in metastatic TNBC]. [Data from OptiTROP-Breast01] showed improvement in both progression-free survival [PFS] and overall survival in a pretreated population. Therefore, there is interest in trying to study [sacituzumab tirumotecan] in a less-pretreated population in the metastatic setting. There is more to come with other TROP-2–directed ADCs.

How do you and colleagues view the potential sequencing of ADCs in TNBC?

We're not sure how to think about sequential ADCs. We don't have any prospective clinical trials that have been completed to understand efficacy. What we do have are retrospective data from patients who have been treated with sequential ADCs.

There have been many real-world datasets that have now been presented at meetings, and in general, the take-home message—at least in my mind—is that what we see with the second ADC after someone's had a first [ADC] is that the PFS on the second one is generally a lot shorter than it was on the first ADC. However, that's not consistent, which is a problem. In general, yes, the median PFS is less [with the second ADC], but if you look at the individual patient level, you can see sometimes a patient who may not respond to the first ADC, then have a home run response to the second, or vice versa.

That tells us that we really don't understand why it is that some people are benefiting from a second ADC vs not, and this suggests that we don't fully understand resistance mechanisms to ADCs. We suspect [resistance] may be in part [due to] payload resistance. Since sacituzumab govitecan and fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd] are both using topoisomerase I inhibitor payloads, one would guess that you're not going to get as much benefit from the second ADC because, in essence, you're reusing the same type of chemotherapy. However, it's far more complex than that, because there's an issue about whether target expression matters and whether lysosomal processing matters.

We need prospective studies, and there are prospective studies planned. One of my colleagues will be running a [study] called TRADE-DXd, which will look at sequential Dato-Dxd and T-DXd, given [as] Dato-Dxd followed by T-DXd or vice versa, in [patients with] hormone receptor–positive [disease] or TNBC. There are also other studies also underway. We'll learn [more with additional data], but right now, most of us are utilizing sequential ADCs, despite having limited data for doing so.

Are there any other future strategies in TNBC that you would like to highlight?

We've come a long way with TNBC, now seeing availability of immunotherapy, PARP inhibition, and ADCs, and we will see more. There are new ADCs that are being studied in this space, so that is very exciting. Hopefully, we'll get other ADCs that have different payloads than just a topoisomerase I inhibitor payload because that has limited us a little bit to date. This field is rapidly evolving, and hopefully there will be more to come.