TNBC Treatment Innovations Build on ADC Optimization, Provide Impetus for Individualized Care

Alexis LeVee, MD

Novel antibody-drug conjugates (ADCs) and emerging predictive biomarkers are reshaping the metastatic triple-negative breast cancer (TNBC) treatment paradigm, offering potential new opportunities to personalize treatment, optimize immunotherapy response, and reduce toxicity, according to Alexis LeVee, MD.

In an interview with OncLive®, LeVee, the chief Hematology & Medical Oncology fellow at City of Hope in Duarte, California, discussed ongoing phase 3 trials in metastatic TNBC that are evaluating upfront use of ADCs in both PD-L1–positive and –negative patient populations; investigational biomarkers that may predict immunotherapy response and personalize clinical decision-making in TNBC; and how these biomarkers may aid efforts to de-escalate treatment approaches and improve outcomes for patients across TNBC subtypes and settings.

LeVee also noted anticipation surrounding the readout of data from the phase 3 ASCENT-04 trial (NCT05382286), which is investigating sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) in patients with previously untreated, PD-L1–positive advanced TNBC. An April 2025 news release reported positive PFS outcomes with the investigational combination in the trial, and full data from this study will be presented at the 2025 ASCO Annual Meeting. ASCENT-04 will join a host of other presentations spotlighting ADCs in breast cancer.

Lastly, LeVee dove into research developments in early-stage TNBC. Her insights on this topic have been shared in another article.

OncLive: What are some ongoing trials of interest in metastatic TNBC?

LeVee: In the metastatic setting, primarily, the exciting phase 3 trials are investigating ADCs with or without immunotherapy. In the first-line setting, the phase 3 TROPION-Breast05 trial [NCT06103864] is evaluating datopotamab deruxtecan-dlnk [Dato-DXd; Datroway] plus or minus durvalumab [Imfinzi] vs chemotherapy plus pembrolizumab in patients with PD-L1–positive mTNBC. That’s based on the promising data that were shown from the phase 1/2 BEGONIA study [NCT03742102]. We also have the phase 3 TROPION-Breast02 trial [NCT05374512] that’s ongoing examining Dato-DXd alone in first-line, PD-L1–negative, mTNBC. The phase 3 ASCENT-03 trial[EudraCT: 2021-005743-79] is investigating sacituzumab govitecan in first-line mTNBC. [Lastly,] the phase 3 TroFuse-011 trial [NCT06841354] is investigating sacituzumab tirumotecan [MK-2870] plus or minus pembrolizumab in first-line mTNBC.

Then we have ASCENT-04, [findings from] which will be presented at the 2025 ASCO Annual Meeting. [This study] is comparing sacituzumab govitecan plus pembrolizumab vs treatment of physician’s choice plus pembrolizumab in the first-line, PD-L1–positive mTNBC setting. A news release showed that this novel combination strategy resulted in improved PFS, so it’ll be exciting to see those results presented at ASCO.1

What potential biomarkers are under investigation in TNBC that may further personalize treatment selection?

Some of the biomarkers we’ve studied so far are PD-L1, tumor mutational burden, and tumor-infiltrating lymphocytes. These have all shown that they predict for a more favorable response to immunotherapy in TNBC. However, they are not currently FDA-approved biomarkers [for TNBC, and the question remains]: can patients still benefit from immunotherapy regardless of their PD-L1 status?

Ongoing studies are exploring immune gene signatures, such as the ImPrint immune signature, which was developed through the phase 2 I-SPY2 trial [NCT01042379]and has been shown to predict pathologic complete response in patients receiving pembrolizumab.2 There have also been studies investigating spatial transcriptomics to see how we can better understand the tumor microenvironment and how immune cells interact with tumor cells. That may also be used as a potential biomarker.

Lastly, I have performed several studies on how the gut microbiome may be a biomarker to predict response to immunotherapy. We have several studies ongoing at City of Hope investigating how the gut microbiome could be used as a biomarker to predict which patients will benefit from pembrolizumab in TNBC. I’m doing 2 other correlative studies in hormone receptor–positive metastatic breast cancer and HER2-positive early breast cancer. All these studies are trying to identify how the gut microbiome can predict response to immunotherapy. We know in other cancer types that the gut microbiome can predict immunotherapy response, but there are limited data in breast cancer, so hopefully we’ll have those data soon.

What are some remaining unmet needs for patients with TNBC that future research could address?

One of the biggest unmet needs is trying to identify a biomarker for patients to personalize our therapies. Right now, what we use for early TNBC is a regimen that includes 5 agents: 4 different chemotherapy agents combined, plus immunotherapy. This strategy is toxic for patients and [associated with] a lot of adverse effects. [Regimens that attempt] to de-escalate therapy, minimize toxicity, and simultaneously still improve outcomes is needed. Hopefully, some of these biomarker studies will better personalize therapies for patients.

References

1. Trodelvy plus Keytruda demonstrates a statistically significant and clinically meaningful improvement in progression-free survival in patients with previously untreated PD-L1+ metastatic triple-negative breast cancer. News Release. Gilead. April 21, 2025. Accessed May 20, 2025. https://www.gilead.com/news/news-details/2025/trodelvy-plus-keytruda-demonstrates-a-statistically-significant-and-clinically-meaningful-improvement-in-progression-free-survival-in-patients-with-previously-untreated-pd-l1-metastatic-trip
2. Mittempergher L, Kuilman MM, Barcaru A, et al. The ImPrint immune signature to identify patients with high-risk early breast cancer who may benefit from PD1 checkpoint inhibition in I-SPY2. J Clin Oncol. 2022;40(suppl 16). doi:10.1200/JCO.2022.40.16_suppl.514