Immunotherapy Agents and ADCs May Redefine Early-Stage TNBC Management

Alexis LeVee, MD

The early-stage triple-negative breast cancer (TNBC) research paradigm contains several clinical trials that may refine or replace standard-of-care treatment backbones to personalize therapy and improve treatment tolerability, according to Alexis LeVee, MD.

“Lots of trials in the early TNBC setting are ongoing,” LeVee said in an interview with OncLive®. “[Several phase 3 studies] will be exciting and potentially change the treatment paradigm for TNBC.”

In the interview, LeVee discussed the patient populations most at risk for developing TNBC; treatment challenges associated with the lack of estrogen receptor (ER), progesterone receptor (PR), and HER2 receptors in this disease; and ongoing clinical research that aims to improve outcomes for patients with early-stage disease by building on the immunogenic nature of TNBC tumors and the mechanism of action of antibody-drug conjugates (ADCs).

LeVee is the chief fellow of Hematology & Medical Oncology at City of Hope in Duarte, California.

OncLive: How prevalent is TNBC compared with other subtypes of breast cancer?

LeVee: TNBC occurs in approximately 10% to 20% of patients with breast cancer, and it tends to be more common in patients who are younger, as well as those who have a BRCA1 mutation and those who are African American. It is fairly common, but it is one of the rarer subtypes of breast cancer.

What unique treatment challenges are associated with this subtype?

Because TNBC doesn’t have any of the classic receptors, such as ER, PR, and HER2, those receptors cannot be targeted. However, there are a lot of exciting ongoing trials in TNBC. Because TNBC is more immunogenic compared with the other breast cancer subtypes, immunotherapy works in this disease. TNBC tends to have higher PD-L1 expression, higher tumor infiltrating lymphocyte [TIL] levels, and often a higher tumor mutational burden, [of which] each of those tends to characterize responses to immunotherapy. Currently, immunotherapy [agents are] approved in both early and metastatic breast cancer, and there are ongoing trials investigating immunotherapy in other tumor types as well.

What research is ongoing for patients with early-stage TNBC?

Some of the exciting trials in TNBC are investigating immunotherapy regimens, as well as novel targets. We have some neoadjuvant trials, [including] the phase 3 SCARLET trial [NCT05929768], which is evaluating an anthracycline-free regimen prior to surgery. [This trial is] comparing that regimen with the phase 3 KEYNOTE-522 [trial (NCT03036488) regimen of pembrolizumab (Keytruda)], which is currently FDA approved for early-stage TNBC.1 There’s also the phase 3 TROPION-Breast04 trial [NCT06112379], which is examining neoadjuvant datopotamab deruxtecan-dlnk [Dato-DXd; Datroway] plus durvalumab [Imfinzi] compared with the KEYNOTE-522 [regimen]; it will be exciting to see those results. There are also trials investigating a chemotherapy-free backbone to try to remove the toxicity related to chemotherapy. Some exciting trials, such as the phase 3 BELLINI study [NCT03815890], showed encouraging results in patients with high levels of TILs [when treated with nivolumab (Opdivo) plus ipilimumab (Yervoy)].

There are also some adjuvant trials in early TNBC, both for patients who achieve a pathologic complete response [(pCR) with neoadjuvant therapy], as well as those who have residual disease at the time of surgery. The phase 3 OptimICE-pCR trial [NCT05812807] is evaluating whether we can remove adjuvant pembrolizumab in patients who achieve a pCR [after neoadjuvant therapy]. We also have lots of trials for patients who have residual disease at the time of surgery [that are examining] ADCs, such as Dato-DXd or sacituzumab govitecan-hziy [Trodelvy], with or without immunotherapy. Then, we have the [phase 3 TroFuse-012] trial [NCT06393374] investigating sacituzumab tirumotecan [SKB264/MK-2870] plus pembrolizumab. [There is] a lot to do in TNBC, and these trials showcase how much the treatment regimens and the ways we manage TNBC are changing.

In 2024, you were the lead study author on a real-world analysis investigating the effect of neoadjuvant pembrolizumab adherence on pCR rates in TNBC. What was the impetus for conducting this research, and how might the findings influence clinical practice going forward?

Currently, there’s no FDA-approved biomarker to help us identify which patients would benefit from the addition of pembrolizumab to chemotherapy in early TNBC. We did this study to try to identify which patients have a favorable response to the neoadjuvant chemoimmunotherapy combination from KEYNOTE-522, and then try to identify what the optimal chemotherapy backbone would be. In our study, we found that younger patients tend to have a better response to neoadjuvant chemoimmunotherapy. Then, a multivariate analysis showed that patients who received at least 8 cycles of neoadjuvant pembrolizumab achieved higher pCR rates.2

This suggests that patients who complete all 8 cycles of their treatment have better responses. However, because of the overlapping treatment schedule [of pembrolizumab] with chemotherapy, it’s a bit unclear whether patients [derive the] most benefit from the pembrolizumab or the chemotherapy. We are expanding that study to 2 other hospital systems to try to further identify which patients benefit from this chemoimmunotherapy regimen and which patients do not, and further identify what the optimal chemotherapy backbone will be [for this patient population].

References

1. FDA approves Keytruda (pembrolizumab) for treatment of patients with high-risk early-stage triple-negative breast cancer in combination with chemotherapy as neoadjuvant treatment, then continued as single agent as adjuvant treatment after surgery. News release. Merck. July 27, 2021. Accessed May 16, 2025. https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-treatment-of-patients-with-high-risk-early-stage-triple-negative-breast-cancer-in-combination-with-chemotherapy-as-neoadjuvant-treatment-then-continued/
2. LeVee A, Wong M, Flores S, et al. Impact of neoadjuvant pembrolizumab adherence on pathologic complete response in triple-negative breast cancer: a real-world analysis. Oncologist. 2024;29(7):566-574. doi:10.1093/oncolo/oyae064