Dr LeVee on Ongoing Research With Immunotherapy and ADCs in TNBC

“There are a lot of exciting ongoing trials in TNBC, and because TNBC is more immunogenic compared with the other breast cancer subtypes, immunotherapy works [for this subtype].”

Alexis LeVee, MD, the chief fellow of Hematology & Medical Oncology at City of Hope, discussed ongoing research with immunotherapy agents and chemotherapy-free treatment strategies in patients with triple-negative breast cancer (TNBC).

TNBC is characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression, which precludes the use of targeted therapies directed at these receptors, LeVee began. Despite this limitation, TNBC demonstrates a heightened level of immunogenicity relative to other breast cancer subtypes, which makes it more responsive to immune checkpoint blockade, she explained. This increased immunogenic potential is evidenced by higher levels of PD-L1 expression, greater infiltration by tumor-infiltrating lymphocytes (TILs), and elevated tumor mutational burden, all of which are biomarkers associated with responses to immunotherapy, she stated.

Currently, immune checkpoint inhibitors have received regulatory approval for use in both early-stage and metastatic TNBC, LeVee noted. Numerous ongoing clinical trials are investigating the optimal use of immunotherapy in TNBC, including combination regimens and novel therapeutic targets, according to LeVee. Moreover, multiple phase 3 trials are underway in the neoadjuvant setting, she reported. Notable among these is the phase 3 SCARLET trial (NCT05929768), which is comparing an anthracycline-free neoadjuvant regimen with the standard-of-care phase 3 KEYNOTE-522 trial (NCT03036488) regimen of pembrolizumab (Keytruda) plus chemotherapy in patients with early-stage TNBC, LeVee said.

Another significant study is the phase 3 TROPION-Breast04 trial (NCT06112379), which is assessing neoadjuvant datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) in combination with durvalumab compared with the KEYNOTE-522 regimen in patients with early-stage disease, LeVee reported. Several other trials are investigating chemotherapy-free regimens to potentially reduce toxicity, she continued. For instance, the phase 3 BELLINI study (NCT03815890) of ipilimumab (Yervoy) plus nivolumab (Opdivo) has shown promising results in patients with early-stage TNBC with high TIL levels, suggesting a potential role for less toxic therapeutic backbones in this patient population, she added.

In the adjuvant setting, trials are being conducted for patients who achieve a pathologic complete response (pCR), as well as for those with residual disease, LeVee emphasized. The phase 3 OptimICE-pCR trial (NCT05812807) is examining the possibility of de-escalating adjuvant therapy by omitting pembrolizumab in patients who achieve pCR after neoadjuvant therapy. Conversely, for patients with residual disease following neoadjuvant therapy, combination strategies involving antibody-drug conjugates like Dato-DXd or sacituzumab govitecan-hziy (Trodelvy) with or without immunotherapy, are under active investigation. One such trial is the phase 3 TroFuse-012 study (NCT06393374), which is evaluating sacituzumab tirumotecan (SKB264/MK-2870) in combination with pembrolizumab.