Alexis LeVee, MD, is chief Hematology & Medical Oncology fellow at City of Hope

Dr LeVee on ADC Trials That May Inform the Evolution of Breast Cancer Management

Alexis LeVee, MD, chief Hematology & Medical Oncology fellow at City of Hope, discussed highly-anticipated readouts of clinical trials investigating antibody-drug conjugates (ADCs) in patients with HER2-positive metastatic breast cancer and triple-negative breast cancer (TNBC) that will be presented at the 

One trial generating substantial interest is the phase 3 DESTINY-Breast09 trial (NCT04784715), which compared fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) with the current standard first-line regimen of docetaxel, trastuzumab (Herceptin), and pertuzumab in HER2-positive metastatic breast cancer, LeVee began. 

 shared that treatment with T-DXd plus pertuzumab improved progression-free survival (PFS) compared with the standard of care; this benefit was observed across all prespecified patient subgroups. These findings may have important implications for the first-line treatment paradigm in this breast cancer subtype, she explained.

Similarly, the phase 3 ASCENT-04 trial (NCT05382286), which evaluated sacituzumab govitecan-hziy (Trodelvy) in combination with pembrolizumab (Keytruda) vs physician’s choice of chemotherapy plus pembrolizumab in patients with PD-L1–positive metastatic TNBC, reported improved PFS with the investigational combination in a separate 

. The safety profile of the investigational combination was consistent with the known toxicities of each individual agent, supporting the potential clinical utility of this regimen, LeVee highlighted.

Several phase 2 studies of ADCs in breast cancer will be also presented at the meeting, LeVee stated. The phase 2 NeoSTAR trial (NCT04230109) evaluated neoadjuvant sacituzumab govitecan plus pembrolizumab in patients with early-stage TNBC. Additionally, the phase 2 OptiTROP-Breast05 study (NCT05445908) invetigated a novel ADC, sacituzumab tirumotecan (formerly SKB264/MK-2870), as a first-line treatment for patients with metastatic TNBC. Both studies may provide valuable insights into evolving treatment strategies for TNBC, LeVee concluded.

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Alexis LeVee, MD, discusses clinical trials investigating ADCs that may change treatment standards for patients with various subtypes of breast cancer.

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.

Alexis LeVee, MD, discusses ongoing trials investigating immunotherapy agents and antibody-drug conjugates that may challenge the current SOC for TNBC.

Alexis LeVee, MD, discusses immune-related adverse effects in patients with early breast cancer treated with immune checkpoint inhibitors. 

Dr LeVee on Immune-Related AEs Associated With ICIs in Early Breast Cancer

“We found a much higher rate of immune-related adverse [effects] than what has been previously published based on the [phase 3] KEYNOTE-522 trial.”

Alexis LeVee, MD, chief hematology/oncology fellow, City of Hope, discusses findings from a multi-institutional study investigating the rates of and risk factors for immune-related adverse effects (iRAEs) in patients with early-stage breast cancer treated with immune checkpoint inhibitors.

2024 San Antonio Breast Cancer Symposium (SABCS)

. The multi-institutional study included 423 real-world patients who previously received immune checkpoint inhibitors for early-stage breast cancer, LeVee explains. The study included patients with stage I to III breast cancer who were treated with ICIs at 1 of 4 academic institutions between 2014 and 2024. An irAE was defined as a toxicity that was determined via an oncologist to be potentially or definitely related to immune checkpoint inhibitors or high dose steroids after the causative agent was not identified.

Of note, LeVee and colleagues found a higher rate of irAEs in their multi-institutional study compared with previous findings from the phase 3 KEYNOTE-522 trial (NCT03036488). The trial investigated the combination of pembrolizumab (Keytruda) and chemotherapy in previously untreated patients with stage II or III triple-negative breast cancer. Among patients from the multi-institutional study, 72.6% of patients experienced any-grade irAEs, LeVee says, and 18.9% experienced high-grade irAEs. She emphasizes that these findings were derived from patients treated in a real-world setting who were not selected for clinical trials because of comorbidities, which may be the reason for increased rates of irAEs.

LeVee notes that the association between comorbidities and increased rates of irAEs led them to focus on specific risk factors that may cause increased rates of irAEs. Based on their multivariate analysis, they found that patients older than age 50 and patients who had chronic kidney disease experienced higher rates of irAEs, she says. Therefore, it is crucial to identify patients at higher risk of irAEs to make informed treatment choices, she concludes.

Alexis LeVee, MD

Articles

Dr LeVee on ADC Trials That May Inform the Evolution of Breast Cancer Management

Dr LeVee on Ongoing Research With Immunotherapy and ADCs in TNBC

Dr LeVee on Immune-Related AEs Associated With ICIs in Early Breast Cancer