TROPION-Breast01: Dato-DXd Significantly Delayed Progression in HR-Positive/HER2-Negative Breast Cancer

The TROP2-targeting antibody-drug conjugate (ADC) Dato-DXd significantly improves progression-free survival (PFS) in patients with metastatic HR-positive/HER2-negative (HR-positive/HER2-negative) breast cancer compared with standard chemotherapy, according to results from the phase 3 TROPION-Breast01 study.¹

Patients assigned to Dato-DXd had a 37% reduction in the risk for progression or death compared with investigator’s choice of chemotherapy (HR 0.63, 95% CI [0.52, 0.76]; P <.0001).

“[Dato-DXd] could potentially be a new option to consider for patients with HR-positive metastatic breast cancer who have received 1 prior line of therapy,” said study principal investigator Aditya Bardia, MD, MPH, of University of California, Los Angeles Jonsson Comprehensive Cancer Center. “If approved, this would be the third antibody-drug conjugate approved in this setting.”

Trastuzumab deruxtecan was approved for HER2-low metastatic breast cancer in August 2022 and sacituzumab govitecan was approved for HR-positive/HER2-negative disease in 2023.^2,3

Dato-DXd is a TROP2-directed ADC comprising a humanized anti-TROP2 immunoglobulin G1 monoclonal antibody linked with a TOP1 inhibitor. Dato-DXd first showed activity in HR-positive/HER2-negative metastatic breast cancer in the phase 1 TROPION-PanTumor01 trial.⁴

Published earlier this year in the Journal of Clinical Oncology, the umbrella TROPION-PanTumor01 clinical trial included 85 patients with breast cancer.⁴ Among the 41 patients with HR-positive/HER2-negative tumors, the objective response rate (ORR) was 26.8% with a median PFS of 8.3 months.

“The phase 1 study demonstrated that this drug is active in HR-positive/HER2-negative breast cancer, which led to the phase 3 TROPION-Breast01 trial,” Dr. Bardia said.

The phase 3 TROPION-Breast01 trial enrolled patients with HR-positive/HER2-negative disease who were ineligible for or had disease progression on endocrine therapy and had received 1 to 2 prior lines of chemotherapy. Patients were randomly assigned to Dato-DXd (365 patients) once every 3 weeks or investigator’s choice of chemotherapy (367 patients). The trial has a dual primary endpoint of PFS and OS.

“Once patients with HR-positive/HER2-negative disease have endocrine-resistant disease, single-agent chemotherapy has traditionally been the standard of care, but chemotherapy can have significant side effects, impact quality of life, and has limited activity with a median PFS of approximately 4 to 5 months in the later-line setting,” Dr. Bardia said. “Clinically, there is an unmet need for better therapies for patients with HR-positive metastatic breast cancer.”

Median PFS by blinded independent central review was 6.9 months with Dato-DXd compared with 4.9 months with standard chemotherapy. The 1-year PFS rate was 25.5% with Dato-DXd compared with 14.6% with chemotherapy.

“There was also a higher [ORR] with Dato-DXd and a trend toward improved OS,” Dr. Bardia said.

The ORR with Dato-DXd was 36.4% compared with 22.9% with chemotherapy. There were 2 complete responses with Dato-DXd. Median duration of response was 6.7 months with Dato-DXd compared with 5.7 months with chemotherapy.

OS data are still immature; however, there was a trend toward improvement with Dato-DXd (HR 0.84, 95% CI [0.62, 1.14).

The researchers noted that at the data cutoff, almost 2.5 times as many patients remained on treatment with Dato-DXd as compared with chemotherapy.

“One interesting thing about this study, which is usually not seen in other studies, is that the rate of treatment-related adverse events [TRAEs] was lower in the intervention arm (Dato-DXd) than control arm (chemotherapy of physician choice),” Dr. Bardia said. “Usually, we see the opposite; here, the rate of grade ≥ 3 TRAEs was almost half of that with standard chemotherapy.”

Although the majority of patients in both arms experienced a TRAE of any grade, the rate of grade ≥ 3 TRAEs was 20.8% with Dato-DXd compared with 44.7% with chemotherapy. Additionally, a smaller percentage of patients on the intervention arm required dose reductions (20.8% vs 30.2%) or dose interruptions (11.9% vs 24.5%) as compared with chemotherapy. The most common AEs of any grade were nausea, stomatitis, alopecia, and neutropenia.

“There are 2 specific AEs with Dato-DXd that providers specifically need to be aware off,” Dr. Bardia said, “mucositis and dry eye.”

Oral mucositis/stomatitis of any grade occurred in about half (55.6%) of patients but were mostly low grade. “The use of a prophylactic mouthwash is an important consideration to potentially prevent and/or reduce the severity of mucositis,” Dr. Bardia noted.

Ocular surface events of any grade occurred in 40.0% of patients. The most common event in the Dato-DXd arm was dry eye (21.7%).

Dato-DXd is currently being evaluated as an earlier line of therapy in both metastatic disease as well as localized breast cancer, Dr. Bardia said.

In addition to HR-positive/HER2-negative disease, Dato-DXd is also being evaluated in triple-negative breast cancer (TNBC) in the first-line metastatic setting in the TROPION-Breast02 trial (NCT05374512). TROPION-Breast03 is evaluating Dato-DXd in patients with TNBC with residual disease despite neoadjuvant therapy (NCT05629585). TROPION-Breast04 is evaluating Dato-DXd as neoadjuvant therapy for localized TNBC (NCT06112379).

— Leah Lawrence