Dato-DXd Extends PFS in HR+/HER2- Inoperable or Metastatic Breast Cancer

Dato-DXd (datopotamab deruxtecan) compared to chemotherapy showed improvements with progression-free survival (PFS, the time from randomization or initiation of treatment to disease progression or death.) among patients with previously treated, hormone receptor-positive/HER2-negative inoperable or metastatic breast cancer. Findings from the phase 3 TROPION-Breast01 trial were presented during the 2023 San Antonio Breast Cancer Symposium.

Results showed that the study met its dual primary PFS end point; at the July 17, 2023, data cutoff, the median PFS by blinded independent central review (BICR) was 6.9 months in the Dato-DXd arm (365 patients) compared with 4.9 months in the chemotherapy arm (367 patients.) Additionally, the median PFS per investigator assessment was 6.9 months vs 4.5 months, respectively.

By investigator assessment, the 6-, 9-, and 12-month PFS rates in the Dato-DXd arm were 55.2%, 34.7% and 21.7%, respectively. In the chemotherapy arm, these rates were 36.9%, 20.9% and 9.9%, respectively.

“Clinically, there is a need for better therapies in this setting,” Dr. Aditya Bardia, a medical oncologist at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School in Boston, said during the presentation. “Dato-DXd is a Trop-2-directed ADC that selectively delivers a potent Topo-I payload to tumor cells. It has several unique properties. First, it has an optimized drug to antibody ratio. Second, it allows for tumor-selective delivery of the payload because of the cleavable linker, and this reduces off-target toxicity. Third, it has a stable linker payload which reduces off target toxicity. And fourth, it has [a] bystander anti-tumor effect which can address Trop-2 heterogeneity.”

TROPION-Breast01 was an open-label, global study that enrolled patients with hormone receptor-positive/HER2-negative breast cancer who previously received 1 or 2 prior lines of chemotherapy in the inoperable or metastatic setting. Eligible patients also needed to have an ECOG (how able an individual is to do something on their own) performance status of 1 or less and experienced progression on, or were deemed unsuitable for, endocrine therapy. Patients were stratified by number of lines of chemotherapy received in the unresectable/metastatic setting (1 vs 2), geographic location (United States/Canada/Europe vs the rest of the world) and treatment with a previous CDK4/6 inhibitor (yes vs no).

Once enrolled, patients were randomly assigned in a 1:1 manner to receive either Dato-DXd or investigator’s choice of chemotherapy. Dato-DXd was given at a dose of 6 mg/kg intravenously on day 1 every 3 weeks. Investigator’s choice of chemotherapy consisted of eribulin mesylate, vinorelbine, or gemcitabine, all given on days 1 and 8 every 3 weeks, as well as capecitabine given on days 1 through 14 every 3 weeks. Treatment continued until disease progression, unacceptable tolerability, or other discontinuation criteria.

The coprimary end points were PFS by BICR per RECIST 1.1 and overall survival. Secondary end points included overall response rate, investigator-assessed PFS, safety, patient reported outcomes and time to first subsequent therapy (TFST).

The baseline patient characteristics were well-balanced between the 2 arms; the median age in the investigational and chemotherapy arms was 56 years vs 54 years, respectively. Most patients in both arms were not Hispanic or Latino (88% vs 87%, respectively), underwent 1 prior line of chemotherapy (63% vs 61%), received a prior CDK4/6 inhibitor (82% vs 78%) and received a prior taxane and/or anthracycline (90% vs 92%).

Additional findings from the study demonstrated that treatment with Dato-DXd offered a PFS benefit over chemotherapy in patients with and without brain metastases. The median PFS among patients with brain metastases at study entry in the investigational (35 patients) and chemotherapy (23 patients) arms was 5.6 months vs 4.4 months, respectively. Patients without brain metastases experienced a median PFS of 7.0 months vs 4.9 months in the investigational (330 patients) and chemotherapy (344 patients) arms, respectively.

Similarly, patients achieved a PFS benefit with Dato-DXd vs chemotherapy regardless of prior duration of treatment with a CDK4/6 inhibitor. Patients in the Dato-DXd (151 patients) and chemotherapy (136 patients) arms who received a prior CDK4/6 inhibitor for a maximum of 12 months achieved a median PFS of 6.9 months vs 4.2 months, respectively. Patients who received treatment with a prior CDK4/6 inhibitor for more than 12 months achieved a median PFS of 7.1 months in the investigational arm (153 patients) vs 5.0 months in the control arm (164 patients).

Regarding TFST, patients in the Dato-DXd arm and the chemotherapy arm experienced a median TFST of 8.2 months vs 5.0 months, respectively. The median time to deterioration (TTD) in global health status/quality of life at first instance was 3.4 months vs 2.1 months, respectively. The confirmed median TTD was 9.0 months vs 4.8 months, respectively.

The median TTD at first instance favored Dato-DXd over chemotherapy regarding physical functioning and pain and the median confirmed TTD in physical functioning and pain did as well.

In the safety population, treatment-related side effects of any grade occurred in the Dato-DXd (360 patients) and chemotherapy (351 patients) arms at rates of 94% vs 86%, respectively, including 21% and 45%, respectively, of grade 3 or higher severity. Patients in both arms also experienced treatment-related side effects associated with dose reduction (21% vs 30%), interruption (12% vs 25%) and discontinuation (3% vs 3%). Serious treatment-related side effects of any grade (6% vs 9%) and of grade 3 or higher severity (5% vs 8%) were reported in both arms; 1 patient in the chemotherapy arm experienced a treatment-related side effect associated with death.

Treatment-related neutropenia of any grade occurred at rates of 11% and 42% in the Dato-DXd and chemotherapy arms, respectively. Treatment-related neutropenia led to dose interruption, reduction and discontinuation at rates of 17%, 13%, and 0.3%, respectively in the chemotherapy arm; these rates were 0%, 0.3% and 0%, respectively, in the Dato-DXd arm.

Any grade treatment-related stomatitis was present in both the investigational (50%) and control arms (13%), including grade 3 events at rates of 6% and 3%, respectively. Patients in both arms experienced dose interruption (1% vs 1%) and reduction (12% vs 1%) due to treatment-related stomatitis. One patient in the Dato-DXd arm discontinued treatment due to treatment-related stomatitis.

“TROPION-Breast01 met its primary end point by demonstrating a statistically significant and clinically meaningful improvement in PFS by both BICR as well as investigator-assessed PFS,” Bardia said. “The results support Dato-DXd as a potential new therapeutic option for patients with endocrine resistant, metastatic hormone receptor-positive breast cancer.”

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