Datopotamab Deruxtecan Shows Durable Efficacy and Manageable Safety in HR+/HER2- Breast Cancer

Early results from the TROPION-PanTumor01 demonstrate the potential of achieving durable response with datopotamab deruxtecan while maintaining tolerability in patients with hormone receptor-positive or HER2-negative breast cancer.

Datopotamab deruxtecan (DS-1062a) demonstrated promising and long-lasting efficacy in patients with heavily pretreated hormone receptor (HR)-positive, HER2-low, or HER2-negative unresectable or metastatic breast cancer.1

These results come from a 41-patient cohort of a phase 1, multicenter, first-in-human study (TROPION-PanTumor01; NCT03401385). Datopotamab deruxtecan achieved a complete response rate of 27% with an 85% disease control rate. All responses were partial responses, and 56% of patients achieved stable disease.

For patients with HR-positive, HER2-negative breast cancer who progressed on or after endocrine therapy, treatment options are limited. As a protein that is highly expressed on breast tumors and is associated with a poor prognosis, TROP is evidenced to be a strong target for therapy in breast cancer. Datopotamab deruxtecan, an anti-body drug conjugate, consists of a humanized anti-TROP2 IgG1 monoclonal antibody.

“Patients with HR-positive, HER2-low, or negative metastatic breast cancer who are not eligible for endocrine therapy or have exhausted treatment options have a poor prognosis. These preliminary results with datopotamab deruxtecan in patients with heavily pretreated HR-positive, HER2-low or negative metastatic breast cancer are encouraging and warrant further evaluation in this setting,” said Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, in a press release.

The 2 primary end points of the study are safety and tolerability determined by the number of patients with dose-limiting toxicities, adverse events, and grade 2 or higher oral mucositis/stomatitis in the sub study. Secondary end points of the study will evaluate efficacy, pharmacokinetics, and antidrug antibodies.2

Patients enrolled in the HR-positive, HER-negative breast cancer cohort were unselected for TROP2 expression and were aged 18 years or older. All patients were required to have an ECOG performance status of 0-1, measurable disease per RECIST 1.1, and patients with brain metastases were permitted if this condition was stable and treated.

Of the patients enrolled, most were from Japan but 15% were from the United States. Fifty-one percent of patients had de novo metastatic disease, and 15% had brain metastases. The median time to initial treatment in this patient population was 42.7 months (range, 10.2-131.1).

In terms of prior treatment, the median number of prior therapies in the metastatic setting was 5 (range, 3-10), and the median number of chemotherapy regimen in the metastatic setting was 2 (range, 1-6). Thirty-six percent of patients were given neoadjuvant chemotherapy. The majority received either endocrine therapy in the metastatic setting for at least 6 months (80%) or CDK 4/6 inhibitors (95%). Among those previously treated with CDK 4/6 inhibitors, 46% were treated for 12 months or less and 49% were treated for more than 12 months. Other prior therapies included capecitabine (83%), taxanes (59%), anthracyclines (54%), mTOR inhibitors (29%), and PI3K inhibitors (20%).

Only 12% of patients had progressive disease. The median duration of response was not evaluable [NE] (4.4-NE). The clinical benefit rate was 44%. Notably, many responses were ongoing at the time of data cutoff. The median progression-free survival was 8.3 months (95% CI, 5.5-11.0). the median overall survival was not reached, but 59% of patients were alive for more than a year.

Treatment was manageable and the safety profile was consistent with previous trials of datopotamab deruxtecan. Treatment-emergent adverse events (TEAEs) of any cause occurred in 100% of patients and were grade 3 or higher in 41%. The most common any-grade TEAEs were stomatitis (83%) nausea (56%), fatigue (46%), and alopecia (37%). The most common grade 3 or higher TEAEs were decreased lymphocyte count (15%), and stomatitis (10%).

Due to TEAEs, 12% of patients required dose reductions, 37% had treatment interruptions and 12% discontinued treatment. The serious AEs observed were treatment related.

These early results warrant further study of datopotamab deruxtecan in breast cancer.

“Many of these patients with metastatic breast cancer in TROPION-PanTumor01 had exhausted most of their available treatment options, having received a striking median of five prior regimens including a CDK4/6 inhibitor for nearly all patients. These promising results with datopotamab deruxtecan in such a heavily pretreated patient population support our strong belief that this TROP2-directed antibody drug conjugate has the potential to improve outcomes for patients with HR-positive, HER2-low or negative breast cancer in this, and possibly earlier settings,” Cristian Massacesi, chief medical officer and Oncology chief development officer at AstraZeneca stated.

Meric-Bernstam F, Krop IE, Juric D, et al. Phase 1 TROPION-PanTumor01 study evaluating datopotamab deruxtecan (Dato-DXd) in unresectable or metastatic hormone receptor–positive/HER2–negative breast cancer (BC). Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract PD13-08.
Datopotamab deruxtecan showed encouraging and durable efficacy in patients with heavily pretreated HR-positive, HER2-low or negative metastatic breast cancer. News release. AstraZeneca. December 8, 2022. Accessed December 14, 2022. https://bit.ly/3UXZzpm
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