Trial to Assess DB-1303 in HER2-Low Metastatic Breast Cancer

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A phase 3 study plans to assess the antibody-drug conjugate (ADC) DB-1303 against investigators choice of chemotherapy for the treatment of patients with hormone receptor (HR)-positive, HER2-low, metastatic breast cancer whose disease has progressed on endocrine therapy (DYNASTY-Breast02; NCT06018337).¹

DB-1303 is a topoisomerase-1 inhibitor in which phase 1/2 trial (NCT05150691) data have shown the treatment to be well-tolerated. In an already heavily pretreated population of patients with breast cancer, DB-1303 elicited encouraging antitumor activity.

In the phase 1/2 study, 85 patients were treated with DB-1303 across 6 dose levels, including 2.2 mg/kg, 4.4 mg/kg, 6.0 mg/kg, 7.0 mg/kg, 8.0 mg/kg, and 10.0 mg/kg, and 68 (80%) patients remained on treatment. Findings showed that 23 (44.2%) patients had objective partial tumor response per RECIST v1.1. The disease control rate (DCR) among all patients was 88.5%, while DCR rates were 96.2% and 84.6% for patients with HER2-positive breast cancer and HER2-low breast cancer, respectively.²

Regarding safety, treatment-emergent adverse events (TEAEs) were seen in 74 patients (87.1%) and grade 3 or greater TEAEs occurred in 18 patients (21.2%), respectively. The most commonly reported TEAEs and TEAEs deemed grade 3 or greater were nausea (51.8%, 3.5%), vomiting (43.5%, 1.2%), platelet count decreased (35.3%, 3.5%), and anemia (29.4%, 5.9%). Few pts experienced neutropenia (11.8%) and alopecia (3.5%), and no dose-limiting toxicities or TEAEs resulted in death.

"DB 1303 is an antibody drug conjugate that has an anti-HER antibody linked to a DNA topoisomerase inhibitor via a cleavable linker," Erika Hamilton, MD, director, Breast Cancer Research, Sarah Cannon Research Institute, told Targeted Oncology^TM. "Results from the phase 1 study were presented at ASCO 2023 and included data from 85 patients treated at 6 dose levels from 2.2 to 10.0 mg/kg. At the time of data cutoff, 80% remained on treatment. This data disclosure showed exciting preliminary activity with an ORR of 44.2% and DCR of 88.5%. Among HER2-positive breast cancer, the ORR was 50%, among HER2-positive breast cancer with brain mets, the ORR was 55.6% and DCR of 100%, and among HER2-low breast cancer, the ORR 38.5% and DCR of 84.6%. There was also responses among colorectal, ovarian, endometrial, and others. In terms of safety, there were not DLTs observed in all 6 dose levels. ILD occurred in 2 patients (2.4%, grade 1), and a few patients experienced neutropenia (11.8%) and alopecia (2.5%)."

Now, the open-label, multicenter, randomized, phase 3 study will span across 180 centers globally. Approximately 466 patients with HR-positive, HER2-low breast cancer whose disease progressed on at least 2 lines of prior endocrine therapy or within 6 months of first-line endocrine therapy with a CDK4/6 inhibitor in the metastatic setting will be included in the study.³

Enrollment is open to patients aged 18 years and older with advanced or metastatic breast cancer that has not been reported as HER2-positive. Adequate tumor tissue samples must be available, patients musy have an ECOG performance status of 0-1, a life expectancy of at least 12 weeks, at least 1 measurable lesion as defined per RECIST v1.1 and have received no prior chemotherapy for their breast cancer.

Patients will be randomized 1:1 to receive either DB-1303 or investigator's choice single-agent chemotherapy, consisting of either capecitabine, paclitaxel or nab-paclitaxel, until RECIST 1.1 defined disease progression, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.

The primary end points of the study will assess the efficacy and safety of DB-1303 compared with investigator's choice of single-agent chemotherapy and secondary end points consist of overall survival, progression-free survival, overall response rate, duration of response, disease control rate, pharmacokinetics, health-related quality of life, and disease progression.

The primary completion date for the phase 3 study is set for August 2025.

If approved, DB-1303 may provide a potential alternative to treatment with fam-trastuzumab deruxtecan-nxki (Enhertu), a HER2-directed antibody and topoisomerase inhibitor indication for the treatment of patients with breast cancer.¹

"The goals of the phase 3 trial DYNASTY-Breast02 is to show that DB-1303 is better than standard chemotherapy [capecitabine, paclitaxel, or nab-paclitaxel] for patients with HR-positive metastatic breast cancer who have progressed on endocrine therapy. The study will be conducted in 16 countries with a goal of enrolling 466 patients in United States and globally. Enrollment is planned to start in November 2023 in the United States with planned enrollment through May 2025," added Hamilton.

REFERENCES:

1. BioNTech, DualityBio move ADC into phase III for HER2-low breast cancer. News release. BioNTech. September 1, 2023. Accessed September 6, 2023. https://tinyurl.com/yypbpdc8

2. Moore KN, Sabanathan D, Du Y, et al. Safety and efficacy of DB-1303 in patients with advanced/metastatic solid tumors: A multicenter, open-label, first-in-human, phase 1/2a study. [published online ahead of print, 2023 May 31]. J Clin Oncol. 2023;41(16):3023 doi:10.1200/JCO.2023

3. A Study of DB-1303 vs Investigator's Choice Chemotherapy in Metastatic Breast Cancer. ClinicalTrials.gov. Updated August 30, 2023. Accessed September 6, 2023. https://clinicaltrials.gov/study/NCT06018337?term=DB-1303&rank=2&tab=history&a=1