Novel ADC AZD8205 demonstrates manageable safety profile and preliminary efficacy in first-in-human trial

The antibody-drug conjugate (ADC) puxitatug samrotecan (AZD8205) demonstrated a manageable safety profile consistent with similar ADCs and initial efficacy in heavily pretreated patients with advanced or metastatic solid tumors, according to interim data shared at the 2024 European Society for Medical Oncology (ESMO) Congress by researchers from The University of Texas MD Anderson Cancer Center.

Results from the first-in-human Phase I/II trial were presented by Funda Meric-Bernstam, Chair of Investigational Cancer Therapeutics.

The study included 47 patients with a median age of 57 and a median of five prior lines of treatment. Of the 44 patients treated at 1.6 mg/kg dose or higher, nine had partial responses, including patients with ovarian, breast or endometrial cancer.

Because this patient population was heavily pretreated, while 91.5% of patients experienced treatment-related adverse events of any grade and 55.3% of patients experienced adverse events above grade three, the fact that only two patients had to discontinue treatment due to toxicities is promising. The most common adverse effects at grade three or higher were neutropenia (34%), anemia (17%) and a decrease in white blood cell count (17%) and were managed with with dose delays and dose reductions.

“This first-in-human trial with AZD8205 demonstrated promising clinical activity, especially in gynecologic tumors and breast cancer, and a safety profile consistent with the mechanism of action. We look forward to additional data from this study as we continue working to advance ADCs as an emerging class of cancer therapy,” – said Meric-Bernstam.

AZD8205 is a topoisomerase 1 inhibitor (Top1i) ADC that targets B7-H4, an immunoregulatory protein that is highly expressed in some solid tumors but has limited expression in normal tissue. High expression of B7-H4 has been associated with a poor prognosis and disease progression. Like other ADCs, AZD8205 aims to turn that high expression into a vulnerability by binding to the B7-H4 protein and delivering the Top1i payload, which interferes with DNA replication and ultimately leads to cell death.

Phase II expansion cohorts are ongoing in ovarian, breast, endometrial and biliary tract cancer. This study was funded by AstraZeneca. A full list of authors and their disclosures is available in the abstract here.

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