B7-H4 is a promising ADC target that is highly expressed in several solid tumors including cholangiocarcinoma (CCA) and breast, ovarian, and endometrial cancers, and is associated with poor prognosis.  AZD8205 is the first ADC bearing a novel proprietary topoisomerase I inhibitor (TOP1i) linker payload to enter the clinic. Robust AZD8205 anti-tumor response has previously been reported in B7-H4-expressing preclinical models across multiple tumor types.

Initial results from the dose escalation part of a BLUESTAR Phase I/IIa of AZD8205 monotherapy in patients with advanced/metastatic select solid tumors were presented in a Proffered Paper Session at the ESMO 2024. Eligible patients were ≥18 years old with advanced/metastatic ovarian, breast cancer, endometrial cancer, or cholangiocarcinoma expressing B7-H4 with progression after available standard of care therapy.

As of February 23, 2024, 46 patients received AZD8205, with a median age of 56 and a median of 4 prior treatment regimens. Treatment-emergent adverse events (TEAEs) occurred in 97.8% of patients, with the most common being nausea (58.7%), neutropenia (56.5%), and anemia (50.0%). Grade ≥3 TEAEs were seen in 82.6% of patients, including neutropenia (37.0%) and anemia (30.4%). Two patients discontinued due to TEAEs, and two experienced dose-limiting toxicities. Among 43 patients treated with ≥1.6 mg/kg, nine showed confirmed partial responses (20.9%) in ovarian, breast, or endometrial cancer.

AZD8205 demonstrated a manageable safety profile and showed early signs of efficacy in heavily pre-treated patients who had previously progressed on standard therapies.

Conclusion 

The PhaseI/IIa results of AZD8205, a novel B7-H4–directed topoisomerase I inhibitor (Top1i) ADC,  presented at the ESMO 2024 showed that the drug exhibited a manageable safety profile, consistent with other Top1 inhibitor ADCs, and delivered promising early efficacy in patients heavily pre-treated with standard therapies. Phase II expansion trials are underway in ovarian, breast, endometrial, and biliary tract cancers, offering new hope for these challenging cases.

ADCs like ENHERTU and TRODELVY have raised the bar in their respective areas, but AZD8205's focus on the lesser-known B7-H4 target could carve out a distinct niche. Unlike the well-established HER2 and TROP2 targets, B7-H4 is relatively unexplored, positioning AZD8205 to tap into tumor types that current ADCs may overlook. Its unique targeting ability could unlock new therapeutic possibilities, offering a critical advantage in cases where other ADCs face limitations.

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the following reports:

• Breast Cancer - Market Insight, Epidemiology and Market Forecast - 2032 report

• Ovarian Cancer - Market Insight, Epidemiology And Market Forecast - 2034

• Endometrial Cancer - Market Insight, Epidemiology And Market Forecast - 2032

• Biliary Tract Cancer Market Insight, Epidemiology And Market Forecast - 2034