Changes in metastatic breast cancer (MBC) bone lesions and SREs/fractures via a single intratumoral injection for a first-of-its-kind drug: Preliminary phase 2a results.

589 Background: Lytic bone metastases develop in ~70% of breast cancer patients that lead to pain, functional decline, and skeletal-related events (SREs) that reduce quality of life (QoL) and survival. Prophylactic denosumab/bisphosphonate treatment offers limited protection, and current local palliative interventions, EBRT and surgery, don’t reverse lytic destruction. Zeta-BC-003 is a first-in-class intratumoral (IT) injectable biomaterial infused with N-allyl noroxymorphone, a small molecule drug that acts through the p21 pathway to drive bone healing and local tumor control. Reports on two Compassionate Use patients (7 lesions, 2-yr follow-up; Palma et al, Pain Manag 2023) showed no SREs/fractures or tumor activity coupled with neo-trabecular bone regeneration and therapeutic spread to other lesions within treated bone, which align with these Phase 2a results. Methods: ZGMBC (NCT05280067), an open-label Phase 2a study, enrolled women (N=10; 8/23-3/25) with MBC lytic lesions and a Spinal Instability Numeric Score (SINS) ≥3 - ≤9. A single intratumoral (IT) Zeta-BC-003 injection was administered via fluoroscopic guidance. CT defect volume; pain via the Numeric Rating Scale (NRS); post-op pain control via the Morphine Equivalent Dose (MED); and AE/SAEs. Secondary endpoints: QoL (SF-12v2); SINS; and tumor response. Results: Subjects (mean age 52) had the following MBC subtypes: HR+ (N=6), HR+/HER2+ (N=2), HER2+/HR- (N=1), and TNBC (N=1). Breakthrough lesions were seen in 5 subjects despite bisphosphonate therapy and 1 subject died from pleural edema prior to study end. Zeta-BC-003 was injected into 10 subjects with 11 lesions with additional therapeutic effect seen in 4 adjacent untreated lesions. A CR was shown for all lesions and there were no SREs/fractures. The bone defect volume decreased 65.4% (±20.5%; p=0.0003) and 84.1% (±13.1%; p<0.0001) at Days 84 and 180. NRS pain scores decreased 4.2% (p<0.05) and MED decreased ≥33% in opioid-treated subjects. SINS scores improved 18.5% (p<0.05), indicating increased stability. Increased PCS (24%) and MCS (12%) scores showed increased QoL. There were no treatment emergent SAE/AEs. Conclusions: Zeta-BC-003 prevented SREs/fractures in all lesions, reduced lytic defect volume, improved spinal stability, decreased pain/opioid use, improved QoL, ceased tumor activity, and demonstrated therapeutic spread to untreated lesions in the same vertebral body. These findings contrast with historical SRE rates of 53% in MBC and align with the durable CR seen in our Compassionate Use patients. Zeta-BC-003 may represent a first-of-its-kind intratumoral drug that ceases lytic activity, stimulates neo-trabecular bone growth, and improves QoL by eliminating SREs/fractures while also increasing overall survival. Clinical trial information: NCT05280067 .