(P 154) INTERIM SAFETY AND EFFICACY RESULTS FROM A PHASE 1/2 STUDY OF BA3011, A CAB-AXL-ADC, IN PATIENTS WITH ADVANCED SARCOMA OR OTHER SOLID TUMORS

Abstract ID: 1818855

Objective: BA3011 is a conditionally active biologic anti-AXL antibody-drug conjugate (CAB-AXL-ADC) being developed as an anticancer therapy for patients with advanced solid tumors. Conditional and reversible binding by CABs is designed to reduce off-tumor toxicity and immunogenicity, avoid tissue-mediated drug deposition, and improve pharmacokinetics (PK). AXL is a cell-surface transmembrane receptor protein tyrosine kinase highly expressed in several tumor types including sarcoma. Increased AXL expression has been associated with tumor resistance to chemotherapy, programmed death-1 (PD-1) inhibitors, molecular targeted therapy, and radiation therapy. In the current study, we sought to identify the safety profile, recommended Phase 2 dose (RP2D), and preliminary evidence of antitumor activity of BA3011 in patients with advanced sarcoma or other solid tumors.

Methods: Study BA3011-001 is an ongoing, multi-center, open-label, Phase 1/2 first-in-human trial of BA3011. In Phase 1, BA3011 is administered once (Q3W) or twice (2Q3W) every 3 weeks via intravenous (IV) infusion. Phase 2 is an open label assessment of the efficacy and safety of BA3011 alone and in combination with a PD-1 inhibitor in patients with AXL-expressing tumor membrane percent score (TmPS) ≥ 50 with advanced refractory sarcoma who have measurable disease and documented progression. Interim Phase 1 data from this study are described here.

Results: In Phase 1, a total of 60 subjects have received BA3011 at dose levels from 0.3 to 3.0 mg/kg Q3W, and 1.2 to 1.8 mg/kg 2Q3W, including 22 subjects with sarcoma. Of the first 75 sarcoma patients screened for AXL tumor membrane expression, approximately 50% had a TmPS ≥ 70. No clinically meaningful on-target toxicity was observed, with a low rate of constipation. Dose-limiting toxicities were limited to monomethyl auristatin E (MMAE) conjugate-associated toxicity at the highest dose tested, including reversible neutropenia. In Phase 1 sarcoma subjects, treatment-emergent adverse events (TEAEs) in 2 (9.1%) subjects led to treatment discontinuation (Table 1). Eight subjects had grade 3 related TEAEs and 1 subject had grade 4, which generally were MMAE related, including reversible myelosuppression, transient liver enzyme elevations, and some metabolic disturbances (hypokalemia, hyponatremia) (Table 2). Transient grade 1-2 liver enzyme elevations seen during cycle 1 treatment generally did not re-occur upon re-treatment. The RP2D was determined to be 1.8 mg/kg Q2W based on an integrated evaluation of Phase 1 data, including PK modeling. The PK profile of BA3011 was approximately dose proportional; in Phase 1 the half-life was determined to be approximately 4 days. BA3011 antitumor activity that correlated with AXL tumor membrane expression was observed in sarcoma subjects. Confirmed partial responses were demonstrated in 4 sarcoma subjects (2 with undifferentiated pleomorphic sarcoma, 1 with leiomyosarcoma, and 1 with Ewing sarcoma) treated with BA3011 at the RP2D dose of 1.8 mg/kg (Q3W; 2Q3W), with all having TmPS ≥ 70 (Figure 1). Phase 1 sarcoma subjects had on average failed 4 prior lines of therapy. Durability of response in sarcoma subjects at the RP2D dose in this ongoing study is demonstrated in Figure 2.

Conclusion: Based on preliminary efficacy and safety results from this study, the benefit-risk profile of BA3011 monotherapy appears to be favorable in subjects with sarcoma. No clinically meaningful on-target toxicity was observed. In Phase 1 sarcoma subjects, evidence of antitumor activity was observed, with higher AXL tumor membrane expression correlating with response. These results suggest focused enrollment of patients with high levels of AXL tumor membrane expression may result in increased clinical benefit. AXL appears to be expressed at a consistent rate throughout all sarcoma subtypes tested; a larger sample size for some subtypes is required to confirm these findings. Phase 2 is ongoing in subjects with AXL-expressing advanced refractory sarcoma.