Phase 1 study of BA3071, an anti–CTLA-4 conditionally active biologic, in combination with nivolumab in advanced solid tumors.

2602 Background: Immune checkpoint inhibition of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) in combination with programmed cell death protein 1 (PD-1) has demonstrated durable clinical benefit in patients with advanced solid tumors. However, dose density is limited due to toxicity. BA3071 is a conditionally active biologic (CAB) anti–CTLA-4 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands CD80 and CD86 1. CABs are activated within the acidic tumor microenvironment. Conditional and reversible binding of BA3071 may reduce on- and off-tumor immune-related adverse events (AEs) and autoimmunity, avoid tissue-mediated drug deposition, and improve pharmacokinetics. We evaluated the safety and antitumor activity of BA3071 in patients with advanced solid tumors. Methods: Patients naïve to anti–CTLA-4 therapy with advanced solid tumors received escalating doses of single-agent BA3071 every 3 weeks (Q3W) at cycle 1, followed by combination BA3071 + nivolumab from cycle 2 onward. Treatment continued until disease progression or unacceptable toxicity. Response assessment was performed Q6W with RECIST v1.1. Results: Eighteen patients were treated with BA3071 (7–700 mg) and nivolumab (240 mg); 61% had received ≥3 lines of prior systemic therapy, and all patients had experienced failure of anti–PD-1 therapy. Four patients experienced grade 3 related treatment-emergent AEs (TEAEs; hypertension, increased lipase, atrial fibrillation, gastritis, and diabetic ketoacidosis); no grade 4 related TEAEs were observed. Two patients experienced grade 3 immune-related TEAEs (diarrhea BA3071 350 mg and diabetic ketoacidosis BA3071 700 mg). Among 16 efficacy-evaluable patients, 9 experienced stable disease, and 2 out of 5 patients receiving BA3071 in the 350-mg cohort achieved confirmed RECIST v1.1 responses (complete response in cervical carcinoma and partial response in gastroesophageal carcinoma). One patient with metastatic small cell lung cancer who received 7 mg BA3071 remained without progression for >1 year (69 weeks). Conclusions: Treatment with the novel, conditionally active anti–CTLA-4 agent BA3071, in combination with anti–PD-1 therapy (at doses higher than those currently approved for anti–CTLA-4/PD-1 therapy), yielded confirmed responses with a promising tolerability profile. Phase 1 dose escalation of BA3071 continues at 700 mg up to 1000 mg, and phase 2 monotherapy and combination therapy expansion cohorts are currently enrolling at a starting dose level of 350 mg. 1. Chang HW et al. Proc Natl Acad Sci USA.2021;118(9):e2020606118. Clinical trial information: NCT05180799 .