740P Anti-cytotoxic T-lymphocyte antigen-4 (CTLA 4) probody BMS-986249 ± nivolumab (NIVO) in patients (pts) with advanced cancers: Updated phase I results

Ipilimumab (IPI; anti–CTLA-4) ± NIVO (anti–PD-1) has demonstrated clinical activity across many tumor types. BMS-986249, a peptide-masked version of IPI unmasked by tumor-associated proteases, has a differentiated pharmacologic profile compared to IPI in preclinical studies, consistent with the mechanism of action of the Probody® therapeutic technology platform (Pb-Tx, CytomX Therapeutics; Engelhardt et al. AACR 2020. Abstract 4551). We present safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) data from a first-in-human, phase 1/2 study of BMS-986249 ± NIVO in pts with advanced cancer (NCT03369223). Anti–CTLA-4 naive pts with advanced cancer and ECOG PS of 0–1 received BMS-986249 240–2400 mg Q4W or 1600 mg Q8W as monotherapy (mono), or 240–1200 mg Q4W or 800–1600 mg Q8W + NIVO 480 mg Q4W (combo). Combo pts were also anti–PD-(L)1 naive. Pts with various (> 12) tumor types received mono (n = 39) or combo (n = 64); 100% and 91%, respectively, had received prior systemic therapy. Any-grade/grade 3/4 treatment-related adverse events (TRAEs) were reported in 62%/23% of mono pts and 86%/38% of combo pts. The most common any-grade TRAEs were diarrhea (23%) and fatigue (15%) in mono pts, and fatigue (27%) and diarrhea (20%) in combo pts. The most common grade 3/4 TRAEs were diarrhea in mono pts (15%) and diarrhea and colitis in combo pts (8% each). TRAEs leading to discontinuation occurred in 13% of mono pts and 19% of combo pts. TRAEs were dose-dependent, and both Q4W and Q8W were tolerable. One grade 5 TRAE was reported (sepsis; 1600 mg Q8W + NIVO). Objective response and disease control rates (complete/partial response, stable disease) with mono were 0% and 26%, respectively, and with combo were 16% and 38%, respectively, including responses in tumor types typically insensitive to immuno-oncology drugs. Tumor PK showed dose-dependent increases in unmasked BMS-986249 concentrations. Peripheral and tumor PD markers were increased and were consistent with historical data for IPI ± NIVO. BMS-986249 demonstrated a tolerable safety profile with no unexpected signals and promising preliminary activity. PK and PD supported unmasking at the tumor site.