Anti-CTLA-4 probody BMS-986249 alone or in combination with nivolumab in patients with advanced cancers: Initial phase I results.

Abstract

3058 Background: Blockade of the CTLA-4 pathway with ipilimumab (IPI) ± nivolumab (NIVO; anti–PD-1) is an effective treatment for a variety of cancers. To optimize the risk-benefit profile of CTLA-4–directed therapy, a Probody therapeutic technology platform (Pb-Tx, CytomX Therapeutics) was used to generate BMS-986249, a peptide-masked version of IPI that is unmasked by tumor-associated proteases. Pb-Tx may localize CTLA-4 activity to the tumor, minimize systemic toxicity, and allow for higher doses of anti–CTLA-4 ± anti-PD-1. In preclinical studies, BMS-986249, given at similar doses, showed comparable intratumoral and reduced peripheral pharmacodynamic activity relative to IPI (Engelhardt, AACR 2020). Here, we present the initial results of the first-in-human phase 1/2 study of BMS-986249 ± NIVO in pts with advanced (adv) cancers (NCT03369223). Methods: During dose escalation, pts received BMS-986249 at or above the approved doses of the parent molecule using a Q4W or Q8W dosing schedule as monotherapy (240–2400 mg Q4W or 1600 mg Q8W; ≈ 3–30 mg/kg vs approved 3 mg/kg Q3W IPI) or in combination (240–1200 mg Q4W or 800 mg Q8W) + NIVO 480 mg Q4W. Safety and pharmacokinetics (PK) were evaluated. Efficacy is being assessed in the dose-expansion phase. Results: As of December 7, 2019, 82 anti–CTLA-4 naive pts with various adv cancers received BMS-986249 ± NIVO (mono, n = 39; combo, n = 43). Median age 60 (25–78) y; 95% pts had prior systemic therapy. TRAEs occurred in 59% of pts (Gr 3/4, 23%) with mono and 74% of pts (Gr 3/4, 30%) with combo. Diarrhea was the most common any-Gr TRAE (mono, 23%; combo, 21%) and Gr 3/4 TRAE (mono, 15%; combo, 7%). Rates of Gr 3/4 TRAEs increased with higher doses of BMS-986249 but were substantially reduced with Q8W schedule (eg, 800 mg Q4W, 18%; 1600 mg Q4W, 60%; 1600 mg Q8W, 9%). Most TRAEs resolved, no Gr 5 TRAEs occurred. The peptide-masked intact probody accounted for most (73%) of the systemic BMS-986249-related species; elimination of the probody indicated involvement of both catabolism and cleavage processes. Conclusions: BMS-986249 ± NIVO displayed a clinically manageable safety profile, allowing assessment of comparably higher BMS-986249 dose intensity (240-1200 mg; ≈ 3-15 mg/kg) + NIVO (480 mg Q4W, full dose) than that tested with IPI + NIVO. The types of TRAEs were consistent with CTLA-4 blockade, and the overall data align with the proposed Pb-Tx mechanism of action. The preclinical and clinical data support the ongoing randomized BMS-986249 + NIVO expansion in pts with adv melanoma, in addition to other adv tumors. Clinical trial information: NCT03369223 .