1464 Phase 1 results of OR502, an antibody against leukocyte immunoglobulin-like receptor B2 (LILRB2), in patients with advanced cancers

<h3>Background</h3> OR502 reverses and prevents LILRB2-mediated immune suppression by myeloid cells and restores T cell functions (figure 1). OR502 showed preclinical anti-tumor activity alone and in combination with anti-PD-1.¹ Study OR502-101 evaluates OR502 safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy alone or combined with cemiplimab. We report the completed monotherapy dose escalation. <h3>Methods</h3> Primary objectives were to evaluate OR502 safety and tolerability and recommend a dose for the next stage of study, by assessing dose-limiting toxicities (DLTs), adverse events (AEs) and serious AEs/deaths per CTCAE v5.0, clinical laboratory values, LILRB2 receptor occupancy (RO) and biological activity parameters. OR502 was given IV as 21-day cycles in 5 cohorts from 100–1600 mg. Patients progressed on/did not tolerate/refused ≥1 prior standard therapy for advanced disease. Safety assessments were weekly C1-C3 and on D1 thereafter. RECIST 1.1 response was assessed Q6W to week 24, Q12W to week 48, and Q6 months thereafter. Serial PK sampling was performed C1 and C3, then D1 every other cycle. Peripheral RO was assessed weekly C1 and C3. <h3>Results</h3> Nineteen patients (6 sarcoma/soft tissue, 4 lung, 2 urothelial, 1 melanoma, 6 other) were: 63% females, median age 62 years (47–82), median 2 prior systemic treatments (0–11) and median ECOG 1 (0–1). There were no DLTs or G≥3 treatment-related AEs (TRAE). Ten patients (53%) experienced G1-2 TRAE, unrelated to exposure. Three patients (16%) had G1-2 infusion related reactions (IRR): 1 at 800 mg (2 IRRs) and 2 at 1600 mg. All IRRs resolved with standard management within ≤6 hours. We subsequently extended the infusion to 60 minutes with premedication. One patient at 400 mg had 2 immune-related TRAEs (G2 hypothyroidism and G2 pneumonitis; both resolved). There were no treatment-related deaths/SAEs. Of 16 evaluable patients, 2 (13%) with melanoma and non-small cell lung cancer (NSCLC), PD(L)-1 pretreated for &gt;6 months, experienced confirmed partial responses at 200 mg and 800 mg; melanoma patient ongoing for &gt;9 months. Five (31%) had stable disease for 4–8 cycles (tumor growth control rate 44%). OR502 showed dose-proportional PK with t_½10–14 days. Peripheral RO was dose-proportional, near-complete across doses, and 100% at doses ≥400 mg. <h3>Conclusions</h3> OR502 was well tolerated without DLT or G≥3 TRAE at 100–1600 mg Q3W, with encouraging efficacy and durable clinical benefit in patients with advanced cancer. The few TRAEs seen were low-grade, reversible, and manageable. PK and RO support Q3W dosing. Expansion cohorts are evaluating 800 mg IV Q3W in PD(L)-1 pretreated cutaneous melanoma and NSCLC. <h3>Trial Registration</h3> Study OR502-101 is registered as NCT06090266 on www.clinicaltrial.gov. Study is conducted with support from the Cancer Prevention Research Institute of Texas (CPRIT) DP230076. <h3>Reference</h3> Bouchlaka M, Zuck M, Dinh N, <i>et al.</i> OR502, a best-in-class anti-LILRB2 antibody that enhances both innate and adaptive anti-tumor immune responses. <i>J Immunother Cancer</i> 2023;<b>11</b>(Suppl 1):A556. <h3>Ethics Approval</h3> Study OR502-101 has been approved by the Salus non-profit Institutional Review Board in Austin, TX.