Safety and efficacy of OR502, an antibody targeting leukocyte immunoglobulin-like receptor B2 (LILRB2), ± cemiplimab in patients with advanced solid tumors from a phase 1 study.

Abstract

2524 Background: OR502 is a humanized IgG1 antibody that targets LILRB2, blocking its binding to HLA ligands A, B and G. OR502 prevents and reverses myeloid cell-mediated immune suppression and rescues T cell effector functions. Preclinical data demonstrate best-in-class properties. We report on the completed monotherapy and combination dose escalation cohorts from the ongoing, first-in-human, phase 1-2 study of this novel antibody. Methods: Patients had progressive, histologically confirmed, metastatic/unresectable solid tumors with ≥ 1 prior systemic standard of care treatments. Primary objectives were OR502 safety/tolerability and identifying a dose for future study supported by LILRB2 receptor occupancy (RO) and pharmacokinetics (PK). Secondary objectives included assessment of anti-tumor activity. We used a modified toxicity probability interval-2 design with a 25% dose-limiting toxicity (DLT) rate and a 20–30% equivalence interval. Patients received OR502 IV (100–1600 mg) over 30 minutes, every 3 weeks (Q3W) as monotherapy (n = 19) or with cemiplimab (350 mg) (n = 20). Results: In dose escalation (n = 39), there were no DLTs, treatment-related deaths, related SAEs, grade ≥ 3 treatment-related AEs or signals from vital signs, ECGs or laboratory results. One patient (monotherapy, 400 mg) discontinued due to grade 2 AEs. Infusion-related reactions (IRRs) occurred in 6 patients (3 monotherapy [1 at 800 mg and 2 at 1600 mg] and 3 combination [400, 800 and 1600 mg]). All IRRs were grade ≤ 2 and were mitigated by extending infusion duration to 60 minutes, with secondary prophylaxis if necessary (acetaminophen, diphenhydramine). All but 4 patients were evaluable for efficacy, see table. Monotherapy responses were seen at 200 and 800 mg in melanoma and non-small cell lung cancer (NSCLC), respectively. In combination, 1 patient with soft tissue sarcoma (1600 mg) had a cPR. There were 13 deaths due to progressive disease. Durable stable disease (SD) was seen in: sarcomas, cutaneous squamous cell carcinoma, thymoma, thyroid, melanoma, hepatocellular carcinoma and colorectal cancer. OR502 RO was near-complete at ≥ 200 mg and PK was roughly dose-proportional. Combination with cemiplimab did not affect RO or PK. Conclusions: OR502 has excellent safety and tolerability ± cemiplimab. Based on efficacy, predictable PK and near-complete RO, two mini-expansion cohorts are evaluating OR502 800 mg Q3W ± cemiplimab in patients with cutaneous melanoma or NSCLC who have failed or progressed after ≥ 12 weeks of anti-PD-(L)1. Clinical trial information: NCT06090266 . Best objective response (RECIST 1.1), PK and RO. OR502 (n=17) OR502 + cemiplimab (n=18) PR 2 1 cPR 1 1 SD 9 8 Durable SD (≥ Week 12) 7 4 Best overall response rate % 12 6 Disease control rate (CR+PR+SD)% 65 50 PK (100–1600 mg)t½ (day) 7.6–15.9 8.4–12.4 Peripheral RO% (100–1600 mg)Classical monocytes 91–101 88–99 Neutrophils 89–100 84–100