Re-sensitizing PD-1/PD-L1 relapsed/refractory solid tumors: Phase 1a results of IOS-1002, a LILRB1/2 and KIR3DL1 checkpoint inhibitor, in combination with pembrolizumab.

2501 Background: Despite anti-PD-1/PD-L1 therapy success, 60-70% of patients develop progression with limited options (ORR 6-8% to retreatment). Upregulation of inhibitory receptors LILRB1/2 and KIR3DL1 mediates immune escape in anti-PD-1/PD-L1-resistant tumors. IOS-1002, a novel LILRB1/2 and KIR3DL1 antagonist, restores anti-tumor immunity when combined with pembrolizumab. Methods: Open-label, multicenter, dose-escalation Phase 1a study (NCT05235308) evaluated IOS-1002 (300-1800mg, Q2W IV) plus pembrolizumab 400mg (Q6W IV) in advanced solid tumors progressing on prior anti-PD-1/PD-L1 therapy. Primary endpoints: safety, tolerability; secondary: ORR, DCR, duration of response (DOR). Comprehensive biomarker analysis included serial cytokine profiling, target receptor expression (LILRB1/2, KIR3DL1), and tumor immune score (TIS) by gene expression analysis. Responses were assessed by RECIST v1.1. Results: As of January 1st, 2026, 28 patients received combination treatment with 16 anti-PD-1/PD-L1-relapsed/refractory patients (median age 65, ECOG 0-1). 3 confirmed PRs (tumor reduction -35% to -58% from baseline) leading to an ORR of 20% (3/15 evaluable) were noted with a DCR of 54% at week 12 (7/13) and 40% at week 24 (4/10), respectively. Durable responses included: 1 metabolic CR (urothelial cancer), 1 pathological CR confirmed by repeat biopsy showing absence of viable tumor cells (cutanteous SqCC), and 1 cervical cancer patient achieving -29% tumor reduction with concomitant > 90% decline in CA-125 tumor marker. Median treatment DOR was 30+ weeks (range 12-46+); 8 patients remain on treatment. Biomarker analysis demonstrated strong predictive value for TIS and target receptor expression achieving 75% ORR (3/4) versus 0% in dual-low patients (0/5). Combined biomarker score significantly correlated with depth of response (R² = 0.72, p = 0.008) and progression-free survival (HR 0.31, 95% CI 0.11-0.88, p = 0.04). Safety profile was favorable with no increase in grade≥3 immune-related adverse events beyond pembrolizumab monotherapy. Conclusions: IOS-1002 plus pembrolizumab demonstrated clinically meaningful efficacy in pretreated anti-PD-1/PD-L1-relapsed/refractory patients. Biomarker-driven patient selection using dual-high TIS and target receptor expression enhanced ORR to 75% and strongly predicted response depth, durability, and survival benefit. The favorable safety profile with no incremental immune-related toxicity, coupled with durable responses and high disease control rates, provides compelling rationale for Phase 1b expansion in biomarker-selected PD-1/PD-L1-refractory solid tumors. Clinical trial information: NCT05235308 . Endpoint Result ORR (evaluable) 20% (3/15) DCR Week 12 54% (7/13) DCR Week 24 40% (4/10) Biomarker-selected ORR 75% (3/4) Ongoing treatment 8/16 (50%)