Phase 1 study of anti–immunoglobulin-like transcript 3 (ILT3) monoclonal antibody MK-0482 + pembrolizumab + gemcitabine + nab-paclitaxel (Gem/Nab-P) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Golan Talia , Cohen Jonathan , Voskoboynik Mark , Gutierrez Martin , Park John J. , Valente Monica , Renouf Daniel John , Liu Qi , Edmondson Mackenzie , Myer Nicole , Kapadia Kishan J. , Chen Mei , Victoria Iván 
Published: June 2024

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Background: Standard first-line treatment of mPDAC includes Gem/Nab-P doublet therapy, which typically results in an ORR of 23%-35%, a median PFS of 5-6 mo, and a median OS of 7-10 mo. ILT3 is an inhibitory receptor expressed on monocytic myeloid cells, including tolerogenic dendritic cells and myeloid-derived suppressor cells. MK-0482 is a novel humanized IgG4 monoclonal antibody targeting ILT3. ILT3 inhibition with MK-0482 has the potential to relieve immunosuppression within the tumor microenvironment. In the expansion cohort of the first-in-human phase 1 study MK-0482-001 (NCT03918278), the combination of MK-0482 + pembrolizumab + Gem/Nab-P was evaluated in pts with treatment-naive mPDAC. The safety and efficacy data from this cohort are presented. Methods: Pts aged ≥18 y with previously untreated mPDAC, measurable disease per RECIST v1.1, and an ECOG PS of 0 or 1 received MK-0482 750 mg Q3W + pembrolizumab 200 mg Q3W IV for ≤35 cycles + Gem/Nab-P (gemcitabine 1000 mg/m2; nab-paclitaxel 125 mg/m2) on days 1, 8, and 15 Q4W until PD or treatment discontinuation. The primary end point was safety. Secondary end points were ORR, DCR (CR + PR + SD), and DOR by investigator assessment per RECIST v1.1. Exploratory end points included PFS per RECIST v1.1 and OS. Results: A total of 37 pts were enrolled and received study treatment. At data cutoff (Oct 3, 2023), median follow-up was 13 mo (range 8.9-18.9). Median age was 65 y (range, 39-77). Most pts were male (54%), had an ECOG PS 1 (65%), and had ≥3 sites of metastasis (54%). Any-cause adverse events (AEs) occurred in all pts and treatment-related AEs (TRAEs) occurred in 36 pts (97%). Grade 3 or 4 TRAEs occurred in 27 pts (73%); the most frequent (≥10%) were decreased neutrophil count (27%), anemia (19%), and neutropenia (19%). No deaths due to TRAEs occurred. Immune-mediated AEs occurred in 12 pts (32%); the most frequent (≥10%) was hypothyroidism (11%). Grade 3 immune-mediated AEs occurred in 5 pts (14%; hepatitis, n = 2; severe skin reactions, n = 2; colitis, n = 1); no grade 4 or 5 events occurred. Confirmed ORR was 43% (16/37; 95% CI, 27.1-60.5), DCR was 84% (31/37; 68.0-93.8), and median DOR was 8.5 mo (range, 3.7-17.8+). Median PFS was 8.5 mo (95% CI, 5.7-12.3) and median OS was 15.6 mo (10.5-22.1); 12-mo PFS and OS rates were 35% and 60%, respectively. Biomarker data will be included in the presentation. Conclusions: MK-0482 + pembrolizumab + Gem/Nab-P showed a manageable AE profile in patients with treatment-naive mPDAC, which was generally consistent with the combined safety profiles of pembrolizumab-based immunotherapy and Gem/Nab-P, respectively. The 4-drug combination showed increased clinical efficacy compared with that historically observed for chemotherapy regimens. Further evaluation is needed to confirm the clinical activities observed. Clinical trial information: NCT03918278 .