A phase 1b study of NC410 in combination with pembrolizumab in immune checkpoint inhibitor (ICI) naïve, and refractory microsatellite stable (MSS)/microsatellite instability-low (MSI-L) colorectal cancer (CRC) and ovarian cancer.
Authors: Christenson Eric , Mahadevan Daruka , Kazmi Syed Mohammad Ali , Manda Sudhir , Sohal Davendra , Hutson Thomas E. , Fu Siqing , Martz Ashley , Kordahi Stephanie , Barbu Emilia Alina , Flies Dallas , Langermann Solomon , Chisamore Michael Jon , Gutierrez Martin , Matrana Marc Ryan , Spira Alex , Wadlow Raymond Couric , Guha Udayan , Myint Han , Le Dung T. 
Published: June 2024

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Background: Treatment options for advanced, refractory MSS/MSI-L CRC and Ovarian cancer are limited, with no FDA-approved ICI therapies. Such tumors have higher collagen deposition resulting in inherent resistance to ICI therapy partly due to the tumor extracellular matrix (ECM) functioning as a physical barrier to immune cell infiltration. Furthermore, dysregulated collagen in ECM inhibits immune cell function through binding to the inhibitory receptor, Leukocyte Associated Immunoglobulin-Like Receptor-1 (LAIR-1) expressed on immune cells. This inhibition can be reversed by endogenous LAIR-2 decoy protein, that competes with LAIR-1 binding. NC410 is a dimeric LAIR-2 protein fused to a human IgG1 Fc domain. NC410 promotes ECM remodeling by targeting collagen, promoting immune cell infiltration, and reversing LAIR-1-mediated immunosuppression. In preclinical models, NC410 in combination with anti-PD-1/anti-PD-L1 further potentiates immune function and anti-tumor activity in recalcitrant tumors. Methods: An open-label, single-arm Phase 1b/2 study was initiated to determine the safety, tolerability, and RP2D of NC410 when combined with pembrolizumab in metastatic solid tumors (NCT05572684). Participants received a fixed dose of pembrolizumab (400mg Q6W) on Day 1 and NC410 Q2W on Days 1, 15, and 29 of each 42-day cycle following a modified Toxicity Probability Interval (mTPI) design. The data cut-off was 4-Jan-2024 and the study continues to enroll. Results: To date, 65 participants with ICI naïve and refractory MSS/MSI-L CRC and Ovarian cancer received escalating doses of NC410 at 30 (n=3), 60 (n=11), 100 (n=39), and 200mg (n=12) in combination with pembrolizumab. The therapy appears safe and tolerable with diarrhea and fatigue being the most common, and Gr≥3 treatment emergent (14.8%) and related (1%) adverse events; one participant discontinued study due to myocarditis (Gr 3). Of the 32 MSS/MSI-L CRC treated with 100mg NC410, 28 are ICI naïve, of which 17 are currently evaluable with at least one 9-week scan. Of the 17, two confirmed PRs remain ongoing (>9 mo and > 4 mo), 6 durable SD (DCR 47%, ≥ 4 months), and 9 reported PD. Of the 11 Ovarian treated, 9 are currently evaluable: 2 ongoing PRs (>6mo at 200mg and 2mo at 100mg), 2 durable SD ≥4 months at 60mg NC410, and 5 PD. Preliminary assessment of pre- and on-treatment biopsies (N=12) shows decrease in immature collagen, suggesting ECM remodeling. Pre- and on-treatment peripheral blood immunophenotyping shows relatively higher CD8+ effector memory T cells and lower myelosuppressive neutrophils in CRC subjects without liver metastasis. Conclusions: Taken together, NC410 in combination with pembrolizumab shows promising clinical activity in hard-to-treat, advanced metastatic CRC and Ovarian cancer. Clinical trial information: NCT05572684 .