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: Eric Christenson, Daruka Mahadevan, Syed Mohammad Ali Kazmi, Sudhir Manda, Davendra Sohal, Thomas E. Hutson, Siqing Fu, Ashley Martz, Stephanie Kordahi, Emilia Alina Barbu, Dallas Flies, Solomon Langermann, Michael Jon Chisamore, Martin Gutierrez, Marc Ryan Matrana, Alex Spira, Raymond Couric Wadlow, Udayan Guha, Han Myint, Dung T. Le
Journal: Journal of Clinical Oncology (2024)

2538 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 (&gt;9 mo and &gt; 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 (&gt;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 .