577P - Results of the phase Ib study of NC410 combined with pembrolizumab in MSS/MSI-L colorectal cancer patients

Background

Treatment options for refractory MSS/MSI-L CRC are limited, with no FDA-approved ICI therapies. Such tumors have high collagen deposition in the extracellular matrix (ECM) resulting in a barrier to immune cell infiltration and ICI resistance. NC410 is a dimeric Leukocyte Associated Immunoglobulin-Like Receptor-2 (LAIR-2) protein fused to a human IgG1 Fc domain. NC410 targets collagen, promotes ECM remodeling, immune cell infiltration, and reverses immunosuppression mediated by LAIR-1 inhibitory receptor. NC410 and anti-PD-1/PD-L1 combination potentiates anti-tumor activity in preclinical models.

Methods

A Phase 1b study of NC410 plus pembrolizumab in advanced solid tumors was conducted (NCT05572684). MSS/MSI-L CRC patients (n=70) received pembrolizumab (400mg Q6W) on Day 1 and escalating doses of NC410 at 30 (n=3), 60 (n=9), 100 (n=48), and 200mg (n=10) Q2W on Days 1, 15, and 29 of a 42-day cycle following a modified Toxicity Probability Interval (mTPI) design. The data cut-off was 1-May-2024.

Results

The combination therapy is safe and tolerable with Gr≥3 treatment emergent (31%) and related (4%) adverse events (AEs). The study was enriched for CRC without liver metastases (LM-) at 100 and 200mg NC410, evaluated for RP2D. There were 50 evaluable LM- CRC patients at various dose levels, with 2 PRs and 24 SD (DCR: 52%), compared to 13 evaluable LM+ patients with 2 SD (DCR: 15%). At the 200mg dose level, amongst 9 evaluable patients (all LM-), 5 were SD (no reduction in tumor size) and 4 PD per RECIST 1.1. The 100mg dose level was comprised of 44 ICI naïve, of which 41 were LM- with 5 median prior lines of treatment (range 1-10), and 4 ICI refractory patients. Of the ICI refractory group, only 1 had SD. Of the 37 evaluable LM- CRC, 2 had confirmed ongoing PRs (>12+ mo and > 7+ mo), 17 SD, and 18 PD. DCR of the 100mg LM- group was 51.3% (19/37) [CI: 34.4, 68.1], with ORR of 5.4% (2/37) [CI: 0.7, 18.2]. On-treatment biopsy of a PR patient showed an increase in CD8+ effector memory T cells and reduction in myelosuppressive cells in the TME, compared to baseline.

Conclusions

NC410 plus pembrolizumab combo is a well-tolerated treatment option with clinical benefit in hard-to-treat metastatic CRC that merits further evaluation in a randomized study.

Clinical trial identification

NCT05572684.

Editorial acknowledgement

Legal entity responsible for the study

NextCure Inc.

Funding

NextCure Inc.

Disclosure

E.S. Christenson: Financial Interests, Personal, Advisory Board, Consultant for Seres Therapeutics: Seres Therapeutics; Financial Interests, Personal, Advisory Board, Advisory board: SIRTex therapeutics; Financial Interests, Institutional, Coordinating PI, PI on a trial for NextCure: NextCure; Financial Interests, Institutional, Research Grant, Research grant from Pfizer: Pfizer; Financial Interests, Institutional, Coordinating PI, PI for clinical trial with Regeneron: Regeneron; Financial Interests, Institutional, Local PI, PI for clinical trial: Affimed Gmbh. S. Kazmi: Financial Interests, Personal, Stocks/Shares: johnson and johnson. D. Sohal: Financial Interests, Personal, Invited Speaker: InCyte, SeaGen; Financial Interests, Personal, Advisory Board: Totus, Valar, Cancer Commons; Financial Interests, Institutional, Trial Chair: Ability Pharma, AstraZeneca; Financial Interests, Institutional, Local PI: Amgen, Apexigen, Astellas, Bexion, BMS, FibroGen, Genentech, Hengrui, Merck, Mirati, NextCure, PanCAN, Regeneron, Roche. S. Manda: Financial Interests, Personal, Advisory Board, Scientific advisor: Reglagene; Financial Interests, Personal, Stocks/Shares: Reglagene. A. Martz: Financial Interests, Personal, Full or part-time Employment: NextCure, Inc; Financial Interests, Personal, Stocks/Shares: NextCure, Inc. S. Kordahi: Financial Interests, Personal, Full or part-time Employment, Senior Director, Clinical Operations: NextCure, Inc.; Financial Interests, Personal, Stocks/Shares, Stock Options Grant: NextCure, Inc. M. Zika: Financial Interests, Personal, Full or part-time Employment: nextcure; Financial Interests, Personal, Stocks/Shares: nextcure. P. Kothari: Financial Interests, Institutional, Full or part-time Employment: NextCure. S. Kahan: Financial Interests, Personal, Full or part-time Employment, Employeed by Nextcure, Inc,: Nextcure, Inc. E.A. Barbu: Financial Interests, Institutional, Full or part-time Employment: NextCure, Inc.; Financial Interests, Personal, Stocks/Shares: NextCure, Inc.; Non-Financial Interests, Institutional, Proprietary Information: NextCure, Inc. A. Morawski: Financial Interests, Institutional, Full or part-time Employment: NextCure, Inc.; Financial Interests, Institutional, Stocks/Shares, Granted Stock Options: NextCure, Inc. D. Flies: Financial Interests, Personal, Full or part-time Employment: NextCure; Financial Interests, Personal, Stocks/Shares: NextCure. S.A.R. Langermann: Financial Interests, Institutional, Full or part-time Employment, CSO: NextCure, Inc.; Financial Interests, Institutional, Stocks/Shares: NextCure, Inc. M. Chisamore: Financial Interests, Institutional, Full or part-time Employment: Merck & Co. Inc; Financial Interests, Institutional, Stocks/Shares: Merck & Co. Inc. S. Fu: Financial Interests, Institutional, Research Grant, Partial grant funding supporting facilities necessary for clinical trials.: NIH/NCI P30CA016672 – Core Grant (CCSG Shared Resources); Financial Interests, Institutional, Local PI: Abbisko, Antengene, BeiGene, Ltd, BeyondSpring Phamaceuticals, Inc., BioAtla, LLC., Boehringer Ingelheim, CUE Biopharma, Inc., DEKA Biosciences, Eli Lilly & Co., Exelixis, Greenfire Bio, Inc., Hookipa Biotech, ImmavRx, Inc. (IMV), Innovent Biologics, Co., Ltd., Jazz Pharmaceuticals, K-Group Beta, Lantern Pharma Inc., Lyvgen Biopharm, Co., Ltd., MacroGenics, MediLink Therapeutics, Co. Ltd., Millennium Pharmaceuticals, inc., Nerviano Medical Sciences, NeuPharma, Inc., NextCure, Inc., Ningbo NewBay Technology Development Co., Ltd., Novartis, NovoCure, Nykode Therapeutics, Parexel International, LLC, PharmaMar USA, Inc., Pionyr Immunotherapeutics, Inc., PureTech Health, LLC, Qurgen, Inc., Sellas Life Sciences Group, Shanghai Huaota Biopharmaceutical Co., Ltd., Soricimed Biopharma, Inc., SQZ Biotechnologies, Sumitomo Dainippon, Taiho Oncology and NCCN, Treadwell Therapeutics, Turnstone Biologics, Tyligand Bioscience, Ltd., Virogin Biotech, Ltd. R. Wadlow: Financial Interests, Personal, Advisory Board, Advisory Board: Exact Sciences; Financial Interests, Personal, Advisory Board: Pfizer. U. Guha: Financial Interests, Personal, Full or part-time Employment, employee of NextCure Inc.: NextCure Inc.; Financial Interests, Personal, Stocks/Shares, current employee stock options: NextCure Inc.; Financial Interests, Personal, Stocks/Shares, Prior employee of TCR2 Therapeutics- now Adaptimmune: TCR2/Adaptimmune. H. Myint: Financial Interests, Personal, Full or part-time Employment, Chief Medical Officer: NextCure Inc; Financial Interests, Personal, Stocks/Shares: NextCure Inc. D. Le: Financial Interests, Personal, Advisory Board: Merck, BMS, Nouscom, Janssen, Regeneron, G1 Therapeutics, Tavotek, Catenion, Sirtex, Tango Therapeutics, Endeavor Biosciences, Merus; Financial Interests, Personal, Other, Advice: Bayer; Financial Interests, Institutional, Local PI: Merck, BMS, Curegenix, Nouscom, Abbvie, Dynamicure. All other authors have declared no conflicts of interest.