1000MO - A phase I/II, open-label study of the novel checkpoint IGSF8 inhibitor GV20-0251 in patients with advanced solid tumors

Background

IGSF8 is a newly discovered innate immune checkpoint that suppresses NK cell cytotoxicity in antigen presentation deficient tumors which are often resistant to immune checkpoint inhibitors. GV20-0251 is a cross-species reactive, Fc-attenuated IgG1 antibody against IGSF8. It enhances NK cell killing of malignant cells in vitro, and upregulates antigen presentation, NK cell-mediated cytotoxicity, and T cell signaling in vivo. In syngeneic tumor models, anti-IGSF8 alone, or in combination with anti-PD1, inhibits tumor growth.

Methods

Eligible adult patients with advanced solid tumors received increasing doses of GV20-0251 using a 3+3 design to estimate toxicity and to determine the maximum tolerated dose and preliminary recommended phase 2 dose. Plasma PK and target occupancy were characterized using standard methods. Preliminary efficacy was assessed by RECIST v1.1.

Results

As of July 1, 2024, 38 patients were enrolled across six dose levels (0.5, 1, 3, 6, 10, and 20 mg/kg) and two schedules (Schedule A D1/D8 Q3W, Schedule C D1 Q3W).The median age of enrolled patients was 62 years and the median lines of prior treatment was 4. GV20-0251 was well tolerated at all doses withoutdose limiting toxicities.Treatment-related adverse events (TRAEs) occurred in 50% of patients that were all grade 1/ 2 with the exception of one patient with grade 3 pneumonitis. The most common AEs were rash, pruritis, fatigue, and anemia with no apparent trends by dose level. There were dose proportional PK and full target occupancy on circulating T cells in cohorts ≥ 3 mg/kg. Two partial responses (one confirmed, another not yet confirmed) were observed in metastatic cutaneous melanoma patients treated with GV20-0251 at 3 mg/kg (Schedule A) and 10 mg/kg (Schedule C), respectively. Fourteen of the 29 evaluable patients showed stable disease, including 4 with tumor shrinkage.

Conclusions

GV20-0251, a first-in-class antibody against a novel immune checkpoint IGSF8, is safe and well-tolerated up to 20 mg/kg in heavily treated patients with advanced solid tumors, and demonstrates preliminary clinical efficacy. Additional enrollment, safety, PK, PD and efficacy data will be presented.

Clinical trial identification

NCT05669430; Released on December 30, 2022.

Editorial acknowledgement

Legal entity responsible for the study

GV20 Therapeutics.

Funding

GV20 Therapeutics.

Disclosure

K. Wentzel: Financial Interests, Institutional, Invited Speaker, Presented the: OncLive; Non-Financial Interests, Principal Investigator: GV20 Therapeutics, Astellas Pharma, Exelixis, Incyte Corporation. J. Peguero: Non-Financial Interests, Institutional, Local PI: GV20 Therapeutics. S. Kummar: Financial Interests, Personal, Advisory Board: Bayer, Gilead, Mundibiopharma, Springworks Theraepeutics, HarbourBiomed, Oxford BioTherapeutics, BPGbio Therapeutics, XYOne Therapeutics, GI Innovation Inc.; Financial Interests, Personal, Advisory Board, Spouse: Cadila Pharmaceuticals; Financial Interests, Personal, Other, Chair, DSMC: Mirati; Financial Interests, Personal, Advisory Board, Consultant: Genome Insight; Financial Interests, Personal, Ownership Interest: Pahtomiq; Financial Interests, Personal, Ownership Interest, Spouse (co-founder): Arexeon; Financial Interests, Personal, Stocks/Shares: Fortress Biotech; Financial Interests, Personal, Other, co-founder: Pathomiq; Financial Interests, Institutional, Local PI, Trial funding: ADC Therapeutics, Pionyr Therapeutics, Eisai, Bristol Myers Squibb, Syndax, SeaGen, ORIC, EMD Serono, Genome & Company, Moderna, Amgen, ASTX Therapeutics, PMV Pharmaceuticals, Elevation Oncology, Gilead, Day One BioPharmaceuticals, Sillajen Inc.; Financial Interests, Institutional, Local PI, Trial Funding: 23&Me; Financial Interests, Institutional, Local PI, Trial Funding: Deciphera Pharmaceuticals Llc, AstraZeneca, Immunitas Therapeutics, Inc., Mirati Therapeutics Inc, Transcenta Therapeutics, Inc., Adanate, Inc, GV20 Therapeutics Llc, Blueprint Medicines Corp, Nuvectis Pharma, Inc., Fog Pharmaceuticals. P. Lorusso: Non-Financial Interests, Institutional, Principal Investigator: GV20 Therapeutics. J.M. Mehnert: Financial Interests, Institutional, Advisory Board, Scientific advisory board: Merck; Financial Interests, Institutional, Advisory Board: Regeneron. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi; Financial Interests, Personal, Other, Consulting or Advisory Role/Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med, Regeneron, Loxo, Alkermes, Medikine, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, Arrivent Biopharma. A. Naing: Financial Interests, Personal, Advisory Board: CTI, Deka Biosciences, Janssen Biotech, NGM Bio, PsiOxus Therapeutics, Immune-Onc Therapeutics, STCube Pharmaceuticals, OncoSec Keynote 695, Genome & Company, CytomX Therapeutics, Nouscom, Merck Sharp & Dohme Crop, Servier, Lynx Health, AbbVie, PsiOxus; Financial Interests, Institutional, Invited Speaker: AKH Inc., ASCO Direct Oncology Highlights, European Society for Medical Oncology; Financial Interests, Personal, Invited Speaker: Lynx Group, Society for Immunotherapy of Cancer, Korean Society of Medical Oncology, Scripps Cancer Care Symposium, CME Outfitters; Financial Interests, Institutional, Coordinating PI: NCI, EMD Serono; Financial Interests, Personal, Local PI: MedImmune, Healios Onc. Nutrition, Atterocor/Millendo; Financial Interests, Institutional, Local PI: Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab PsiOxus, Arcus Biosciences, NeoImmuneTech, Immune-Onc Therapeutics, Surface Oncology, Monopteros Therapeutics, BioNTech Se, Seven & Eight Biopharma, SOTIO Biotech AG; Other, Travel and Accommodation: ARMO BioSciences, NeoImmune Tech; Other, Travel and Accommodation: NGM BioPharmaceuticals. O. Hamid: Financial Interests, Personal, Advisory Board: Alkermes, Amgen, BMS, Bactonix, BeiGene, Bioatla, Eisai, GSK, Georgiamune, GigaGen, Grit Bio, IO Biotech, Idera, Immunocore, Incyte, Instil Bio, Iovance, Janssen, KSQ, Merck, Novartis, Obsidian, Pfizer, Roche Genentech, Seagen, Sanofi/Regeneron, Tempus, Vial, Zelluna; Financial Interests, Personal, Invited Speaker: BMS, Immunocore, Novartis, Pfizer, Sanofi/Regeneron; Financial Interests, Personal, Stocks/Shares: Bactonix; Financial Interests, Institutional, Local PI: Aduro, Akeso, Amgen, Arcus, BMS, Bioatla, CytomX, Exelixis, GSK, Idera, Immunocore, Incyte, Iovance, Merck, Merck Serono, Moderna, Nextcure, Novartis, Pfizer, Roche Genentech, Seagen, Sanofi/Regeneron, Torque, Zelluna. I. Mehmi: Financial Interests, Personal, Invited Speaker: Immunocore, BMS; Financial Interests, Personal, Stocks/Shares: Delcath, Immunocore, Ideaya, In8Bio, Iovance. K. Benhadji: Financial Interests, Personal, Officer: GV20 Therapeutics; Financial Interests, Personal, Stocks/Shares: Lilly; Financial Interests, Personal, Full or part-time Employment: Taiho Oncology. L. Alland: Financial Interests, Personal, Advisory Role: GV20 Therapeutics. X. Hu, X. Bao, J. Chen: Financial Interests, Personal, Full or part-time Employment: GV20 Therapeutics. H. Xiao: Financial Interests, Personal, Full or part-time Employment: GV20 Therapeutics; Financial Interests, Personal, Stocks/Shares: GV20 Therapeutics. Y. Gong: Financial Interests, Personal, Full or part-time Employment: GV20 Therapeutics; Financial Interests, Personal, Stocks/Shares: Roche. X.S. Liu: Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Invited Speaker: Xilio Therapeutics; Financial Interests, Personal, Full or part-time Employment: GV20 Therapeutics; Financial Interests, Personal, Stocks/Shares, Founder and CEO with stocks: GV20 Therapeutics.