730MO - First-in-human phase I study of INCAGN02390, a TIM-3 monoclonal antibody antagonist in patients with advanced malignancies

Background

TIM-3 is a transmembrane checkpoint receptor expressed on multiple immune cells that promotes an inhibitory tumor microenvironment. INCAGN02390 is a fully human Fc-engineered IgG1κ monoclonal antibody that selectively inhibits TIM-3 ligand interactions. This study is primarily aimed to determine the safety and tolerability and define the MTD or PAD of INCAGN02390 monotherapy.

Methods

This is a phase 1, multicenter, open-label, dose-escalation study that enrolled pts with locally advanced or metastatic solid tumors that failed available therapies, were intolerant to treatment, or refused noncurative standard treatment. A 3+3 dose-escalation design was used; pts received intravenous INCAGN02390 Q2W in 7 dose levels (DLs): 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. The primary endpoint was safety and tolerability. Other endpoints were PK, PD and preliminary efficacy per RECIST v1.1.

Results

Forty pts (median age, 63 y) were enrolled; 53% were male and 83% had ECOG PS 1. Lead cancer types were breast (15%), lung (13%), and colorectal (10%). 98% received prior systemic therapy (58% had prior immunotherapy). No DLT was observed and MTD was not reached. Most frequent treatment-emergent adverse events (TEAEs) were anemia (35%), back pain (30%), and fatigue (28%). Drug-related grade ≥3 TEAEs were observed in 7.5% of pts (anemia, adrenal insufficiency, and amylase increased [n=1 each]; all Gr3). One drug-related serious TEAE (adrenal insufficiency) occurred at the 1600 mg DL. One drug-unrelated fatal TEAE (multi-organ failure) occurred in the 800-mg DL. INCAGN02390 trough serum concentrations achieved steady state around Cycles 4 to 6. Maximum concentration and area under the serum concentration-time curve were linear across most DLs. Doses ≥400 mg led to trough TIM-3 receptor occupancy levels of ≥90% in peripheral blood. Disease control rate was 17.5%, with 1 confirmed partial response in a pt with an adenoid cystic carcinoma in lung.

Conclusions

INCAGN02390 monotherapy was generally well tolerated, with linear PK. The 400 mg Q2W dose is selected for further investigation in phase 1b/2 studies in combinations with other immunotherapies (NCT04370704, NCT05287113).

Clinical trial identification

NCT03652077.

Editorial acknowledgement

Writing assistance was provided by Cory Pfeiffenberger, PhD (ICON, Blue Bell, PA, USA), and was funded by Incyte Corporation.

Legal entity responsible for the study

Incyte Corporation.

Funding

Incyte Corporation.

Disclosure

M.E. Gutierrez: Financial Interests, Institutional, Funding: Incyte. S. Tang: Financial Interests, Institutional, Funding: Incyte. J.D. Powderly: Financial Interests, Personal, Consulting: Boxer Capital; Financial Interests, Personal, Invited Speaker, Consulting: Aavocyte; Financial Interests, Personal, Invited Speaker, Founder and Owner: Carolina BioOncology Institute, PLLC, BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner: BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner of phase 1 cancer research clinic.: Carolina BioOncology Institute, PLLC; Financial Interests, Personal, Founder and Owner, developing intellectual property for cellular therapies: BioCytics Inc; Financial Interests, Personal and Institutional, Invited Speaker: Bristol Myers Squibb, Cullinan, Genentech/Roche, AstraZeneca/MedImmune, EMD Serono, Macrogenics, InCyte, Top Alliance BioSciience, Seattle Genetics, AbbVie, FLX Bio, Alkermes, Arcus BioSciences, Tempest Therapeutics, Calico Life Sciences, Apros, Jounce Therapeutics, Atreca, Sequenom, Repertoire Immune Medicines, Molecular Templates, I-MAB Pharma, NexCure, Xilio Therapeutics, Immune-Onc, Trethera, Zenshine Pharma, Adagene, BJ BioScience, Fate Therapeutics, Conjupro BioTherapeutics; Financial Interests, Institutional, Funding: Precision for Medicine, MT Group, STEMCELL Technologies, Replimmune, Merck, Xilis; Financial Interests, Personal and Institutional, Funding: PIOMA; Financial Interests, Personal and Institutional, Invited Speaker, Also funding for contract laboratory services: Nuvation; As Founder and Owner of BioCytics Inc. developing immune cellular therapy.: BioCytics Inc.. A.S. Balmanoukian: Financial Interests, Personal, Speakers Bureau: BMS, Genentech, AstraZeneca; Financial Interests, Institutional, Sub-investigator on the industry sponsored trial at our institution.: BMS; Financial Interests, Institutional, Sub-investigator on the industry sponsored trial at our site. No direct compensation.: MedImmune; Financial Interests, Institutional, Sub investigator on the industry sponsored trial at our site.: Regeneron; Financial Interests, Institutional, Both PI and Sub-I on Seattle Genetics trials at our site.: Seattle Genetics; Financial Interests, Institutional, sub-I on industry sponsored trial at our site: Pfizer; Financial Interests, Institutional, sub-I on industry sponsored trial at out site: Nextcure; Financial Interests, Institutional, Other, sub-I on industry sponsored trial at our site: Incyte, Rubius Therapeutics; Financial Interests, Institutional, Sub-I on industry sponsored study at our site: TAIGA therapeutics, Treadwell Therapeutics, Tyrnovo, Mereo Biopharma, Surface therapeutics, Tmunity; Financial Interests, Institutional, Invited Speaker, Both PI and sub-I on GSK sponsored trials at our site: GSK; Financial Interests, Institutional, sub-I on industry sponsored trials at our site: Epizyme; Financial Interests, Institutional, Invited Speaker, Both PI and sub-I on Arcus sponsored trials at our site: Arcus; Financial Interests, Institutional, Sub-I on industry sponsored trials at our site: amgen. J. Janik: Financial Interests, Personal, Full or part-time Employment: Incyte. P. Hoyle: Financial Interests, Personal, Full or part-time Employment: Incyte. W. Wei: Financial Interests, Personal, Full or part-time Employment: Incyte. X. Gong: Financial Interests, Personal, Full or part-time Employment: Incyte. O. Hamid: Financial Interests, Personal, Invited Speaker: BMS, Novartis, Pfizer, Sanofi / Regeneron; Financial Interests, Personal, Advisory Board: Aduro, Akeso, Amgen, Beigene, BMS, Roche Genentech, GSK, Immunocore, Idera, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi / Regeneron, Seagen, Tempus, Zelluna, Bioatla, Alkermes, Instil Bio, Iovance; Financial Interests, Institutional, Invited Speaker: Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, CytomX, Exelixis, Roche Genentech, GSK, Immunocore, Idera, Incyte, Iovance, Merck, Moderna, Merck Serono, Nextcure, Novartis, Pfizer, Sanofi / Regeneron, Seagen, Torque, Zelluna, Rubius.