Abstract 176P
Background
A2A/A2B receptors drive adenosine-mediated immunosuppression in the tumor microenvironment; blockade has shown clinical activity in advanced solid tumors. This ongoing, 2-part (dose-escalation/expansion) phase 1 study is investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of INCB106385, an oral, potent, selective dual A2A/A2B receptor antagonist, alone or combined with an anti-PD-1 antibody retifanlimab for advanced solid tumors (NCT04580485). Part 1 (dose-escalation) monotherapy results are reported herein.
Methods
Eligible adults had confirmed advanced solid tumors by histology/cytology, disease progression after available therapy (including PD-[L]1 therapy, if applicable), measurable disease (RECIST v1.1), and ECOG PS 0-1. INCB106385 dosing started at 40 mg QD and was escalated using a BOIN design. PK parameters were calculated from INCB106385 plasma concentrations using non-compartmental, model-independent methods. PD was evaluated by measuring the reversal of adenosine-dependent inhibition of T cell and monocyte inflammatory cytokine production.
Results
As of July 16, 2022, 18 pts (male, n=16; age ≥65 years, n=17) had received INCB106385 monotherapy (40 mg QD, n=4; 40 mg BID, n=4; 80 mg BID, n=6; 160 mg BID, n=4); 16 discontinued therapy (progressive disease, n=14). The median (range) duration of treatment was 9.5 (0.9–40) weeks. Treatment-emergent AEs (TEAEs) occurred in 17 pts, most commonly asthenia, constipation, and diarrhea (each n=4). One pt had a grade ≥3 TEAE (grade 3 neutropenia; 40 mg BID); 2 had serious TEAEs (tumor pain; encephalopathy; both 40 mg BID); none were treatment-related. There were no dose-limiting toxicities or discontinuations due to TEAEs. INCB106385 plasma concentration remained above EC90 (∼300 nM) for all BID doses during the inter-dose 0-12 h. In PD analysis, doses ≥80 mg BID approached EC90 at steady state in most pts.
Conclusions
INCB106385 was generally well tolerated in pts with advanced solid tumors, with asthenia and gastrointestinal events being the most common TEAEs. Doses ≥80 mg BID were sufficient for target inhibition in most pts. Further dose escalation is ongoing in parallel with dose expansion.
Clinical trial identification
NCT04580485.
Editorial acknowledgement
Medical writing assistance was provided by Simon J. Slater, PhD, CMPP, of Envision Pharma Group (Philadelphia, PA, USA), and funded by Incyte Corporation.
Legal entity responsible for the study
Incyte Corporation.
Funding
Incyte Corporation.
Disclosure
A. Italiano: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, IPSEN, Merck CgA, MSD, Novartis, Parthenon, Roche, Springworks; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Bayer, Daiichy Sankyo, Ipsen, Merck CgA, Merck CgA, MSD, Novartis, Parthenon, Roche. O. Saavedra Santa Gadea: Financial Interests, Personal, Other, Travel, accommodations: Affimed. K. Papadopoulos: Financial Interests, Personal, Advisory Role: Basilia, Turning Point Therapeutics, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant: AbbVie, MedImmune, Daiichi Sankyo, Regeneron, Amgen, Calithera Biosciences, Incyte, Merck, Peloton Therapeutics, ADC Therapeutics, 3D Medicines, EMD Serono, Syros Pharmaceuticals, Mersana, MabSpace Biosciences, Jounce Therapeutics, Bayer, Anheart, F-star, Linnaeus, Mirati, Tempest Therapeutics, Treadwell Therapeutics, Lilly, Pfizer, Biontech, Bicycle Therapeutics, Kezar Life Sciences. A. Naing: Financial Interests, Institutional, Research Grant: Amplimmune, Arcus Biosciences, Armo BioSciences, Atterocor/Millendo, Bristol Myers Squibb, Calithera Biosciences, CytomX Therapeutics, Eli Lilly, EMD Serona, Healios Oncology Nutrition, ImmuneOncia, Incyte, Karyopharm, Kymab, MedImmune, Merck, NCI, NeoimmuneTech, Neon Therapeutics, Novartis, Pfizer, PsiOxus, Regeneron, Surface Oncology, TopAlliance Biosciences; Financial Interests, Personal, Advisory Board: CytomX Therapeutics, Genome & Company, Kymab, Novartis, OncoSec KEYNOTE-695, STCube Pharmaceuticals; Financial Interests, Personal, Other, Travel and accomodation expense: Armo BioSciences. C.A. Gomez-Roca: Financial Interests, Personal, Other, Honoraria/Speaker fee: AstraZeneca, Bristol Myers Squibb, Foundation Medicine Eisai, Pierre Fabre, Roche/Genentech; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Foundation Medicine, Genentech, Macomics, PharmaMar; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Roche/Genentech; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Bristol Myers Squibb, Pierre Fabre, Roche. M. Mita: Financial Interests, Institutional, Research Grant: Seattle Genetics. M. Stein: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb/Medarex, Exelixis, Janssen Oncology, Merck Sharp & Dohme, Vaccitech, Xencor, Oxford Oncology; Financial Interests, Institutional, Research Grant: Advaxis, Bellicum Pharmaceuticals, Bristol Myers Squibb, Exelixis, Genocea Biosciences, Harpoon, Janssen Oncology, Lilly, Medivation/Astellas, Merck Sharp & Dohme, Nektar, Oncoceutics, Seattle Genetics, Suzhou Kintor Pharmaceuticals, Xencor, (Inst); Tmunity Therapeutics, Inc. . I. Rybicka: Financial Interests, Personal, Full or part-time Employment: Incyte Corporation; Financial Interests, Personal, Stocks/Shares: Incyte Corporation. M. van der Velden: Financial Interests, Personal, Full or part-time Employment: Incyte Corporation; Financial Interests, Personal, Stocks/Shares: Incyte Corporation. P. Zhang: Financial Interests, Personal, Full or part-time Employment: Incyte Corporation; Financial Interests, Personal, Stocks/Shares: Incyte Corporation. M. Smith: Financial Interests, Personal, Full or part-time Employment: Incyte Corporation; Financial Interests, Personal, Stocks/Shares: Incyte Corporation. O. Ivanova: Financial Interests, Personal, Full or part-time Employment: Incyte Corporation; Financial Interests, Personal, Stocks/Shares: Incyte Corporation. Y. Loriot: Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, Clovis Oncology, CureVac, Exelixis, Incyte Corporation, Janssen, Medivation, MSD, Nektar, OncoGeneX, Pfizer, Sanofi; Financial Interests, Personal, Advisory Role: Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Immunomedics, Janssen, MSD, Roche, Seattle Genetics, Taiho Pharmaceutical; Financial Interests, Personal, Other, Honoraria: Pfizer, Sanofi; Financial Interests, Personal, Officer, Travel/Accommodation expenses: Astellas Pharma; Financial Interests, Personal, Other, Travel/Accommodation expenses: AstraZeneca, Janssen, MSD, Roche, Seattle Genetics.