Safety, PK, immune activation, and clinical outcomes with RBS2418 treatment, an oral ENPP1 inhibitor, alone or in combination with pembrolizumab in advanced solid tumors

BackgroundENPP1 is a nucleotide pyrophosphatase and phosphodiesterase, and expression is associated with poor prognosis in cancer and the development of metastases. ENPP1 inhibition can protect cGAMP and ATP from hydrolysis, activate APCs, and increase T cell infiltration promoting anticancer immunity. RBS2418 is being evaluated as monotherapy and combination with pembrolizumab in advanced/metastatic solid tumors.MethodsPhase 1 dose escalation (100, 200, 400 and 800 mg BID) and selected expansion cohorts of RBS2418 alone or in combination with pembrolizumab in patients (pts) whose cancer has progressed on all approved treatments including immunotherapy. Primary outcomes are safety and PK. Secondary outcomes include PD and immune profiles in tumors and blood using LC/MS, ENPP1 inhibition, IF, IHC, flow cytometry, and TCR/RNAseq analysis.ResultsAll dose levels evaluated up to 800 mg BID were safe and well tolerated with no DLTs (treatment duration 1-12 months). Plasma and tumor exposures of RBS2418 were dose-proportional and > EC90 of ENPP1 inhibition in serum was seen at all dose levels and in all pts. ENPP1 and cGAS expression (EG+ phenotype) in pre-treatment tumors correlated with RBS2418 treatment-associated immune activation and clinical benefit. Disease control rates (DCR) ranged from 25 – 100% across dose levels in pts with EG+ phenotype (n=19). DCR was 0% in pts with EG- phenotype at baseline (n=9). An increase in activated and proliferating CD8 T cells and other markers of immune activation was seen after therapy. EG+ phenotype and immune activation with RBS2418 correlated with improved clinical outcomes in immunotherapy-unresponsive cold tumors. RBS2418 safety, PK, PD and efficacy data with a data cutoff of June 15, 2024 on enrolled pts will be presented.ConclusionsOral RBS2418 alone or with pembrolizumab is safe and well tolerated in pts with a wide range of advanced solid tumors at exposures consistent with >90% target inhibition in tumors and plasma. Immune activation and treatment benefit correlated with baseline EG+ phenotype in tumors, and occurred in pts with cold tumor phenotype at baseline.Clinical trial identificationNCT05270213.Legal entity responsible for the studyRiboscience, Llc.FundingRiboscience, Llc.DisclosureT. Marron: Financial Interests, Personal, Advisory Board: Regeneron, AstraZeneca, Genentech, G1 Therapeutics, Arcus, Glenmark, Merck, NGMBio, Glenmark, AbbVie, Fate; Financial Interests, Institutional, Coordinating PI: Regeneron, Genentech, Boehringer Ingelheim, Merck. J.D. Berlin: Financial Interests, Personal, Advisory Board: Merck KGA, Mirati, Merus, Bristol Myers, Bexion, Ipsen, Merck, Sharp, Dohme, Biosapien, Insmed, Oxford Biotherapeutics; Financial Interests, Institutional, Local PI: Astellas, Atreca, Bayer, BMS, Dragonfly, I-MAB, Transient Therapeutic, Totus, Tyra, Sumitomo Dainippon Pharma Oncology, 23 and Me, Strata, Eli Lilly, Hibercell; Other, DSMB member: AstraZeneca, Novocure, I-SPY. 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. J. Powderly: Financial Interests, Personal, Other, Consulting: Boxer Capital; Financial Interests, Personal, Writing Engagement, Consulting: Aavocyte; Financial Interests, Personal, Member of Board of Directors, 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, Other, Founder and Owner, developing intellectual property for cellular therapies: BioCytics Inc; Financial Interests, Personal and Institutional, Local PI: 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, PEEL Therapeutics, CUE BioPharma, Pieris Pharmaceuticals, RiboScience, Moderna TX, Phanes Therapeutics, SK Life Science, Harbour BioMed, Simcere, Allarity, Aulos, GI Innovation, IGM BioSciences, Aptevo, Medikine, IconOVir Bio, Qurgen; 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, Local PI, Also funding for contract laboratory services: Nuvation; Financial Interests, Personal and Institutional, Funding, Wugen is sponsor of contract laboratory translational research: Wugen; Financial Interests, Personal and Institutional, Other, AavoCyte & AavoBioCytics are jointly developing cellular therapies with BioCytics Human Applications Lab for point of care manufacturing: AavoCyte; Financial Interests, Personal and Institutional, Local PI, Clinical Trial funding: Glenmark; Financial Interests, Personal and Institutional, Local PI, Clinical Trial Funding: FBD Biologics, MBrace, Astellas, BioNTech, SK Life Sciences, Revolution Medicines, Multitude, Sairopa, Corbus, CytoMx, Apollo; Other, As Founder and Owner of BioCytics Inc. developing immune cellular therapy: BioCytics Inc. Z.A. Wainberg: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Arcus, Bayer, AstraZeneca, Novartis, Roche, Ipsen, Daiichi, Merck, BMS, Merus; Financial Interests, Personal, Other, DMC: Pfizer; Financial Interests, Institutional, Steering Committee Member: Novartis, AstraZeneca; Financial Interests, Institutional, Coordinating PI: Ipsen; Financial Interests, Institutional, Local PI: Merck; Financial Interests, Institutional, Research Grant: BMS, Arcus. J.M. Schanzer: Financial Interests, Personal, Financially compensated role: Riboscience. J. Glenn: Financial Interests, Personal, Ownership Interest: Riboscience, Eiger. K. Klumpp: Financial Interests, Personal, Leadership Role: Riboscience; Financial Interests, Personal, Advisory Board: BioAge. I. Csiki: Financial Interests, Personal, Leadership Role: Riboscience. All other authors have declared no conflicts of interest.