1025MO - Preliminary safety, pharmacokinetics and immunomodulatory activity of RBS2418, an oral ENPP1 inhibitor, alone and in combination with pembrolizumab in patients with solid tumors

Background

ENPP1 is a nucleotide pyrophosphatase and phosphodiesterase and its overexpression is associated with poor prognosis in cancer. ENPP1 inhibition protects cGAMP and ATP from hydrolysis, reduces adenosine levels in the TME, activates APCs and increases T-cell infiltration promoting antitumor immunity. RBS2418, a first-in-class oral ENPP1 inhibitor, is in an ongoing phase I clinical trial in solid tumors.

Methods

Phase 1 dose escalation (3+3 design) with 100, 200, 400 and 800 mg BID dose cohorts of RBS2418 alone or in combination with pembrolizumab (200 mg IV q3w) in patients who have previously failed all SOC therapies. Primary endpoints are safety and PK. On-treatment tumor biopsy and blood samples are collected to determine PK/PD and immune profiles using LC/MS, ENPP1 inhibition, IF, IHC, flow cytometry, and TCR/RNAseq analysis.

Results

The first 3 dose levels evaluated to date in 19 patients were safe and well tolerated with no DLTs. Median plasma concentrations of RBS2418 increased in a dose-dependent manner. Plasma and tumor concentrations of RBS2418 were above the EC90 level of ENPP1 inhibition in all patients at all time-points tested. IHC analyses show baseline ENPP1 and cGAS co-expression in tumors correlating with RBS2418 treatment associated prolonged disease stabilization (SD duration >180 days) and peripheral T-cell activation, increased tumor-infiltrating T-cells and M2 to M1 macrophage repolarization, consistent with the drug’s mechanism of action.

Conclusions

Oral RBS2418 alone or with pembrolizumab has been safe and well tolerated at all dose levels studied to date in the ongoing dose escalation study. The PK profile showed plasma levels enabling complete ENPP1 inhibition. Preliminary analyses support the hypothesis that ENPP1 and cGAS co-expression in tumors correlates with RBS2418 treatment associated immune activation and prolonged disease stabilization suggestive of clinical benefit in multiple patients with refractory malignancies including MSS CRC and HCC (NCT05270213).

Clinical trial identification

NCT05270213.

Editorial acknowledgement

Legal entity responsible for the study

Riboscience, LLC.

Funding

Riboscience.

Disclosure

T.U. Marron: Financial Interests, Personal, Research Grant: Regeneron, BMS, Merck, BI; Financial Interests, Personal, Advisory Board: Regeneron, BMS, Merck, BI, AbbVie, AZ, Genentech, Atara, Arcus, Astellas, Celldex, Chimeric, G1 Therapeutics, Surface, Simcere, Glenmark, NGMbio, DBV Technologies. C. chen: Financial Interests, Personal, Other, consultant: Boxer Capital, Guidepoint Global Advisors; Financial Interests, Institutional, Local PI: Kinnate Biopharma, ADC Therapeutics, Riboscience, Gilead Sciences, Palleon; Financial Interests, Local PI: Rain Oncology, Oric Pharmaceuticals, Mersana, Pionyr. 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; Other, Other, As Founder and Owner of BioCytics Inc. developing immune cellular therapy.: BioCytics Inc.. I. Csiki: Financial Interests, Personal, Officer: Riboscience. J.M. Schanzer: Financial Interests, Personal, Financially compensated role: Riboscience. L. O'Toole: Financial Interests, Personal, Full or part-time Employment: Riboscience. N. Huang: Financial Interests, Personal, Full or part-time Employment: Riboscience. J. Seppa: Financial Interests, Personal, Other, consulting: Riboscience. J. Glenn: Financial Interests, Personal, Member of Board of Directors: Eiger Pharmaceuticals, Riboscience. K. Klumpp: Financial Interests, Personal, Member of Board of Directors: Riboscience. 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; 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. All other authors have declared no conflicts of interest.