663P - First-in-human, phase I/II, monotherapy, dose-escalation study of mRNA-4359, an mRNA-encoded PD-L1/IDO1 antigen-specific therapy, in advanced/refractory solid tumors

Background

mRNA-4359 is an mRNA therapy encoding immunogenic peptides of programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1), encapsulated in a lipid nanoparticle, that elicits T cell responses against tumor and immunosuppressive (regulatory T and myeloid) cells expressing IDO1 and PD-L1. We report data from the monotherapy dose-escalation portion of this ongoing study.

Methods

mRNA-4359 P101 monotherapy arm enrolled eligible patients (pts) with advanced solid tumors (refractory to ≥1 prior therapy) into escalating mRNA-4359 dose cohorts (100, 200, 400, and 1000 μg; intramuscularly every 3 weeks for a planned 9 cycles) with escalation decisions guided by a modified continual reassessment method (NCT05533697). Primary endpoint: safety/tolerability; secondary endpoints: anti-tumor activity by Response Evaluation Criteria in Solid Tumors v1.1 and changes in T cell phenotype. Immunogenicity assessment was exploratory.

Results

19 pts were enrolled across all dose levels and received ≥1 dose of mRNA-4359. No dose-limiting toxicities were reported at any dose level and no serious treatment-emergent adverse events were related to mRNA-4359. AEs related to mRNA-4359 were grade 1-2, most common were fatigue (n=7 pts, 37%), injection site pain (n=6 pts, 32%), and pyrexia (n=4 pts, 21%). A maximum tolerated dose was not reached. Of 16 response-evaluable pts, 8 (50%) had a best overall response of stable disease (SD; longest duration: 41 weeks; clinical cutoff: Apr 17, 2024). Antigen-specific T cell responses assessed in vitro by enzyme linked immunosorbent spot (ELISpot) after cell expansion to either PD-L1 or IDO1 were detectable in 13/14 (93%) pts with evaluable peripheral samples. Induction of activated, cytotoxic, and central memory T cells, along with reduction in regulatory T cells post-treatment were observed by flow cytometry in the periphery.

Conclusions

mRNA-4359 monotherapy was well tolerated at all tested dose levels with observation of SD and detectable antigen-specific T cell response. Enrollment continues in the mRNA-4359 + pembrolizumab combination arms, followed by expansion cohorts in pts with melanoma and non-small cell lung cancer.

Clinical trial identification

NCT05533697.

Editorial acknowledgement

Editorial and medical writing support were provided by Joels Wilson-Nieuwenhuis, PhD, of Caudex.

Legal entity responsible for the study

Moderna, Inc.

Funding

Moderna, Inc.

Disclosure

M.A. Khattak: Financial Interests, Personal, Advisory Board: Moderna; Financial Interests, Personal, Invited Speaker: MSD, Evaxion; Financial Interests, Personal, Other, Conference sponsorship: Evaxion; Financial Interests, Personal, Other, Advisory role: One Clinical Research. R.J. Sullivan: Financial Interests, Personal, Advisory Board, Advisory board/consultancy: MSD; Financial Interests, Personal, Other, Consultant: Marengo; Financial Interests, Personal, Advisory Board, Consultancy/SAB: Novartis; Financial Interests, Personal, Other, Consultancy: Pfizer, Replimune; Financial Interests, Personal, Royalties: Up-to-Date; Financial Interests, Institutional, Coordinating PI, Phase 1 trial PI: Marengo; Financial Interests, Institutional, Local PI: Novartis, Synthekine, Immunocore, Springworks; Financial Interests, Institutional, Coordinating PI: Mural, Moderna; Financial Interests, Institutional, Steering Committee Member: Merck. M. Gutierrez: Financial Interests, Personal, Invited Speaker: Guardant Health; Financial Interests, Personal, Other, Consultant: Merck; Financial Interests, Personal, Advisory Board: Sanofi, Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: COTA Healthcare; Financial Interests, Institutional, Local PI: Merck, BMS, Incyte, NexCure, Pfizer, Roche/Genentech, Boehringer Ingelheim, GSB Pharma, Moderna, Eisai, Silenseed, Seattle Genetics, Regeneron, Sanofi, Johnson & Johnson, MedImmune, Checkpoint Therapeutics, Acerta Pharmaceuticals, Arcus Biosciences, Array BioPharma, Bayer, Celgene, Compass Therapeutics, Constellation Pharmaceuticals, Cyter, EMD Serono, Fate Therapeutics, GSK, Infinity, Pharmacyclics, Synlogic, Tesaro, Vedanta, Impact. A. Jimeno: Financial Interests, Personal, Other, Consulting: Bluedot Bio, Purple Biotech; Financial Interests, Personal, Other, NIH support: NCI R01CA149456, R01DE024371, and P50CA261605; Financial Interests, Institutional, Local PI: Cantargia, DebioPharm, Iovance, Khar Biopharma, Merck, Moderna, Pfizer, Sanofi, SQZ. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, AstraZeneca UK Limited, Bayer Healthcare Pharmaceuticals, BioNTech SE, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG, Highlight Therapeutics S.L., IOBiotech, Immunocore Ireland Limited, Innovent Bioilogics USA Inc, Merck Sharp & Dohme, Novartis Pharma AG, PHMR Limited, Pierre Fabre, Regeneron Pharmaceuticals Inc, Scancell Limited, SkylineDX B.V.; Non-Financial Interests, Principal Investigator, GL is PI on over 30 clinical trials: GL is PI on over 30 clinical trials. 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. A. Rohatgi: Non-Financial Interests, Institutional, Local PI: Moderna, Gilead, Apollomics. R.F. Sweis: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, BMS, EMD Serono, Exelixis, Eisai, Janssen, Mirati, Pfizer, Seattle Genetics; Financial Interests, Personal, Invited Speaker: Aveo; Financial Interests, Personal, Stocks/Shares: AbbVie; Financial Interests, Institutional, Local PI: AbbVie, Aduro, Ascendis, Astellas, BMS, Bayer, CytomX, Eisai, Genentech/Roche, Immunocore, Merck, Mirati, Moderna, Novartis, QED, Pyxis Oncology, ALX Oncology; Financial Interests, Institutional, Research Grant: Epivax; Financial Interests, Institutional, Steering Committee Member: Gilead. J.E. Bauman: Financial Interests, Institutional, Advisory Board: Bluedot Bio; Financial Interests, Institutional, Advisory Role: Bluedot Bio, Aveo; Financial Interests, Institutional, Research Grant: Aveo, Celldex, CUE, Moderna; Financial Interests, Institutional, Steering Committee Member: Aveo. V. Boni: Financial Interests, Personal, Advisory Board: EMD Serono, Janssen; Financial Interests, Personal, Other, IDMC participation: Nanobiotix; Financial Interests, Personal, Full or part-time Employment, Director of Clinical Cancer Research, Phase 1 Unit NEXT: NEXT Madrid, University Hospital Quiron Salud; Financial Interests, Personal, Stocks/Shares: 1TRIALSP; Non-Financial Interests, Personal, Member: ASCO, SEOM. S. Parakh: Financial Interests, Personal and Institutional, Advisory Board: Daiichi Sankyo Australia Pty Ltd; Financial Interests, Institutional, Research Funding: Bayer; Non-Financial Interests, Institutional, Steering Committee Member: BeiGene, Ltd; Financial Interests, Personal and Institutional, Speaker’s Bureau: Roche. H.N. Daghestani: Financial Interests, Personal, Full or part-time Employment: Moderna Therapeutics; Financial Interests, Personal, Stocks/Shares: Moderna Therapeutics, Merck. J. Xu: Financial Interests, Institutional, Full or part-time Employment: Moderna, Cytel; Financial Interests, Institutional, Stocks/Shares: Moderna. Y. Li: Financial Interests, Institutional, Full or part-time Employment: Moderna, Cytel; Financial Interests, Institutional, Stocks/Shares: Moderna; Financial Interests, Personal, Stocks/Shares: Pfizer. M. Morrissey: Financial Interests, Institutional, Full or part-time Employment: Moderna; Financial Interests, Institutional, Stocks or ownership: Moderna; Financial Interests, Institutional, Stocks/Shares: Moderna. M. Abadier: Financial Interests, Personal, Full or part-time Employment: Moderna; Financial Interests, Personal, Stocks/Shares: Moderna. F. Barlaskar: Financial Interests, Personal, Advisory Board: Moderna; Financial Interests, Personal, Advisory Role: Moderna; Financial Interests, Personal, Full or part-time Employment: Moderna; Financial Interests, Personal, Stocks or ownership: Moderna; Financial Interests, Personal, Stocks/Shares: Moderna; Financial Interests, Personal, Affiliate: Moderna. D. Sarker: Financial Interests, Personal, Advisory Board: Eisai, Ipsen, Bayer, Surface Oncology, AAA, AbbVie, Boehringer Ingelheim, AstraZeneca, Incyte; Financial Interests, Personal, Invited Speaker: MSD, Bayer, AstraZeneca, Eisai, Servier, Incyte; Financial Interests, Personal, Other, Travel and conference fees: Ipsen; Financial Interests, Personal, Other, Travel and Conference Fees: MiNA Therapeutics; Financial Interests, Institutional, Coordinating PI: UCB, MiNA Therapeutics; Financial Interests, Institutional, Local PI: Eisai, Medivir AB, MSD, Bayer, RedX, GSK, Starpharma, Adaptimmune, Blueprint, H3, Regeneron, Taiho, AstraZeneca, Ipsen; Financial Interests, Institutional, Funding: Roche, Inspirata; Non-Financial Interests, Advisory Role: Medivir, UCB, MiNA Therapeutics. All other authors have declared no conflicts of interest.