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Poster session 01

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

Date

14 Sep 2024

Session

Poster session 01

Topics

Clinical Research;  Targeted Therapy;  Response Evaluation (RECIST Criteria);  Immunotherapy

Tumour Site

Melanoma;  Breast Cancer;  Non-Small Cell Lung Cancer;  Colon and Rectal Cancer;  Head and Neck Cancers

Presenters

Muhammad Khattak

Citation

Annals of Oncology (2024) 35 (suppl_2): S482-S535. 10.1016/annonc/annonc1589

Authors

M.A. Khattak1, R.J. Sullivan2, M. Gutierrez3, A. Jimeno4, S.S. Thomas5, G.V. Long6, S. Kummar7, A. Daud8, A. Rohatgi9, R.F. Sweis10, J.E. Bauman11, V. Boni12, S. Parakh13, H.N. Daghestani14, J. Xu15, Y. Li15, M. Morrissey16, M. Abadier17, F. Barlaskar18, D. Sarker19

Author affiliations

  • 1 Oncology, Fiona Stanley Hospital, 6150 - Perth/AU
  • 2 Medical Oncology/hematology, Massachusetts General Hospital, 02114 - Boston/US
  • 3 Phase I/thoracic/gi Oncology, John Theurer Cancer Center - Hackensack Meridian Health, 07601 - Hackensack/US
  • 4 Medical Oncology, University of Colorado Cancer Center, 80045 - Aurora/US
  • 5 Medical Oncology, Orlando Health Cancer Institute, 32801 - Orlando/US
  • 6 Medical Oncology Department, Melanoma Institute Australia, The University of Sydney, 2065 - Sydney/AU
  • 7 Medicine, Knight Cancer Institute, Oregon Health and Science University, 97239 - Portland/US
  • 8 Medicine, UCSF, 94010 - San Francisco/US
  • 9 Department Of Medicine, Division Of Oncology, Washington University in St. Louis, 63110 - St. Louis/US
  • 10 Medicine, The University of Chicago, 60637 - Chicago/US
  • 11 Gw Cancer Center, George Washington University, 20052 - Washington/US
  • 12 Oncology, NEXT Madrid, Universitary Hospital Quiron Salud, 28233 - Madrid/ES
  • 13 Medical Oncology, Austin Hospital, 3084 - Melbourne/AU
  • 14 Clinical Biomarkers, Moderna, Inc., 02142 - Cambridge/US
  • 15 Oncology, Moderna, Inc., 02139 - Cambridge/US
  • 16 Internal Medicine, Moderna, Inc., 02139 - Cambridge/US
  • 17 Translational Medicine, Moderna, Inc., 02142 - Cambridge/US
  • 18 Clinical Development, Oncology, Moderna, Inc., 02139 - Cambridge/US
  • 19 Early Phase Trials Unit, Guy’s Hospital, King’s College London, SE1 9RT - London/GB

Resources

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Abstract 663P

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.

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