Abstract 747P
Background
SAR’245 a site-specific pegylated human IL-2 blocks IL-2 alpha receptor-binding but retains near-native binding affinity for beta/gamma IL-2 receptor subunits. Preclinical models identified a unique mode of action characterized by ‘T-cell remodeling’ defined as increased ratio of CD8+Teff (CD8)/CD4+Treg (CD4) with potent NK-cell activation/expansion. We report results of the phase 1 trial of SAR’245 and the recommended phase 2 dose (RP2D).
Methods
SAR’245 was given IV as mono Q2W [Arm A] or Q3W [Arm B], Q3W + IV pembro 200 mg Q3W / 400 mg Q6W [Arm C], or Q3W + IV cetux 400 mg/m2 D1 then 250 mg/m2 QW [Arm D]. Study objectives included safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD).
Results
116 pts enrolled with median 3 prior therapies. Doses investigated by arm: [A] 8-32 μg/kg (n=21), [B] 8-40 μg/kg (n=35), [C] 8-32 μg/kg (n=37), [D] 16-32 μg/kg (n=23). The most common AEs were immune-related (most G1-2) without a dose-dependent relationship. 3 DLTs identified: G3 infusion reaction (32 μg/kg [B]), G3 hypoxia with G3 atrial fibrillation (40 μg/kg [B]), and G3 AST/ALT + G2 bilirubin elevation and G2 CRS (24 μg/kg [C]). PK was dose-proportional, and half-life 9-12 hours. Dose-dependent increase in CD8 was observed up to 32 μg/kg in [B], with decline at 40 μg/kg. CD4s were unchanged at mono doses of 8-24 μg/kg and increased at doses >24 μg/kg. Dose dependent increase in T-cell remodeling observed at 8-24 μg/kg (1.59-3.18) and plateaued/declined at 32-40 mg/kg. NK expansion observed at doses up to 32 mg/kg (3.84-28.99-fold). PK/PD-modelling showed the most robust expansion of T-cell remodeling and NK at 24 mg/kg. Based on PD and safety, the RP2D was 24 μg/kg for mono and pembro combination. Six confirmed responses were observed in arms B (1 squamous cell carcinoma [SCC] unknown primary), C (2 basal cell carcinoma, 1 head and neck SCC [HNSCC], 1 appendiceal), D (1 HNSCC); 3 responders had previously received PD1 inhibitors.
Conclusions
SAR’245 was well-tolerated and had anti-tumor activity in heavily pretreated pts, including after anti-PD1 treatment. Phase 2 trials of SAR’245 as mono and combination are underway.
Clinical trial identification
NCT04009681.
Editorial acknowledgement
Legal entity responsible for the study
Synthorx, a Sanofi company.
Funding
This study was sponsored by Synthorx, a Sanofi company.
Disclosure
G.S. Falchook: Financial Interests, Institutional, Advisory Board: FujiFilm, Silicon, Navire, Turning Point, Predicine, Inspirna, Regeneron; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Invited Speaker: Total Health Conferencing, Rocky Mountain Oncology Society; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2015: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2011, 2012, 2013: EMD Serono; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2018: Fujifilm; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2013: Millennium; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, at least once yearly: Sarah Cannon Research Institute (employer); Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Invited Speaker: 3-V Biosciences, Abbisko, AbbVie, ABL Bio ADC Therapeutics, Accutar, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Black Diamond, Boehringer Ingelheim, Celldex, Celgene, Ciclomed, Daiichi, Curegenix, Curis, Cyteir, DelMar, Effector, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MarcoGenics, Incyte, Jacobio, Loxo/Bayer, Jounce, Jubilant, Kolltan, MedImmune, Millennium, Merck, miRNA Therapeutics, Molecular Templates, National Institutes of Health, Navire, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Pyramid, Precision Oncology, Prelude, PureTech, RasCal, Regeneron, Relay, Rgenix, Ribon, Samumed, Sapience, Seagen, Silicon, Simcha, Sirnaomics, Strategia, Syndax, Synthorx/Sanofi, Taiho, Tesaro, Takeda, Tarveda, Teneobio, Tocagen; Financial Interests, Institutional: Turning Point. S. Fu: Financial Interests, Institutional, Research Grant: Novartis , NeuPharma Inc, BeiGene, MacroGenics, BioAtla, Parexel International LLC, Boehringer Ingelheim, Abbisko, Lilly , Hookipa Pharma , IMV, Innovent Biologics, Lyvgen Biopharma, Millennium, Nerviano Medical Sciences, NIH/NCI, Sellas Life Sciences, Soricimed, NovoCure, Turnstone Bio, Taiho Oncology, NCCN, Exelis, Green2Bio, Inc, K-Group Beta, NextCure, Ningbo NewBay Medical Technology, PureTech Health LLC, SQZ Biotech, Sumitomo Dainippon Pharma Oncology, Treadwell Therapeutics, Tyligand Bioscience Ltd, Vaccibody. M.A. Mckean: Financial Interests, Institutional, Advisory Board: Array BioPharma, AstraZeneca, MedPage Today, Pfizer, Regeneron; Financial Interests, Institutional, Research Grant: Acentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GlaxoSmithKline, Ideaya Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therpeutics, Tmunitu Therapeutics, TopAlliance Biosciences. A.A. Azad: Financial Interests, Personal, Other, Consultant: Astellas, Janssen, Novartis, Aculeus Therapeutics; Financial Interests, Personal, Speaker’s Bureau: Astellas, Janssen, Novartis, Amgen, Ipsen, Bristol Myers Squibb, Merck, Serono, Bayer; Financial Interests, Personal, Other, Honoraria: Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Telix, Merck Serono, Janssen, Bristol Myers Squibb, Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Merck Sharpe Dome, Aculeus Therapeutics; Financial Interests, Personal, Advisory Board: Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, Telix, Merck Serono, Janssen, Bristol Myers Squibb, Ipsen, Bayer, Merck Sharpe Dome, Amgen, Noxopharm; Financial Interests, Personal, Other, Travel and Accommodation: Astellas, Merck Sereno, Amgen, Novartis, Janssen, Tolmar, Pfizer; Financial Interests, Personal, Research Grant, Investigator: Astellas, Merck Serono, Astra Zeneca, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: AstraZeneca, Aptevo Therapeutics, Glaxo Smith Kline, Pfizer, MedImmune, Astellas, Synthorx, Bionomics, Sanofi Aventis, Novartis, Ipsen, Exelixis, Merck Sharpe Dome, Janssen, Eli Lilly, Gilead Sciences, Merck Serono. H.K. Gan: Financial Interests, Personal, Other, Honoraria: AbbVie, BristolMyers Squibb, Eisai, EMD Serono, MSD; Financial Interests, Personal, Other, Travel Support: AbbVie, Bristol Myers Squibb, Eisai, EMD Serono, MSD; Financial Interests, Personal, Research Grant: AbbVie, Bristol Myers Squibb, Eisai, EMD Serono, MSD. D. Sommerhalder: Financial Interests, Personal, Full or part-time Employment, Primary Investigator for active studies involving the following drugs:APG-2575, ABBV-400, ABBV-514, ABBV-CLS-484, ADCT-901, BBP-398, BI-765179, BJ-001, BNT-141, BNT-151, BNT-152/153, FT-538, GS-1811, HH-2853, IMC-002, MPT-0118, MRTX-849/Palbociclib, NDI-101150, NGM-707, ORIC-101, PF-06940434, PF-07209960, PF-07248144, PF-07260437, Sitravatinib DDI, Sym-024, THOR-707, Tipifarnib QTc, VIP-152, ZB-131: Texas Oncology. J.S. Wang: Financial Interests, Personal, Invited Speaker, Member of Speaker's Bureau for Tagrisso and Imfinzi: AstraZeneca; Financial Interests, Personal, Invited Speaker, Member of Speaker's Bureau for Lenvima: Eisai; Financial Interests, Personal, Advisory Board, Single Event - Advisory Board Participation: BioNTech, Janssen R&D, Stemline/Menarini; Financial Interests, Institutional, Invited Speaker: 7,8 Pharma, Black Diamond Therapeutics, Klus Pharma, Relay Therapeutics, H3 Biomedicine, Genentech/Roche, ORIC, Celgene/BMS, Olema Therapeutics, Novartis, Portola, MabSpace, Prelude Therapeutics, Treadwell Therapeutics, IGM Biosciences, Forty Seven, StingThera, PureTech Health, Aevi Genomics, Erasca, Artios Pharma, Nurix, Teneobio, BioTheryX, Boehringer Ingelheim, Biosplice, Zymeworks, Bayer Healthcare, ImmunoOnc, Cullinan, Immuno-Gen, Accutar, Blueprint, Hutchinson MediPharma, BioNTech, Macrogenics, TopAlliance, AstraZeneca, Revolution Medicines, Kymab, Clovis Pharma, Qilu Pugent Sound, Ribon Therapeutics, Xencor, LSK BioPartners, Syndax, Sanofi, Daiichi Sankyo, Phoenix Molecular Designs, Cyteir, Bicycle Therapeutics. T.J.Y. Tan: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Everest Medicines (Singapore) Pte Ltd, DKSH, Pfizer; Financial Interests, Personal, Invited Speaker: DKSH, AstraZeneca, Novartis, Roche, Pfizer, MSD, DHPL Malaysia SDN BHD; Financial Interests, Institutional, Research Grant: Astra Zeneca; Financial Interests, Institutional, Invited Speaker: Roche, Novartis, AstraZeneca, Odonate, Daiichi Sankyo, Genentech, Sanofi; Non-Financial Interests, Member: ASCO. C.E. Chee: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Roche/Genentech; Financial Interests, Personal, Advisory Role: Guardant Health AMEA; Financial Interests, Personal, Other, Travel, Accommodation & Expenses: Taiho Pharmaceutical. M. Barve: Financial Interests, Personal and Institutional, Funding: Mary Crowley Cancer Research; Financial Interests, Personal and Institutional, Stocks/Shares: Texas Oncology Physician Associates. J. Moser: Financial Interests, Personal, Advisory Role: BMS, Amunix, Thirona Bio, Adagene, Imaging Endpoints; Financial Interests, Institutional, Research Grant: NovoCure, Genentech, Alpine Immune Sciences, Amgen, Trishula Therapeutics, BioEclipse Therapeutics, FujiFilm, ImmuneSensor, Simcah, Repertoire Immune Sciences, Nektar Therapeutics, Synthorx Inc, Istari Oncology, Ideaya Biosciences, Rubius; Financial Interests, Institutional, Other, Honoraria: Caris Life Sciences, Daiichi-Sankyo, TGen; Financial Interests, Personal, Member of the Board of Directors: Caris Molecular Tumor Board, Caris Consultant; Financial Interests, Personal, Speaker’s Bureau: Caris Life Sciences, Immunocore. J. Mooney: Financial Interests, Personal, Full or part-time Employment: Synthorx, Inc. a Sanofi Company. N. Acuff: Financial Interests, Personal, Full or part-time Employment: Synthorx, Inc. a Sanofi Company. R. Wang: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi. N. Marina: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi. G. Abbadessa: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi. M. Streit: Financial Interests, Personal, Full or part-time Employment: Sanofi. S. Ramusovic: Financial Interests, Personal, Full or part-time Employment: Sanofi; Financial Interests, Personal, Stocks/Shares: Sanofi. T. Meniawy: Financial Interests, Personal, Other, Honoraria: AstraZeneca. All other authors have declared no conflicts of interest.