A phase I, first-in-human, dose escalation and expansion study of oral pan-RAF/MEK molecular glue NST-628 in subjects with solid tumors harboring RAS-MAPK pathway alterations

BackgroundThe RAS-MAPK (RAS-RAF-MEK-ERK) signaling pathway is frequently mutated in malignancy, with activating RAS-MAPK pathway mutations driving tumor cell proliferation and viability. NST-628 is an oral, fully brain penetrant small molecule that functions as a non-degrading, pan-RAF/MEK molecular glue, preventing phosphorylation and activation of MEK by RAF, thus inhibiting MEK-dependent cell signaling and leading to tumor cell death. NST-628 demonstrated robust activity in cell lines and xenograft/patient-derived models, including intracranially implanted, with broad spectrum of RAS-MAPK pathway mutations.Trial designNST-628-001 is a global Phase 1, open-label, single-arm, 2-part study to investigate safety, pharmacokinetics, and preliminary efficacy of the orally administered NST-628. Eligible subjects will be adults with advanced cancer, adequate organ function, and performance status ≤ 1, without curative options. Part A, the dose escalation part of the study, will estimate NST-628 maximum tolerated dose utilizing Bayesian Optimal Interval method, to establish the recommended dose for expansion. Successive cohorts of subjects with RAS-MAPK pathway altered tumors will receive escalating doses of NST-628 once daily, in 28-day cycles. Accelerated titration is implemented in the initial dose cohorts. The primary endpoint is the dose-limiting toxicity of NST-628. Part B, the expansion part of the study, will evaluate NST-628 anti-tumor activity of up to 6 cohorts of subjects with measurable disease of the following types: melanoma with (1) NRAS mutations or (2) BRAF Class 2 or 3 alterations; solid tumors with (3) NRAS mutations, (4) KRAS mutations, or (5) BRAF Class 2 or 3 alterations; and (6) glioma with BRAF alterations. The primary endpoints are radiographic objective response and adverse events. Secondary endpoints are PFS/OS, while exploratory translational endpoints include levels of circulating tumor DNA, serum tumor markers, and tumor/blood pERK. Subjects have been treated and recruitment is ongoing.Clinical trial identificationNCT06326411.Editorial acknowledgementChristine Kuepfer, ProCom Consult.Legal entity responsible for the studyNested Therapeutics, Inc.FundingNested Therapeutics, Inc.DisclosureJ.J. Luke: Financial Interests, Personal, Steering Committee Member, DSMB: AbbVie, Agenus, Evaxion, Immutep, Shionogi; Financial Interests, Personal, Advisory Board: Affivant, 7 Hills, BioCytics, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Elipscience, Kanaph, NeoTx, Onc.AI, OncoNano, physIQ, STipe, Tempest; Financial Interests, Personal, Financially compensated role: AbbVie, Agenus, Alnylam, AstraZeneca, Askgene, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Geneos, Glenmark, HotSpot, Kadmon, Ko Bio Labs, Krystal, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, LegoChem, Lyvgen, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Storm, Sumoitomo, Synlogic, Synthekine, Teva; Financial Interests, Institutional, Advisory Role: AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Hot Spot, Ikena, Immatics, Imugene, Incyte, Janux, Kadmon, Kahr, Macrogenics, Merck, Moderna, Nektar, Next Cure, Novartis, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Tscan, Werewolf, Xencor; Other, Personal, Other, Patents: Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof: US-11638728. G.S. Falchook: Financial Interests, Institutional, Advisory Board, 2018: FujiFilm; Financial Interests, Institutional, Advisory Board, 7/24/2020, 9/17/2021: Silicon; Financial Interests, Institutional, Advisory Board, 3/10/21: Navire; Financial Interests, Institutional, Advisory Board, 4/22/21: Turning Point; Financial Interests, Institutional, Advisory Board, 10/2/21: Predicine; Financial Interests, Institutional, Advisory Board, 10/26/21: Inspirna; Financial Interests, Institutional, Advisory Board, 10/28/21: Regeneron; Financial Interests, Personal, Advisory Board, 6/2010, 3/2011: EMD Serono; Financial Interests, Institutional, Advisory Board, 1/18/22 and 8/17/22: Jubilant; Financial Interests, Institutional, Advisory Board, 6/4/22: BostonGene; Financial Interests, Institutional, Advisory Board, 9/30/22: AbbVie; Financial Interests, Personal, Invited Speaker, 2019: Total Health Conferencing; Financial Interests, Personal, Invited Speaker, 2020: 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, to present research at a conference (Cholangiocarcinoma Foundation meeting), 2018: Fujifilm; Financial Interests, Personal, Other, Travel, to present research at a conference (ESGO), 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, Other, Travel, to present research at a conference (WCLC), 2022: Amgen; Financial Interests, Personal, Other, Travel, to present research at a conference (ESMO), 2022: Synthorx / Sanofi; Financial Interests, Institutional, Advisory Board, Scientific advisory board 11/18/22: Teon Therapeutics; Financial Interests, Institutional, Advisory Board, 12/8/22: Merck; Financial Interests, Personal, Invited Speaker, CME presentation about NSCLC and thyroid cancer, 2/20/24: Clinical Care Options; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Local PI, Unknown end date, before 1/2021: 3-V Biosciences, ARMO/Eli Lilly, Celldex, DelMar, eFfector, Kolltan, miRNA Therapeutics, OncoMed, Precision Oncology, Strategia; Financial Interests, Institutional, Local PI, 12/2019 - 6/2023: Abbisko; Financial Interests, Institutional, Local PI, ending 4/2019: AbbVie; Financial Interests, Institutional, Local PI, 8/2021 - present: ABL Bio; Financial Interests, Institutional, Local PI, 12/2021 - 8/2023: Accutar; Financial Interests, Institutional, Local PI: Aileron, Amgen, AstraZeneca, BeiGene, Fujifilm, Jacobio, Jounce, Loxo/Bayer, Merck, Regeneron, Rgenix, Takeda; Financial Interests, Institutional, Local PI, ending 6/2014: American Society of Clinical Oncology, Celgene, EMD Serono, Genmab, MedImmune, National Institutes of Health, Oncothyreon, U.T. MD Anderson Cancer Center, Vegenics; Financial Interests, Institutional, Local PI, 9/2021 - present: Artios, NiKang; Financial Interests, Institutional, Local PI, 4/2019 - present: Bioatla; Financial Interests, Institutional, Local PI, 6/2020 - present: Bioinvent; Financial Interests, Institutional, Local PI, ending 11/2018: Biothera; Financial Interests, Institutional, Local PI, 8/2020 - present: Bicycle; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 3/2022 - present: Black Diamond, Seagen; Financial Interests, Institutional, Local PI, 5/2021 - present: Boehringer Ingelheim, Erasca; Financial Interests, Institutional, Local PI, ending 5/2021: Ciclomed; Financial Interests, Institutional, Local PI, ending 7/2018: Curegenix; Financial Interests, Institutional, Local PI, ending 3/2019: Curis; Financial Interests, Institutional, Local PI, 9/2019 - present: Cyteir, Xencor; Financial Interests, Institutional, Local PI, 11/2019 - present: Daiichi; Financial Interests, Institutional, Local PI, ending 9/2022: Eli Lilly, Tesaro; Financial Interests, Institutional, Local PI, 12/2019 - present: Epizyme; Financial Interests, Institutional, Local PI, ending 10/2023: Exelixis, GSK; Financial Interests, Institutional, Local PI, 7/2021 - present: Freenome, Samumed; Financial Interests, Institutional, Local PI, ending 10/2022: Hutchison MediPharma; Financial Interests, Institutional, Local PI, 10/2020 - present: IGM Biosciences, ImmunoGen/MarcoGenics; Financial Interests, Institutional, Local PI, ending 6/2019: Ignyta; Financial Interests, Institutional, Local PI, ending 9/2019: Incyte; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 04/2022 - present: Jubilant; Financial Interests, Institutional, Local PI, ending 5/2008, when Millennium was purchased by Takeda: Millennium; Financial Interests, Institutional, Local PI, 10/2021 - 6/2023: Molecular Templates; Financial Interests, Institutional, Local PI, 2/2021 - present: Navire; Financial Interests, Institutional, Local PI, ending 2/2024: Novartis; Financial Interests, Institutional, Local PI, 3/2020 - 2/2024: Oncorus; Financial Interests, Institutional, Local PI, 3/2020 - present: Poseida; Financial Interests, Institutional, Local PI, 12/2019 - 2/2024: Prelude; Financial Interests, Institutional, Local PI, 12/2020 - present: PureTech, Silicon; Financial Interests, Institutional, Local PI, 06/2021 - 06/2023: Pyramid; Financial Interests, Institutional, Local PI, 3/2021 - present: RasCal; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 12/2021 - present: Relay; Financial Interests, Institutional, Local PI, 8/2019 - present: Ribon, Turning Point; Financial Interests, Institutional, Local PI, 7/2020 - present: Sapience; Financial Interests, Institutional, Local PI, 12/2021 - present: Simcha; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 11/2021 - present: Sirnaomics; Financial Interests, Institutional, Local PI, ending 5/2019: Syndax; Financial Interests, Institutional, Local PI, 09/2019 - 02/2024: Synthorx/Sanofi; Financial Interests, Institutional, Local PI, ending 12/2017: Taiho; Financial Interests, Institutional, Local PI, ending 7/2022: Tarveda; Financial Interests, Institutional, Local PI, 5/2021 - present. TeneoBio was purchased by Amgen.: Teneobio; Financial Interests, Institutional, Local PI, ending 1/2020: Tocagen; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 05/2022-11/2022: Metabomed; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 6/2022 - present: Agenus; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 06/2022 - present: Tallac; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 7/2022 - present: Zhuhai Yufan, Mirati; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 10/2022 - present: Immunitas, Jazz Pharmaceuticals; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 11/2022 - present: Bayer; Financial Interests, Institutional, Local PI, 1/2019 - present: ADC Therapeutics; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 3/2023 - present: Kineta, Roche; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 03/2023 - present: NGM BioPharmaceuticals; Financial Interests, Institutional, Local PI, 4/2023 - present: Tarus; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 05/2023 - present: Pyxis; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 06/2023 - present: Harbour BioMed, Centessa Pharmaceuticals; Financial Interests, Institutional, Local PI, 07/2023 - present: Ideaya, Tango Therapeutics; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 08/2023 - present: Biomea Fusion; Financial Interests, Institutional, Local PI, 09/2023 - present: Conjupro Biotherapeutics; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 09/2023 - present: Phanes Therapeutics; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 9/2023 - present: Sarah Cannon Development Innovations; Financial Interests, Institutional, Local PI, 10/20/23 - present: Nuvectis Pharma; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 1/20/24 - present: Kura Oncology; Financial Interests, Institutional, Local PI, 1/2024 - present: Eikon Therapeutics. M. Mckean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, IQVIA, Merck, Moderna; Financial Interests, Institutional, Research Grant: Acentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GSK, Ideaya Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therpeutics, Tmunity Therapeutics, TopAlliance Biosciences, Aadi Biosciences, Alpine Immune Sciences, Arcs Biosciences, Arvinas, ASCO, Astellas, Bayer, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, EMD Serono, Erasca, Foghorn Therapeutics, G1 Therapeutics, Gilead Sciences, ImmVira Pharma, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Nektar, OncoC4, PACT Pharma, Pfizer, Poseida, Pyramid Biosciences, Scholar Rock, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Xilio, Aulos Bioscienc, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, InconVir, Jazz Pharmaceutical, Krystal Biotech, NucMito Pharmaceuticals, OnKure, Remix Therapeutics. A.L. Vandross: Financial Interests, Institutional, Other, Consulting: BoxerCapitol; Financial Interests, Institutional, Advisory Board, Scientific Advisory Board: Pliant; Financial Interests, Institutional, Full or part-time Employment, Phase 1 investigator: NEXT Oncology; Financial Interests, Institutional, Local PI, Phase 1 study: Mabwell, AbbVie, AstraZeneca, Ascentage Pharma, Asana Bio, BioOneCure, BJ Bioscience, Cybrexa Therapeutics, Deciphera, Elpiscience Biopharma, Nanjing Immunophage Biotech, Chugai Pharmaceutical, Lyvgen Biopharma, NGM Bio, OncoResponse, Zhuhai Yufan Biotecnologies, Immunomedics, Inc, siRNAomics, Sorrento therapeutics, Vincerx, Exelixis, Xilio Development Inc, Ziel Bio, Nested therapeutics, Nikang, Oncternal Therapeutics, Pasithea Therapeutics, Pliant Pharmaceuticals, Vividion, Iambic, Gilead, Bolt Biotherapeutics; Financial Interests, Institutional, Local PI, Phase 1: Nitto therapeutics, Mbrace Therapeutics, Institut de Recherches Internationales Servier. M.A. Salkeni: Financial Interests, Personal, Stocks/Shares: NEXT; Financial Interests, Institutional, Local PI: Prelude Therapeutics, Boehringer Ingelheim, Agenus, BeiGene, Kronos Bio, CrystalGenomics, Chugai Pharma, Tarus Therapeutics, Stemline Therapeutics, Bolt Biotherapeutics, Oncternal Therapeutics, Takeda, MBrace Therapeutics, 1ST Biotherapeutics, Inmune Bio, OncoResponse; Financial Interests, Personal, Local PI: Ideaya Biosciences; Other, honorarium: Healthcasts. V.G. Atkinson: Financial Interests, Personal, Advisory Board: BMS, MSD, Novartis, Pierre fabre, QBiotics; Financial Interests, Personal, Invited Speaker: BMS, MSD, Novartis, Pierre fabre, Limbic; Financial Interests, Personal, Other, Travel Support: BMS; Financial Interests, Personal, Other, Travel support: Pierre Fabre; Financial Interests, Personal, Other, Advisory Board: immunocore. J.J. Liu: Financial Interests, Personal, Invited Speaker: Specialised Therapeutics; Financial Interests, Personal, Other, Travel Reimbursement: ImmVirX, Starpharma; Financial Interests, Personal, Other, Conference registration reimbursement: MSD; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Institutional, Advisory Board: Greywolf Therapeutics, Starpharma; Financial Interests, Institutional, Local PI: BMS, Aveo, Regeneron, MSD, Carina Biotech, Relay Therapeutics, Starpharma, Greywolf Therapeutics, Innovent, Aspen, ImmVirX, Ideaya Biosciences, BMS; Financial Interests, Institutional, Coordinating PI: AkesioBio, Guardant360. A.M. Kennedy, J. Clark, M. Ryan, O. Schmidt-Kittler, D. Steinhubel, D. Wages: Financial Interests, Institutional, Financially compensated role: Nested Tx. P. Komarnitsky: Financial Interests, Institutional, Full or part-time Employment: Nested Tx. I. Puzanov: Financial Interests, Personal, Speaker, Consultant, Advisor: I-O Biotech; Financial Interests, Personal, Stocks or ownership: Ideaya Biosciences, Compugen Inc. All other authors have declared no conflicts of interest.