Abstract
BBP-398 is a selective allosteric SHP2 inhibitor designed to inhibit mitogen-activated protein kinase (MAPK) pathway–driven tumors. We performed the first-in-human phase 1 trial described herein to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of BBP-398 in patients with advanced solid tumors harboring MAPK pathway mutations. Once-daily BBP-398 was administered at 350-550 mg in the dose-escalation phase (1a; n = 35) followed by a dose-expansion phase (1b; n = 37). The study endpoints were dose-limiting toxicities, treatment-emergent adverse events, pharmacokinetics, target engagement, disease control rate, progression-free survival, and overall survival. In phase 1a, 26% of the 23 evaluable patients had stable disease, with a median progression-free survival duration of 1.8 months (range, 1.7-4.1 months). In phase 1b, 30% of the 27 evaluable patients had stable disease (31% at 350 mg, 27% at 450 mg), with median progression-free survival of 2.2 months and 1.9 months at 350 mg and 450 mg, respectively. We halted dose escalation at 550 mg owing to an increased rate of thrombocytopenia and edema. At daily doses of up to 450 mg, BBP-398 exhibited an acceptable safety profile and produced disease stabilization in nearly 30% of heavily pretreated patients.
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Anonymized individual participant data on completed studies and applicable supporting clinical study documents are available upon request in a secured access environment. Requests for access to data can be submitted to the corresponding author. Access will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement.
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Acknowledgements
The authors express their sincere gratitude to the patients and their families for their participation in this study and to all investigators involved, particularly Dr. Aditya Sarvaria, for their invaluable efforts in enrolling patients onto the protocol. We also thank the Editing Services, Research Medical Library from The University of Texas MD Anderson Cancer Center for their for their support revising the final version of this manuscript.
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D.V.V. and D.S.H. conceptualized the work: E.L. performed statistical data analyses. All authors revised the provided results. C.B.X. wrote the initial draft. All authors reviewed the final manuscript.
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G.F. has received royalties from Wolters Kluwer; been an advisor for AbbVie, Jubilant, BostonGene, Teon, Merck, Sanofi, BridgeBio, and Beijing Avistone (2024); received a speaker honorarium from Clinical Care Options; received travel funds from Sarah Cannon Research Institute, Amgen, Synthorx/Sanofi, GSK, and Cyteir; and received research funding from Abbisko, ABL Bio, Abbvie, ADC Therapeutics, Accutar, Agenus, Aileron, Alterome, Amgen, Arcus, ARMO/Eli Lilly, Artios, Astellas, AstraZeneca, Bayer, BeiGene, Beijing Avistone, Bioatla, Bioinvent, Biomea Fusion, Bicycle, Black Diamond, Boehringer Ingelheim, Boundless, Centessa, Conjupro, Cyteir, Cytomx, D3 Bio, Daiichi, Deciphera, Dynamicure, Eikon, Eli Lilly, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, GSK, Harbour BioMed, Hutchison MediPharma, IGM Biosciences, IDEAYA, Ikena, Immuneering, Immunitas, ImmunoGen/MacroGenics, Incyte, Jacobio, Jazz, Jounce, Jubilant, Kineta, Kumquat, Kura, Loxo/Bayer, Medilink, Merck, Metabomed, Mirati, ModeX, Molecular Templates, Nammi, Navire/BridgeBio, NGM Bio, NiKang, Novartis, Nuvalent, Nuvectis, Oncorus, Oncusp, OnKure, Phanes, Poseida, Prelude, PureTech, Pyramid, Pyxis, Quanta, RasCal, Regeneron, Relay, Rgenix, Ribon, Roche, Samumed, Sapience, Sarah Cannon Development Innovations, Seagen, Silicon/Stingthera, Simcha, Sirnaomics, Synthorx/Sanofi, Tachyon, Takeda, Tallac, Tango, Tarus, Tarveda, Teneobio, Tesaro, TORL, Turning Point, Xencor, and Zhuhai Yufan. D.V.V. has been employed by Navire Pharma. J.M. has been an advisor for Astra Zeneca, Janssen, Abbvie, Jazz, Sanofi, Bristol Myers Squibb, Takeda, and Daiichi Sankyo; been a consultant for Regeneron and Bristol Myers Squibb; been a Data Safety and Monitoring Committee member for Bioatla; and received research funding from NCI/ARPA-H and Astra Zeneca. S.S. has been a consultant and/or served on the speaker bureau for Eisai and BMS. A.R.K. has received grants and/or personal fees from Pfizer, AstraZeneca, Bristol Myers Squibb, EMD Serono, Exelixis, Genentech, Gilead Sciences, Immunomedics, Novartis, Seattle Genetics/Astellas, Amgen, Astellas Medivation, AVEO, Eisai, Genentech/Roche, Janssen, Merck, Myovant Sciences, Sanofi, Bayer, Arvinas, Mirati Therapeutics, and POINT Biopharma and has stock and other ownership interests in ECOM Medical. L.W. has been employed by Navire Pharma. F.R. has received consulting fees from Eikon Therapeutics. E.L. has received consulting fees from Navire Pharma for performing the data analyses and summaries for the present study, which may be considered a potential conflict of interest with respect to the subject matter of this manuscript. A.I.S. has been a consultant or advisor for Incyte, Amgen, Novartis, Mirati Therapeutics, Jazz Pharmaceuticals, Takeda, Janssen Research & Development, Mersana, Gritstone bio, Daiichi Sankyo/AstraZeneca, Regeneron, Eli Lilly, Black Diamond Therapeutics, Sanofi, ArriVent Biopharma, Synthekine, GSK, Crispr Therapeutics, and Revolution Medicines and has received research funding from LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Incyte, AbbVie, Ignyta, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, Gritstone bio, Plexxikon, Amgen, Daiichi Sankyo, ADC Therapeutics, Janssen Oncology, Rubius, Synthekine, Mersana, Blueprint Medicines, Regeneron, Alkermes, Revolution Medicines, Medikine, Black Diamond Therapeutics, BluPrint Oncology, Nalo Therapeutics, Scorpion Therapeutics, ArriVent Biopharma, Prelude Therapeutics, and Eli Lilly. D.S. has been an employee and shareholder of Texas Oncology, a shareholder of NEXT Oncology, received honoraria from Syneos, received consulting fees from Guidepoint, received advisory board payments from Revolution Medicines and Nimbus Therapeutics, and received ongoing or past institutional research funding for studies from Abbvie, Acrivon Therapeutics, ADC Therapeutics, Aprea Therapeutics, Ascentage Pharma Group, Astellas, Avenzo Therapeutics, Biomea Fusion, Boehringer Ingelheim, BJ Bioscience, BioNTech, Bristol Myers Squibb, Compugen, Day One Biopharma, Dicerna/Novo Nordisk, Dren Bio, Exelixis, Fate Therapeutics, Gilead Sciences, GSK, Haihe Pharmaceutical, Iconovir Bio, Ideaya Biosciences, Immuneering, Impact Therapeutics, Incendia, Kura Oncology, MediLink Therapeutics, Mirati Therapeutics, ModeX Therapeutics, Monopteros Therapeutics, Navire Pharma, Nimbus Therapeutics, NGM Biopharmaceuticals, OBI Pharma, OncoResponse, Pfizer, Revolution Medicines, Step Pharmaceuticals, Symphogen, Tachyon Therapeutics, Teon Therapeutics, Tyligand Bioscience, Vincerx Pharma, Vividion Therapeutics, ZielBio, and Zymeworks. I.G.-L. has been a consultant or advisor for SOTIO, AbbVie, Revolution Medicines, Eli Lilly, and Quanta Therapeutics and received research funding from EcoR1, Guidepoint, Novartis, Bayer, Bristol Myers Squibb, Pfizer, MedImmune, Eli Lilly, Incyte, GSK, Tolero Pharmaceuticals, BridgeBio Pharma, Jacobio, Repare Therapeutics, Sumitomo Dainippon Pharma Oncology, Revolution Medicines, Yingli Pharma, Quanta Therapeutics, 280 BIO, ABM Therapeutics, and Tango. D.S.H. has been a consultant or advisor for AbbVie, Acuta, Alpha Insights, Amgen, Axiom, BeiGene, Boxer Capital, COR2ed, EcoR1, Erasca, GLG, Guidepoint, ImmunoGen, Kestrel Therapeutics, Medscape, Mirati Therapeutics, Pfizer, Revolution Medicines, T-Knife, and WebMD; received research funding from AbbVie, Adaptimmune, Adlai-Nortye, Amgen, Astellas, AstraZeneca, Bayer, BeiGene USA, Bristol Myers Squibb, Eisai, Eli Lilly, Endeavor, Erasca, Exelixis, F. Hoffmann-La Roche, Genentech, ImmunoGen, Merck, Mirati, NCI-CTEP, Novartis, Pfizer, Revolution Medicines, STCube, TCR2, and VM Oncology; received for travel, accommodations, and expenses from the American Association for Cancer Research, ImmunoGen, Medscape, and Telperian; and has had other ownership interests in Molecular Match, OncoResponse, and Telperian. The other authors (C.B.X., M.K., and Y.P.) do not have a competing interest.
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Falchook, G., Braganca Xavier, C., Van Veenhuyzen, D. et al. A first-in-human phase 1 study of the SHP2 inhibitor BBP-398 in patients with advanced solid tumors. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01340-1
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DOI: https://doi.org/10.1038/s41698-026-01340-1
