EphA2-targeting bicycle toxin conjugate (BTC) BT5528 in patients (pts) with advanced solid tumors: A phase I/II study

BackgroundBT5528 is a BTC® molecule comprising a bicyclic peptide targeting EphA2 linked to monomethyl auristatin E (MMAE). EphA2 is overexpressed in many tumors leading to oncogenesis, angiogenesis, and metastasis. Favorable preclinical data for BT5528 supported a first-in-human study to assess safety and efficacy in adults with advanced solid tumors (NCT04180371).MethodsPts with relapsed/refractory metastatic solid tumors known to express EphA2 received BT5528 IV (2.2–8.5 mg/m2 QW or 6.5–10.0 mg/m2 Q2W) in dose escalation (DE). Two potential recommended phase 2 doses (RP2D; BT5528 6.5 mg/m2 Q2W and 5 mg/m2 QW) were further assessed, allowing anti-emetic premedication. We report the most current safety, efficacy, and pharmacokinetic (PK) data.ResultsAs of 14 Mar 2024, 128 pts received BT5528 monotherapy (median age, 63 yrs; ECOG 1, 59%; including ovarian [37%], urothelial [UC, 25%], lung [9%], and breast [7%] cancer). BT5528 safety is summarized in the table. Gastrointestinal disorders were the most common treatment-related adverse events overall (64% any grade; 5% Grade 3). Incidence of treatment-related peripheral neuropathy (SMQ broad) was 19% for 6.5 mg/m2 Q2W and 29% for 5 mg/m2 QW (any grade), with no Grade ≥3 events. Objective responses were observed in several tumor types (12/110 efficacy-evaluable [EE] pts: 8 UC, 3 ovarian, and 1 HNSCC). Highest antitumor activity was observed in UC with 45% and 27% ORRs (confirmed + unconfirmed) in EE pts in 6.5 mg/m2 Q2W expansion cohort and 5 mg/m2 QW cohort, respectively (the latter as of 26 Apr 2024). BT5528 and MMAE exhibited dose-dependent increases in PK. Half-life was <1 h for BT5528 and ∼1.6–1.8 d for MMAE at the 2 potential RP2Ds. Table: 647P BT5528 safety profile Event, n (%) BT5528 Monotherapy AllN=128 6.5 mg/m2 Q2W n=74* 5 mg/m2 QW n=24 TRAEs 112 (88) 67 (91) 20 (83) TRAEs Grade ≥3 34 (27) 16 (22) 3 (13) TRSAE 12 (9) 6 (8) 0 TEAEs leading to dose modifications Reduction 12 (9) 2 (3) 1 (4) Interruption 39 (31) 16 (22) 6 (25) Withdrawal 4 (3) 2 (3) 0 ∗Includes DE and expansion. TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event; TRSAE, treatment-related serious adverse event. ConclusionsBT5528 demonstrated acceptable safety with antitumor activity in pts with advanced solid tumors, particularly in UC, supporting further development of BT5528 as monotherapy and in combination with nivolumab in select tumor types. Mature data from the 5 mg/m2 QW cohort will be presented.Clinical trial identificationNCT04180371.Editorial acknowledgementWriting assistance was provided by Tamara Fink, PhD, and Rebecca L. Crepeau, PhD, of Fishawack Communications, part of Avalere Health.Legal entity responsible for the studyBicycleTx Ltd.FundingBicycleTx Ltd.DisclosureE. Fontana: Financial Interests, Personal, Invited Speaker: Caris Life Science, Repair Therapeutics; Financial Interests, Personal, Other, Conference attendance: Sapience Pharma; Financial Interests, Personal, Invited Speaker, Conference Attendance: Bicycles Therapeutics; Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International; Financial Interests, Personal, Officer: EORTC; Financial Interests, Institutional, Coordinating PI: Repair Therapeutics, Amgen, Taiho Pharmaceutical; Financial Interests, Institutional, Local PI: Bicycle Therapeutics, Artios Pharma, Seagen, Nurix Therapeutics, BioNTech SE, Relay Therapeutics, Pfizer, Roche, Daiichi Sankyo, Gilead Science, Basilea Pharmaceutica, Jiangsu Hengrui Medicine, Mereo Biopharma, Hutchmed, Merus, Crescendo Biologics, GSK plc, BeiGene, Turning Point Therapeutics, Sapience Pharma, Arcus Bioscience, Exelixis, Nerviano Medica, Elipsees, Deciphera, Ribon Therapeutics. J.S. Wang: Financial Interests, Personal, Invited Speaker, Previous Member of Speaker's Bureau for Tagrisso and Imfinzi, stopped speaking engagements in 2021: AstraZeneca; Financial Interests, Personal, Advisory Board, Single consultancy engagement, 4/28/22: Kanaph Therapeutics; Financial Interests, Personal, Invited Speaker, Speaker for Speaker's Bureau for Levatinib, stopped in 7/2022: Eisai; Financial Interests, Personal, Advisory Board, on Safety Advisory Board, single engagement 6/22/23: Fusion Pharma; Financial Interests, Institutional, Funding, Clinical Trial PI/Sub-I: 7,8 Pharma, Accutar, Adagene, Artios Pharma, Astellas, AstraZeneca, Bayer Healthcare, BeiGene, Bicycle Therapeutics, BioNTech, BioTheryX, Blueprint, Boehringer Ingelheim, Celgene/BMS, Cullinan, Cyteir, Daiichi Sankyo, Erasca, Forty Seven, Genentech/Roche, GSK, H3 Biomedicine, Hotspot, IGM Biosciences, Immuno-Gen, ImmunoOnc, Janssen, Jazz Pharma, Klus Pharma, Kymab, LSK BioPartners, MabSpace, Macrogenics, Medikine, Moderna, NGM Bio, Novartis, Nurix, ORIC, Olema Therapeutics, Phoenix Molecular Designs, Pionyr, Prelude Therapeutics, PureTech Health, Pyxis, Qilu Pugent Sound, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Sanofi, StingThera, Syndax, Teneobio, TopAlliance, Treadwell Therapeutics, Xencor, Zymeworks, Compass, OnCusp, Tango, Vividion, Allorion, Kura, Georgimmune, Conjupro, Duality Bio, Ellipses, Compugen, Biostar, Centessa, Kineta, C4 Therapeutics. M. Mckean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, IQVIA, Merck, Moderna; Financial Interests, Institutional, Research Grant: Acentage, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentec, GSK, Ideaya Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharma, Moderna, NBE-Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regenero, Sapience, Seattle Genetics, Tizona Therapeutics, Tmunity, Top Alliance Biosciences, Aadi Bioscience, Alpine Immune Sciences, Arc Bio, Arvinas, ASCO, Astellas, Bayer, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, EMD Serono Inc., Erasca, Foghorn, G1 Therapeutics, Gilead Sciences, lmmVira, KeChow Pharmaceuticals, Kezar Life Sciences, Kinnate Biopharma, MedImmune, Mereo BioPharma Group, Metabo, Nektar, OncoC4, PACT Pharma, Pfizer, Poseida, Pyramid, Scholar Rock, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Xilio, Aulos Bioscience, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, IconOVir, Jazz Pharmaceuticals, Krystal Biotech, NucMito, OnKure, Remix Therapeutics. R. Aljumaily: Financial Interests, Institutional, Advisory Role: AstraZeneca, Regeneron; Financial Interests, Institutional, Research Funding: AbbVie, Alliance Foundation Trials, Array BioPharma, AstraZeneca, Baxalta, Boehringer Ingelheim, Boston Biomedical, Bristol Myers Squibb, Checkpoint Therapeutics, EMD Serono, G1 Therapeutics, Genentech, GSK, Huntsman Cancer Institute, Lilly, MedImmune, Merck, Novartis, Peloton Therapeutics, Pfizer, Regeneron, Roche, Syneos Health, Tesaro. J. Machiels: Financial Interests, Institutional, Advisory Board: Novartis, MSD, Pfizer, Roche, Debio, AstraZeneca, Innate, Nanobiotix, Bayer, Boerhinger Ingelheim, BMS, Pfizer, Cue Pharma, Incyte, Janssen, Johnson & Johnson, ALX Oncology, F-star, Nektar, F-star, Seagen, Astellas, Genmab, Merus, GSK, CureVac; Financial Interests, Institutional, Advisory Board, Education: Merck-Serono; Financial Interests, Institutional, Other, Travel expense: Gilead, MSD, Sanofi; Financial Interests, Institutional, Steering Committee Member: AstraZeneca, MSD; Financial Interests, Institutional, Coordinating PI: MSD, iTeos, eTheRNA; Financial Interests, Institutional, Local PI: Pfizer, Ceylad, MSD, Novartis, Kura, Roche, Lilly, Boehringer, Sanofi-Aventis, Incyte, Bayer, Merck - Serono, Janssen, Johnson & Johnson, Amgen, AbbVie, GSK; Non-Financial Interests, Leadership Role, Chair: EORTC head and neck group. M. Vieito: Financial Interests, Personal, Invited Speaker: Novocure; Financial Interests, Personal, Other, Steering committee member: BMS; Non-Financial Interests, Principal Investigator: Roche, BMS, Taiho, Hutchinson Pharma, Novartis, Mundipharma, Enterome, Debiopharm. L. Carter: Financial Interests, Personal, Other, Consultancy: Bicycle Therapeutics, Boehringer Ingelheim, Athenex; Financial Interests, Personal, Full or part-time Employment, Medical Advisor: Cancer research UK Centre for Drug Development; Financial Interests, Institutional, Local PI: Boehringer Ingelheim, Cellcentric, Eli Lilly, Repare Therapeutics, EMD Serono/Merck KGaA, Sierra Oncology, Nurix Therapeutics, Takeda; Financial Interests, Institutional, Coordinating PI: Bicycle Therapeutics, Athenex, Lupin Limited, Cytomx therapeutics, ADC Therapeutics; Financial Interests, Institutional, Local PI, Funding for delivering commercial trial activity: Genmab. H. Prenen: Financial Interests, Institutional, Advisory Board: Amgen, Roche, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Bayer, Ipsen, Sanofi. 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; 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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; 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. A. Greystoke: Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, Boehringer Ingelheim, Takeda, Roche, Novartis; Financial Interests, Personal, Invited Speaker: Merck, MSD, Pfizer, Janssen; Financial Interests, Institutional, Local PI: MSD; Financial Interests, Institutional, Coordinating PI: Pfizer, AstraZeneca, Novartis, Achilles; Non-Financial Interests, Advisory Role: National Institue for Health and Clinical Excellence; Non-Financial Interests, Leadership Role, Steering Committee member: British Thoracic Oncology Group; Other, Clinical Lead for Cancer (paid position): North East Englad and Yorkshire Genomic Laboratory Hub. W.I. Ortuzar Feliu: Financial Interests, Personal, Full or part-time Employment, full time Employee: Bicycle Inc.; Financial Interests, Personal, Stocks/Shares, No longer employed: Agenus. A. De: Financial Interests, Institutional, Full or part-time Employment: Bicycle Therapeutics. X. Gu, M. Li, A. de Rienzo: Financial Interests, Institutional, Full or part-time Employment: Bicycle Therapeutics; Financial Interests, Institutional, Stocks/Shares: Bicycle Therapeutics. B. Bashir: Financial Interests, Personal, Advisory Board: Merck/Eisai, Fate/Ono Therapeutics, Kahr Medical; Financial Interests, Personal, Other, Scientific reviewer: Department of Defense, United States; Financial Interests, Institutional, Local PI: Amgen Inc., Avenzo Therapeutics, Bicycle Therapeutics, Boehringer Ingelheim, Elucida Oncology, Gritstone Bio, Jazz Pharmaceuticals, Kahr Medical, Lyell Immunopharma, Merck, Ikena Oncology, Pionyr Immunopharma, Rascal Therapeutics, Syros Pharmaceuticals, Tarveda Therapeutics; Financial Interests, Personal and Institutional, Steering Committee Member: Fate Therapeutics. All other authors have declared no conflicts of interest.