650P - Initial results from a phase I/II study of BT7480, a novel nectin-4/CD137 bicycle tumor-targeted immune cell agonist, in patients (pts) with advanced solid tumors

Background

BT7480 is a novel, synthetic Bicycle tumor-targeted immune cell agonist (Bicycle TICA®) comprising 3 bicyclic peptides, 1 targeting Nectin-4 and 2 targeting CD137. Nectin-4 is overexpressed in many cancers and CD137 is expressed on activated immune cells. Nectin-4 and CD137 co-ligation by BT7480 is hypothesized to cause tumor-localized enhanced antitumor immune responses. This phase 1/2 study (NCT05163041) will evaluate BT7480 ± nivolumab in pts with cancer. Initial phase 1 monotherapy dose escalation results are reported.

Methods

Adult pts with advanced solid tumors associated with Nectin-4 expression and refractory to/ineligible for standard therapy were included in this 3+3 dose escalation study. Primary endpoint was incidence and severity of adverse events (AEs); secondary endpoints included antitumor activity (RECIST v1.1), pharmacokinetics (PK), and CD137 target engagement. Biomarker analyses were exploratory endpoints.

Results

As of 12 Feb 2024, 39 pts had received BT7480 (0.002–3.5 mg/kg weekly [QW] IV). Median age was 62 yrs; 69% had ECOG PS 1; >75% were Nectin-4+. Non-small cell lung cancer (n=11) was the most common tumor type. Pts had median 4 prior therapies (range 1–9). Grade ≥3 treatment-related AEs were reported in 5% of pts; any grade AEs occurred in 49% with most common being fatigue (23%) and headache (10%). Maximum tolerated dose has not yet been reached. Three prolonged stable diseases (>8 mo) were observed in NSCLC (n=2) and anal squamous cancer (n=1); 2 unconfirmed partial responses were observed in cervical cancer. Initial pharmacodynamic (PD) biomarker analyses showed target saturation at doses ≥0.15 mg/kg and max induction of circulating immune activation markers at doses ≥1.3 mg/kg (serum CD137, CXCL9, and CD4+ T cells). PK was generally dose dependent. Terminal half-life at 1.3–3.5 mg/kg was 13–16 h, with minimal BT7480 accumulation at steady state at QW dosing.

Conclusions

BT7480 was well tolerated and showed antitumor activity in pts with advanced Nectin-4–associated solid tumors. Biomarker analyses suggest BT7480 dual targeting of CD137 and Nectin-4 enhanced immune activation; PD activity was consistent with the BT7480 mechanism of action.

Clinical trial identification

NCT05163041.

Editorial acknowledgement

Writing assistance was provided by Tamara Fink, PhD, and Rebecca L. Crepeau, PhD of Fishawack Communications Ltd.

Legal entity responsible for the study

BicycleTx Ltd.

Funding

BicycleTx Ltd.

Disclosure

K.P. Papadopoulos: Financial Interests, Personal, Advisory Board: Turning Point Therapeutics, Bicycle, Basilia; Financial Interests, Institutional, Full or part-time Employment: START; Financial Interests, Personal, Ownership Interest: START; Financial Interests, Institutional, Local PI, For conduct of clinical trial: 3D Medicines, AbbVie, ADC Therapeutics, Amgen, Anheart Therapeutics, Bayer, Daiichi Sankyo, EMD Serono, F-Star, Incyte, Jounce Therapeutics, Lilly, Linnaeus Therapeutics, Merck, Mersana, Mirati Therapeutics, Pfizer, Regeneron Pharmaceuticals, Syros Pharmaceuticals, Tempest Therapeutics, Treadwell Therapeutics, Revolution Medicine, Fog, Sensei, Storm. A. Dowlati: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Ipsen, Jazz Pharmaceuticals, Prelude Corporation, Puma Biotechnology. J.S. Lopez: Financial Interests, Personal, Advisory Board: Roche Genentech, Basilea, Ellipses Pharma, Cureteq, Pierre Faber, GSK; Financial Interests, Institutional, Research Grant: Roche Genentech, Basilea, Astex. J. Rodon: Financial Interests, Personal, Advisory Board: Ellipses Pharma, iOnctura SA, Aadi Bioscience, Envision Pharma, Molecular Partners, Mekanistic, Amgen; Financial Interests, Personal, Other, Consultancy: Clarion Healthcare, Debiopharm, Cullgen, Pfizer, Macrogenics, Oncology One, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad, Chinese University of Hong Kong, Boxer Capital, Llc, Tang Advisors, Llc, Alnylam Pharmaceuticals, Bridgebio Pharma; Financial Interests, Personal, Other, Consultancy/Advisory Board: Monte Rosa Therapeutics, Merus N.V., Incyte; Financial Interests, Institutional, Other, Clinical Research: Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GSK; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, Bayer, Hutchinson MediPharma; Other: VHIO/Ministero De Empleo Y Seguridad Social; Other, Travel: European Society for Medical Oncology, Loxo Oncology. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med, Regeneron, Loxo, Alkermes, Medikine, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, Arrivent Biopharma. M. Stein: Financial Interests, Personal, Advisory Board: Merck Sharo and dohme, Exelixis, Xencor, Janssen Oncology, Vaccitech, Bristol Myers Squibb/Medarex; Financial Interests, Institutional, Local PI: Janssen Oncology, Seattle Genetics, Regeneron, Bicycle Therapeutics, OncoC4; Financial Interests, Institutional, Research Grant: Advaxis; Financial Interests, Institutional, Trial Chair: Bristol Myers Squibb, Exelixis; Financial Interests, Institutional, Coordinating PI: Xencor. M. Zibelman: Financial Interests, Personal, Advisory Board: Merck, Exelixis, Inc., Adicet Bio; Financial Interests, Institutional, Research Funding: BMS, Exelixis, Inc. 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 here: Agenus. A. Dickson, S. Santos: Financial Interests, Personal, Full or part-time Employment: Bicycle Therapeutics. A. De: Financial Interests, Personal and Institutional, Full or part-time Employment: Bicycle Therapeutics. X. Gu, H. Cohen, J. Bader, C. Bray: Financial Interests, Personal, Full or part-time Employment: Bicycle Therapeutics; Financial Interests, Personal, Stocks/Shares: Bicycle Therapeutics. M. Li, J. Smith, R. Lis: Financial Interests, Personal, Full or part-time Employment: Bicycle Therapeutics; Financial Interests, Personal, Stocks or ownership: Bicycle Therapeutics. T.R.J. Evans: Financial Interests, Institutional, Advisory Board for GI cancers and melanoma (immune checkpoint inhibitors): Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, Invited speaker - GI cancers, melanoma, immunotherapy: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Boards - GI cancers, melanoma: Roche / Genentech; Financial Interests, Institutional, Invited Speaker, Invited speaker GI cancer, melanoma: Roche / Genentech; Financial Interests, Institutional, Advisory Board (Lenvatinib): Eisai; Financial Interests, Institutional, Invited Speaker, Speaker's fees (lenvatinib): Eisai; Financial Interests, Institutional, Advisory Board: MSD, AstraZeneca, Bayer, Bicycle Therapeutics, Clovis; Financial Interests, Institutional, Invited Speaker, Speaker's fees: MSD, AstraZeneca, Bayer; Financial Interests, Institutional, Advisory Board: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees: Nucana; Financial Interests, Institutional, Advisory Board, advisory board; Chair of Scientific Advisory Council (HCC & MIV-818): Medivir; Financial Interests, Institutional, Invited Speaker, speaker's fees (and presentation to potential investors): Medivir; Financial Interests, Personal, Other, Support to attend international conferences: Bristol Myers Squibb, Roche / Genentech, MSD, Nucana, Bayer, Celgene, Pierre Fabre; Financial Interests, Institutional, Advisory Board for Upper GI Cancer: Ascelia; Financial Interests, Institutional, Advisory Board for Oesophageal Cancer: Seagen; Financial Interests, Institutional, Coordinating PI, Educational grant (supply of study agents) for investigator-led study and reimbursement of study costs for commercial studies: AstraZeneca; Financial Interests, Institutional, Local PI, reimbursement of study costs for commercial studies: Astellas, Bayer, Basilea, Celgene, GSK, Roche, Medivir, Starpharma, Immunocore, Novartis, Sapience Therapeutics, MiNa Therapeutics, Lilly, Bicycle Therapeutics, Sierra, CytomX, BeiGene, Pfizer, Johnson & Johnson, UCB, Codiak, Avacta, Nurix, T3P, Amgen, Moderna; Financial Interests, Institutional, Coordinating PI, reimbursement of study costs for commercial studies: Adaptimmune, Bristol Myers Squibb, Eisai, MSD, Nucana, iOnctura, Sanofi; Financial Interests, Institutional, Local PI, support for non-commercial investigator-led study: Verastem; Financial Interests, Institutional, Local PI, reimbursement for costs of commercial studies: Boehringer Ingelheim; Financial Interests, Institutional, Local PI, reimbursement of costs of commercial study: Seagen; Financial Interests, Institutional, Funding, reimbursement of study costs for commercial studies; lead investigator for infrastructure investment to NHS Research Scotland: BioNTech; Financial Interests, Institutional, Local PI, reimbursement of study sots for commercial studies: Exelixis; Non-Financial Interests, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Other, Annual Meeting abstracts committee: International Liver Cancer Association; Non-Financial Interests, Institutional, Product Samples, Supply of investigational and licensed compounds for a non-commercial study for which I'm Chief Investigator: AstraZeneca; Non-Financial Interests, Member, Cancer Society Member: American Society of Clinical Oncology, America Association for Cancer Research, British Association for Cancer Research, Association of Cancer Physicians (UK), European Association for Cancer Research, International Liver Cancer Association; Other, Editor-in-Chief: British Journal of Cancer; Other, Chair of Independent Data Monitoring Committee for a phase 1 trial - honorarium payable to the employing institution: Genmab; Other, Chair and panel member, Scientific Evaluation Committee: early phase trials (Amgen, Merck, AstraZeneca); Chair and panel member, CLIP (early phase trial centres) 5-year review: Institut National du Cancer (France); Other, Panel Member, Pancreas Cancer funding committee, 2023: Foundation ARC; Other, NHS Research Scotland cancer research network national clinical lead: NHS Research Scotland.