795TiP - A first-in-human phase I study of LY4170156, an antibody-drug conjugate targeting folate receptor α (FRα)-expressing advanced solid tumors

Background

Folate receptor alpha (FRα) is an internalizing target overexpressed in several solid tumors. Mirvetuximab soravtansine-gynx, an FRα antibody-drug conjugate (ADC) with a DM4 payload, is approved for the treatment of platinum resistant ovarian cancer (PROC) with high FRα expression representing ∼30% of PROC patients (pts). LY4170156 is an Fc-silent FRα specific humanized IgG1 ADC, linked to exatecan, a topoisomerase I inhibitor, via a novel cleavable polysarcosine (PSAR) linker, at a homogenous drug-antibody ratio (DAR) of 8. Preclinically, LY4170156 has demonstrated in vivo efficacy in high and moderate/low FRα expressing tumor models (Viricel W. et al. 2023 Cancer Res 83 (7_Suppl):1544).

Trial design

LOXO-FRA-24001 is a multicenter, open-label, first-in-human phase 1a/b study of LY4170156 in pts with advanced solid tumors expressing FRα. Eligible pts (≥18 years) must have ovarian, endometrial, cervical, pancreatic, NSCLC, TNBC, or CRC, and must have received standard therapy or not be a candidate for available standard therapies. Prior mirvetuximab soravtansine-gynx therapy is allowed. The study has 2 phases: phase 1a dose escalation/dose optimization and phase 1b dose expansion. Dose escalation follows the mTPI-2 method. Pts are allowed to backfill to previously cleared dose levels that have demonstrated therapeutically relevant exposures or shown direct evidence of clinical activity. LY4170156 is administered intravenously Q3W; DLT evaluation period is 21 days. In dose expansion, pts with select tumor types are enrolled into 4 cohorts: PROC with high (cohort B1) and moderate/low (cohort B2) FRα expression and select advanced/metastatic non-ovarian cancer with high (cohort C1) and moderate/low FRα expression (cohort C2). FRα expression levels in tumor tissue are determined by immunohistochemistry using central testing. Primary objectives are to determine the RP2D and assess the safety of LY4170156. Key secondary objectives are to evaluate the pharmacokinetic profile and antitumor activity of LY4170156 per RECIST v1.1.

Clinical trial identification

NCT06400472.

Editorial acknowledgement

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, adaptimmun, Eisai, Sutro, BMS, Adaptimmune, Daichi-Santyo, ImmunoGen, Seagen, PMV Pharma; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Principal Investigator: PAOLA1; Non-Financial Interests, Other, President: GINECO. J.F. Liu: Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis Oncology, Eisai, Genentech/Roche, GSK, Regeneron Pharmaceuticals, Zentalis; Financial Interests, Personal, Other, Consulting: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: 2X Oncology, Aravive, Arch Oncology, CytoMX Therapeutics, GSK, Impact Therapeutics, Regeneron, Zentalis; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Bristol Myers Squibb, Clovis Oncology; Non-Financial Interests, Advisory Role, Co-Chair of Scientific Advisory Board: Tina's Wish. A. Oaknin: Financial Interests, Personal, Advisory Board: Agenus, AstraZeneca, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Eisai, F. Hoffmann-La Roche, GSK, Genmab, ImmunoGen, Itheos, MSD, Mersana Therapeutics, Novocure, OncoXerna Therapeutics, Inc, PharmaMar, Regeneron, Shattuck Labs, Seagen/Pfizer, Sutro Biopharma, Exelisis, DaIichi Sankyo, Debiopharm International, Myriad Genetics, Zentalis; Financial Interests, Personal, Other, Travel and accommodation: AstraZeneca, PharmaMar, Roche; Financial Interests, Institutional, Funding: Amgen, AbbVie Deutschland, Advaxis Inc., Aeterna Zentaris, Aprea Therapeutics AB, Regeneron Pharmaceuticals, Clovis Oncology Inc, EISAI limited LTD, F. Hoffmann –La Roche Ltd, ImmunoGen Inc, Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc, PharmaMar SA, Tesaro Inc., Bristol Myers Squibb; Non-Financial Interests, Leadership Role, on behalf of GEICO: GCIG; Non-Financial Interests, Officer, Chair of Gynaecological Track ESMO 2019. Scientific Track Member Gynaecological Cancers ESMO 2018, ESMO 2020, ESMO 2022. Member of Gynaecological Cancers Faculty and Subject Editor Gyn ESMO Guidelines.: ESMO; Non-Financial Interests, Leadership Role, ESMO GYN Co-Chair 2023 - 2025: ESMO; Non-Financial Interests, Leadership Role, Chair de Cervix Committee. 2022-2024: GCIG; Non-Financial Interests, Member: ESMO, ASCO, GCIG, SEOM, GOG. B. Pothuri: Financial Interests, Personal, Advisory Board, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board, Advisory board: AstraZeneca; Financial Interests, Personal, Advisory Board: Clovis Oncology, GSK, Merck, Tesaro, Sutro, Mersana, Lily, Seattle Genetics, GOG Foundation; Financial Interests, Personal, Other, consulting: Toray, Arquer Diagnostics, Atossa, Elevar, Deciphera, Imab, WebMD, Onconova Therapeutics, PeerView, Onclive; Financial Interests, Personal, Other, Consulting: Bioascend; Financial Interests, Institutional, Local PI: Tesaro, Clovis Oncology, Roche Genentech, Takeda, Celsion, Celgene, AstraZeneca, ImmunoGen, Merck, GSK, Acrivon; Financial Interests, Institutional, Local PI, clinical trial: Incyte, Toray, Karyopharm, Sutro, Eisai, VBL Therapeutics, Mersana, Seattle Genetics; Non-Financial Interests, Other, Member of GOG Partners group: GOG Foundation; Non-Financial Interests, Member of Board of Directors: Society of Gynecologic Oncology. D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK, Clovis Oncology, PharmaMar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Other, Consultancy: PharmaMar, AstraZeneca, Clovis Oncology, GSK, MSD, ImmunoGen, Genmab, Seagen, Novartis; Financial Interests, Personal, Advisory Board, Invited member of advisory board and invited speaker: Seagen, ImmunoGen, Genmab; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Oncoinvest, Corcept, Sutro; Financial Interests, Institutional, Funding, Grant for founding academic trials: MSD, Clovis Oncology, GSK, PharmaMar; Financial Interests, Institutional, Coordinating PI, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Coordinating PI, ENGOT trial with insitutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clinical trial/contracted research: AstraZeneca, Clovis Oncology, GSK, MSD, Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, ImmunoGen, Incyte, Novartis, Roche; Non-Financial Interests, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Genmab; Non-Financial Interests, Principal Investigator, PI in several trials. No personal compensation received: MSD; Non-Financial Interests, Principal Investigator, PI of clinical trial. No personal compensation received: immunogen, Clovis Oncology, roche, Incyte; Non-Financial Interests, Principal Investigator, PI of several trials, no personal compensation received: Novartis; Non-Financial Interests, Principal Investigator, PI of clinical trial, no personal compensation received: Seagen; Non-Financial Interests, Principal Investigator, PI of clinical trials, no personal compensation received: PharmaMar; Non-Financial Interests, Member, Board of Directors: GCIG; Other, Grants for traveling: AstraZeneca, Clovis Oncology, GSK. S. Westin: Financial Interests, Personal, Advisory Board: AstraZeneca, Caris, Clovis Oncology/Pharma&, Corcept, Eisai, EQRX, Gilead, GSK, Immunocore, ImmunoGen, Lilly/Loxo, Merck, Mereo, Mersana, NGM Bio, Nuvectis, Roche/Genentech, Seagen, Verastem, Vincerx, Zentalis, ZielBio; Financial Interests, Institutional, Research Grant: AstraZeneca, AvengeBio, Bayer, Bio-Path, Clovis/Pharma&, GSK, Jazz Pharma, Mereo, Novartis, Nuvectis, Roche/Genentech, Zentalis. N.J. Lakhani: Financial Interests, Personal, Advisory Board: Innovent Biologics; Financial Interests, Personal, Advisory Board, Participation in Ad Board: Ikena, SK Life Sciences; Financial Interests, Institutional, Local PI: ALX Therapeutics, Ascentage, Constellation Pharma, Alpine Biosciences, Forty Seven, Merck, Pfizer, Regeneron, Symphogen, InhibRx, Seagen, Sapience Therapeutics, Jounce, Northern Biologics, Odonate, Loxo/Lilly, Ikena, Mersana Therapeutics, Astellas, Celgene, Helsinn, Shattuck Labs, Samumed, GSK, Alkermes, Samumed, Tizona Therapeutics, Gilead, Repare Therapeutics, Alkermes, InhibRx, Janssen, cytomX, KSQ Therapeutics, Repare Therapeutics, Arcus Bio, Artios, Revolution Medicines, Volastra; Financial Interests, Institutional, Coordinating PI: Servier. T. Koyama: Financial Interests, Personal, Invited Speaker: Sysmex, Chugai, AstraZeneca; Financial Interests, Institutional, Research Grant: PACT Pharma, Boehringer Ingelheim; Financial Interests, Institutional, Local PI: Novartis, Chugai, Lilly, Daiichi Sankyo, Takeda, AstraZeneca, Zymeworks. S. Kitano: Financial Interests, Personal, Advisory Board, Scientific Advisor: ImmuniT Research, United Immunity, Sumitomo Pharma; Financial Interests, Personal, Advisory Board, Scientific advisor: Rakuten Medical; Financial Interests, Personal, Other, lecture fee: AstraZeneca; Financial Interests, Personal, Other, Lecture fee: Pfizer, Taiho, Novartis, MSD, Eisai, Bristol Myers Squibb, GSK, Chugai, Takeda, Janssen, Merck KGaA; Financial Interests, Personal, Other, Scientific adviser, Lecture fee: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: PMDA(Pharmaceuticals and Medical Devices Agency); Financial Interests, Personal and Institutional, Local PI, Clinical Trial, Research Grant: Daiichi Sankyo; Financial Interests, Personal and Institutional, Local PI, Clinical Trial: AstraZeneca, Pfizer, MSD, Eisai, Incyte, Takeda, Eli Lilly Japan K.K., Loxo Oncology, AbbVie; Financial Interests, Personal and Institutional, Local PI, Clinical trial, Research Grant: Nippon Boehringer Ingelheim; Financial Interests, Personal and Institutional, Local PI, Clinical trial: Astellas; Financial Interests, Personal and Institutional, Coordinating PI, Clinical trial, Research Grant: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal and Institutional, Local PI, Clinical trial: GSK; Financial Interests, Personal and Institutional, Local PI, Clinical Trial, Research Grant: Chugai; Financial Interests, Personal and Institutional, Research Grant, Research Grant: Takara Bio Inc.. C.A. Gomez-Roca: Financial Interests, Personal, Invited Speaker: BMS, Roche / Genentech, Pierre Fabre; Financial Interests, Personal, Other, IDMC member: PharmaMar; Financial Interests, Personal, Advisory Board: Macomics, Ellipses Pharma, PSAD; Financial Interests, Institutional, Research Grant: Roche / Genentech, Amgen; Financial Interests, Institutional, Coordinating PI: Amunix, Kazia Therapeutics, Ideaya; Non-Financial Interests, Member of Board of Directors: FITC (Société française d'Immuno-Thérapies du Cancer); Non-Financial Interests, Officer: ESMO Membership Committee, ESMO - MCBS Extended Working Group; Non-Financial Interests, Officer, Young Investigators Committee at imCORE: inFLAME; Non-Financial Interests, Member of Board of Directors, Network of Early Phase Units: OncoDistinct; Non-Financial Interests, Leadership Role: FITC (Société française d'Immuno-Thérapies du Cancer). J.A. Perez Fidalgo: Financial Interests, Personal, Invited Speaker: AstraZeneca, Clovis, GSK, PharmaMar; Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Clovis, PharmaMar, Roche, Abilify Pharma; Financial Interests, Personal, Full or part-time Employment, Associate Professor: University of Valencia; Financial Interests, Institutional, Research Grant: GSK, PharmaMar; Financial Interests, Institutional, Funding: Novartis, GSK; Financial Interests, Institutional, Coordinating PI: AstraZeneca; Financial Interests, Personal, Steering Committee Member: AstraZeneca, Artios Pharma; Non-Financial Interests, Project Lead, Coordinating PI Phase III trial in breast cancer: Novartis; Non-Financial Interests, Member, Member of the Early Drug Development working group: ENGOT; Non-Financial Interests, Leadership Role, Member of the Executive Committee and Head of the Scientific Committee: GEICO; Non-Financial Interests, Leadership Role, Member of the Executive Commitee and co-coordinator of Uterine Sarcoma Group: GEIS; Non-Financial Interests, Leadership Role, Co-chair Phase 2 group: GCIG; Non-Financial Interests, Member: BIG; Non-Financial Interests, Member, Adolescent and Young Adults working group: SEOM. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Personal, Advisory Board, Advisory Board: Menarini, Gilead; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Coordinating PI, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Officer, Editor of Chief of ESMO Open: ESMO; Non-Financial Interests, Leadership Role, Until the end of 2024: EUSOMA. M. Campone: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Sanofi, Daiichi Sankyo, Lilly, Stemline, Gilead, Seagen; Financial Interests, Institutional, Invited Speaker: Novartis, Lilly. B. Sharkey: Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. E. Avsar: Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company, BMS, GSK, Novo Nordisk, insulet corporation, Regeneron. C. Friedman: Financial Interests, Personal, Advisory Board: Loxo@Lilly; Financial Interests, Personal, Other, One time consulting meeting: Johnson and Johnson; Financial Interests, Institutional, Local PI: AstraZeneca, Hotspot Therapeutics, Immunocore, Mersana, Volastra; Financial Interests, Personal, Steering Committee Member: Marengo, Genentech/Roche; Financial Interests, Institutional, Steering Committee Member: Merck; Other, Travel Support: Puma. All other authors have declared no conflicts of interest.