750P - Phase I safety and efficacy of brenetafusp, a PRAME × CD3 ImmTAC T cell engager, in platinum resistant ovarian cancer (PROC)

Background

Brenetafusp (brene), an ImmTAC bispecific T cell engager (PRAME × CD3), showed robust disease control and tumor reduction in Ph1 (NCT04262466; Hamid 2022, Hamid 2024) in HLA-A*02:01+ patients (pts). We present monotherapy (mono) and chemotherapy combination (CC) data in PROC, and association with a baseline blood T cell fitness (TCF) signature that was also linked with tebentafusp benefit in uveal melanoma (ESMO 2024). Preclinically, chemo increased antigen presentation and ImmTAC activity (ESMO 2024).

Methods

Brene was dosed IV weekly with step-up to target dose of 40-320 mcg in mono escalation or 160 mcg in expansion & in CC. Chemo options were gemcitabine (Gem), nab-paclitaxel (NP), and PLD. Primary objectives: Safety, dose selection, and efficacy (RECIST v1.1). Exploratory endpoints included molecular response (≥ 0.5 log ctDNA reduction by week 9) and TCF (mean RNAseq expression of TESPA1, CD28 and GRP183 in blood at baseline). Data cutoff: Mar 2024.

Results

47 pts with high-grade serous PROC received brene (mono 32, CC 15) at active doses in escalation and expansion. Pts had a median 4 prior regimens. Most common adverse event (AE) was Grade 1/2 cytokine release syndrome (mono 53%, CC 80%). No drug-related AE led to treatment discontinuation or death. CC safety was consistent with individual agents. 40 pts were efficacy evaluable (mono 28, CC 12). Mono disease control rate (DCR; PR+SD) was 61% (17/28) with 2 PR (ORR 7%); mPFS was 3.3 mo and 6-mo OS rate was 73%. In CC, DCR was 67% (8/12) with 3 PR (Gem 1/9; NP 1/2; PLD 1/1). Molecular response (mono 6/25 [24%]; CC 9/10 [90%]) trended with longer PFS and OS. 28 mono pts were TCF-evaluable. Pts with ≥ median TCF had higher DCR (80%) than pts with < median TCF (38%) and longer mPFS (3.7 vs. 2.2 mo, respectively; HR 0.39 [95% CI 0.15-0.97]).

Conclusions

Brenetafusp was well tolerated, alone and with chemotherapy. Monotherapy was active in PROC, demonstrated by DCR and molecular response, which are surrogates of benefit for the ImmTAC platform. Clinical activity associated with blood TCF signature, which is another ImmTAC hallmark. Enhanced activity with chemo and potential for greater TCF in earlier lines support assessing additional combinations in PROC and platinum sensitive disease.

Clinical trial identification

NCT04262466.

Editorial acknowledgement

Legal entity responsible for the study

Immunocore Ltd.

Funding

Immunocore.

Disclosure

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. 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. K. Ouali: Financial Interests, Institutional, Other, As part of the Drug Development Department (DITEP), KO is principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, AstraZeneca Ab, AstraZeneca, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc, Cato Research, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, EverImmune, Exelixis, Faron Pharmaceuticals Ltd, Foghorn Therapeutics Inc, Forma Tharapeutics, Gamamabs, Genentech, Genmab, GSK, H3 Biomedicine, Hoffmann La Roche Ag, IGM Biosciences, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, K-Group Beta, Kinnate Biopharma, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France,: Various drug companies. M.R. Middleton: Financial Interests, Personal, Advisory Board: Alkermes, Boehringer Ingelheim, Brystol-Myers Squibb; Financial Interests, Personal, Other: Immunocore, Infinitopes, GRAIL. F. Thistlethwaite: Financial Interests, Personal, Advisory Board, Ad board: BMS; Financial Interests, Personal, Advisory Board, Ad boards: GSK; Financial Interests, Personal, Advisory Board, Adboard/consultancy: T-Knife Therapeutics; Financial Interests, Personal, Advisory Board: Immatics, Scenic Biotech, F-Star, Leucid; Financial Interests, Personal, Invited Speaker: Kite Gilead; Financial Interests, Personal, Other, Occasional individual consulting: Guidepoint; Financial Interests, Personal, Advisory Board, Advisory board meeting Feb 2023: CytomX; Financial Interests, Personal, Advisory Board, Advisory board Feb 2024: Grey Wolf Therapeutics; Financial Interests, Institutional, Other, iMATCH is a consortium funded by not for profit Innovate UK (UK government body) partners include clinical and academic institutes. I am director and my salary (0.2WTE) is supported through this work as a grant to my institution (The Christie NHS foundation trust - not for profit NHS hospital) from IUK: iMATCH director; Financial Interests, Institutional, Local PI, NCT02890069: Novartis; Financial Interests, Institutional, Research Grant, Sarcoma pathways project and CAR-T PROMs study: GSK; Financial Interests, Institutional, Local PI, NCT02493751: Pfizer; Financial Interests, Institutional, Local PI, NCT03245736, NCT02988817, NCT02552121, NCT02001623, NCT05180474: GenMab; Financial Interests, Institutional, Local PI, NCT02277717: Synthon; Financial Interests, Institutional, Local PI, NCT03013491: CytomX; Financial Interests, Institutional, Local PI, NCT03314935: Incyte; Financial Interests, Institutional, Local PI, NCT02908906 and CAR-T referrals project: Janssen; Financial Interests, Institutional, Local PI, NCT03132792, NCT04044768,: Adaptimmune; Financial Interests, Institutional, Local PI, NCT03400332: BMS; Financial Interests, Institutional, Local PI, NCT04262466, NCT03973333, NCT03515551: Immunocore; Financial Interests, Institutional, Local PI, EudraCT Number: 2018-001005-85, 2018-003446-16: Achilles ltd; Financial Interests, Institutional, Local PI: Agalimmune Ltd; Financial Interests, Institutional, Local PI, NCT02834247: Millenium Pharmaceuticals/Takeda; Financial Interests, Institutional, Local PI, NCT02690350: Daiichi Sankyo; Financial Interests, Institutional, Local PI, NCT04839991: Crescendo; Financial Interests, Institutional, Local PI, NCT05104515: Oxford Vacmedix Ltd; Financial Interests, Institutional, Local PI, NCT05278975: RS Oncology LLC; Financial Interests, Institutional, Coordinating PI, NCT03697824, NCT03391778: GSK; Financial Interests, Institutional, Coordinating PI, NCT04140500, NCT04857138, NCT04826003: Roche; Financial Interests, Personal, Coordinating PI, NCT05008913, NCT04949425, NCT0331509, NCT03313557: AstraZeneca; Financial Interests, Institutional, Coordinating PI, NCT03829501: Kymab Ltd/Sanofi; Financial Interests, Institutional, Coordinating PI, EUDRACT ID No: 2019-003329-11: Chugai; Financial Interests, Institutional, Coordinating PI, NCT05430555: T-Knife Therapeutics; Financial Interests, Institutional, Coordinating PI, NCT03621982: ADCT Therapeutics; Financial Interests, Institutional, Research Grant, IRAS Project ID: 227414: Novartis; Financial Interests, Institutional, Coordinating PI, ITIL-306-202: Instil Bio; Financial Interests, Institutional, Funding, CAR-T referrals project: Gilead, Autolus; Financial Interests, Institutional, Local PI, NCT04763083: Novalgen; Financial Interests, Institutional, Local PI, NCT05714553: Nucana; Non-Financial Interests, Other, Panel member for a funding committee (MRC is a UK government NFP organisation) 2020-2024: MRC DPFS panel member; Non-Financial Interests, Advisory Role, Sarcoma UK is a not-for-profit charity. I act as an advisor on their Research Strategy Committee. This role is not compensated: Sarcoma UK; Non-Financial Interests, Leadership Role, Funding is from not-for-profit government bodies. Role is not compensated.: Chair of the Independent Steering Committee for NIHR Blood & Transplant Research Unit, Oxford; Non-Financial Interests, Advisory Role, Funding panel member for CRUK (not-for profit charity). Role is not compensated: CRUK New Agents Committee Member; Non-Financial Interests, Leadership Role, Chair of Cell therapy subgroup. MRC is a not-for-profit organisation. Role is not compensated.: MRC Advanced Therapies Task Group; Non-Financial Interests, Leadership Role: ESMO Congress 2024 Experimental Immunotherapy Track Chair; Non-Financial Interests, Advisory Role: ESMO TAT conference scientific advisory board 2025; Non-Financial Interests, Advisory Role, Target Ovarian Cancer is a not-for-profit charity. I am Chair of their Scientific Advisory board. This role is not compensated: Target Ovarian Cancer. O. Hamid: Financial Interests, Personal, Advisory Board: Alkermes, Amgen, BMS, Bactonix, BeiGene, Bioatla, Eisai, GSK, Georgiamune, GigaGen, Grit Bio, IO Biotech, Idera, Idera, Immunocore, Incyte, Instil Bio, Iovance, Janssen, KSQ, Merck, NextCure, Novartis, Obsidian, Pfizer, Roche Genentech, Seagen, Sanofi / Regeneron, Tempus, Vial, Zelluna; Financial Interests, Personal, Invited Speaker: BMS, Immunocore, Novartis, Pfizer, Sanofi / Regeneron; Financial Interests, Personal, Stocks/Shares: Bactonix; Financial Interests, Institutional, Local PI: Aduro, Akeso, Amgen, Arcus, BMS, Bioatla, CytomX, Exelixis, GSK, Idera, Immunocore, Incyte, Iovance, Merck, Merck Serono, Moderna, Nextcure, Novartis, Pfizer, Roche Genentech, Rubius, Seagen, Sanofi / Regeneron, Torque, Zelluna. B. Izar: Financial Interests, Personal, Advisory Board: Immunocore. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: Start; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. M.L. Johnson: Financial Interests, Institutional, Other, Consulting: AbbVie, Amgen, Arcus Biosciences, Arrivent, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Immunocore, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Pyramid Biosciences, Alentis Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, D3 Bio Limitied, Fate Therapeutics, Gilead Sciences, Hookipa Biotech, Lilly, Normunity, Novocure, Pfizer, Revolution Medicines, Sanofi-Aventis, Seagen, Synthekine, Takeda Pharmaceuticals, VBL Therapeutics; Financial Interests, Institutional, Research Grant: AbbVie, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GSK, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, Y-mAbs Therapeutics, ArriVent BioPharma, Bayer, LockBody Therapeutics, Taiho Oncology. D. Davar: Financial Interests, Personal, Advisory Board: ACM Bio, Ascendis, Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Immunitas, Medical Learning Group (MLG), Replimmune, Trisalus, Xilio Therapeutics; Financial Interests, Personal, Stocks/Shares: Zola; Financial Interests, Institutional, Other, US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, Dec 11, 2020: None; Financial Interests, Institutional, Royalties, US Patent 63/208,719, “Compositions and Methods For Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021: None; Financial Interests, Institutional, Coordinating PI: Arcus, Immunocore, Merck, Regeneron Pharmaceuticals Inc., Tesaro/GSK. J. Martin-Liberal: Financial Interests, Personal, Invited Speaker: Astellas, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, Pierre Fabre, Roche, Sanofi, Highlight Therapeutics; Financial Interests, Personal, Other, Travel grant: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Ipsen. P. Roxburgh: Financial Interests, Personal, Invited Speaker: GSK, MSD; Financial Interests, Personal, Other, consultancy: Starpharma; Financial Interests, Institutional, Local PI: Starpharma, Eisai, AstraZeneca, Bayer, Atrios, Immunocore, Immutep, Sierra, mersana, iovance, nucana, PsiOxus, Replimune; Financial Interests, Institutional, Research Grant: Atrios; Non-Financial Interests, Institutional, Product Samples: Tesaro/GSK; Non-Financial Interests, Leadership Role, Clinical lead for cancer genomics: Scottish Strategic Network for Genomic Medicine. K.N. Moore: Financial Interests, Personal, Advisory Board: AstraZeneca, aravive, alkemeres, blueprint pharma, eisai, emd serono, gsk/tesaro, genentech/roche, hengrui, immunogen, IMab, mereo, myriad, caris, mersana, novartis, novocure, OncXerna, OncoNova, tarveda, VBL Therapeutics, clovis, Caris, lilly, novartis, Pannavance, verastem, zentalis, merck; Financial Interests, Institutional, Advisory Board, advisory board work for gynecologic trial: Aadi; Financial Interests, Institutional, Advisory Board, work on clinical trial and planning for next trial: duality; Financial Interests, Personal, Full or part-time Employment: GOG Partners Associate Director; Financial Interests, Institutional, Full or part-time Employment: NRG Ovarian Cancer Chair; Financial Interests, Personal, Member of Board of Directors, not reimbursed: ASCO; Financial Interests, Institutional, Member of Board of Directors, not reimbursed: GOG Foundation; Financial Interests, Personal, Royalties: UP to Date; Financial Interests, Institutional, Coordinating PI, international CO-PI, local site PI: AstraZeneca; Financial Interests, Institutional, Coordinating PI: ImmunoGen, GSK/Tesaro, PTC Therapeutics, duality; Financial Interests, Institutional, Local PI: lilly, Daiichi Sankyo, Regeneron, Artios, Bolt, verastem; Non-Financial Interests, Member of Board of Directors: GOG. D. Olson: Financial Interests, Personal, Advisory Board: Novartis, Alphasights, GLG Consulting, Iovance, Obsidian Therapeutics; Financial Interests, Institutional, Local PI: Takeda, Astellas, Inhibrix; Financial Interests, Institutional, Coordinating PI: Immunocore; Non-Financial Interests, Principal Investigator: CTRL Therapeutics. S. Rottey: Financial Interests, Institutional, Advisory Board: pfizer, merck, roche, Ipsen, BMS; Financial Interests, Institutional, Invited Speaker: Ipsen, BMS, Astellas; Financial Interests, Institutional, Research Grant: MSD, Roche, BMS; Non-Financial Interests, Principal Investigator, It is my main task in the hospital to attract and perform clinical trials in oncology phase I-III: all companies performing clinical trials in oncology in Europe. P.B. Kirk, Y. Yuan, S. Marshall: Financial Interests, Personal, Full or part-time Employment: Immunocore. O. Yeku: Financial Interests, Personal, Other, Consultant: GIMV NV, TigaTx Inc; Financial Interests, Personal, Advisory Board: hC Bioscience; Financial Interests, Personal, Full or part-time Employment, Associate Editor: NEJM Evidence; Financial Interests, Personal, Other, Patent Pending: MUC16 Directed Antibodies for therapeutic applications; Financial Interests, Personal, Other, Patent pending: Human Artificial Chromosomes for therapeutic applications; Financial Interests, Institutional, Local PI: Ascendis Pharma A/S, Avenge Bio, Inc, Duality Biologics, Immunocore Limited, Merck Sharp & Dohme Corporation, Pionyr Immunotherapeutics Inc, ProfoundBio. All other authors have declared no conflicts of interest.