151P - Enhanced pharmacodynamic effects upon combination of cibisatamab and FAP-4-1BBL in 3L+ mMSS CRC patients

Background

T cell engaging therapies hold great promise for cancer treatment. While direct TCR stimulation (signal 1) via T cell bispecific antibodies (TCBs) are effective in some cancers, the additive effects of costimulation (signal 2) remain under clinical investigation.

Methods

54 MSS mCRC 3L+ patients (pts) enrolled in the BP42675 phase I dose escalation study received I.V. CEA targeting T- cell bispecific antibody (cibisatamab) every 3 weeks (Q3W) together with escalating doses (35 to 130 mg) of FAP-4-1BBL a bispecific antibody-like fusion protein providing a costimulatory signal to T-cells in tumor, in a weekly (QW, 30 pts) or Q3W (24 pts) schedule. The pharmacodynamic (PD) effects were assessed using ELISA and flow cytometry (FC) for peripheral blood samples, and immunohistochemistry (IHC) and RNAseq for tissue samples. To evaluate the effect of the treatment combination, the PD effect was compared to already available data from cibisatamab and FAP-4-1BBL monotherapies.

Results

We observed PD modulation indicative of immune cell activation. In peripheral blood, FC analysis demonstrated transient increase of 4-1BB+ CD8+ and CD4+ T cells, along with the secretion of inflammatory cytokines and soluble CD25 (sCD25) across all FAP-4-1BBL doses. Compared to cibisatamab monotherapy, the combination group exhibited significantly higher upregulation of IFN-gamma and a greater, more sustained increase in sCD25, while IL-6 level changes were comparable.

On treatment, an increased tissue CD8+ T-cell infiltration with Ki67 evidence for proliferation was observed, together with the induction of transcripts and gene signatures denoting immune cell activation. Importantly, CD8+ T cell infiltration was significantly more abundant in the combination group compared to any monotherapy.

Conclusions

The enhanced clinical PD effects of the combination of cibisatamab and FAP-4-1BBL demonstrate the additive effects of costimulation to signal 1 only providers such as TCBs in a tumor considered largely insensitive to cancer immunotherapies. These encouraging results advocate for further studies exploring the combination of T cell engagers such as TCBs with FAP-4-1BBL, as this approach holds the potential to unlock new frontiers in cancer treatment.

Clinical trial identification

BP42675 “an open-label, multicenter, phase Ib study to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of RO7122290, a fibroblast activation protein-a (FAP) targeted 4-1BB ligand (CD137L), in combination with cibisatamab with obinutuzumab pre-treatment, in participants with previously treated, metastatic, microsatellite-stable colorectal adenocarcinoma”.

Editorial acknowledgement

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

I. Melero: Financial Interests, Personal, Advisory Board: Agneus, Alligator Bioscience, AstraZeneca, BMS, BioLineRx, Boehringer Ingelheim, Boston Pharma, CRISPR Therapeutics, CatalYm GmbH, Crescendo Biologics, Curon BIopharmaceutical, EMD Serono, F-Star, Genentech, Genmab, Gossamer Bio, Highlight Therapeutics, Hookipa Pharma, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., Janssen, MSD, Merus N.V., Monopteros Therapeutics, NOXXON Pharma AG, Numab, Phenomic Bio, Pieris Pharmaceuticals GmbH, Pierre Fabre, Roche, Sanofi, Senti Biosciences, Servier, Shattuck Labs, Third Rock Ventures; Financial Interests, Personal, Other, Consultant: Pharma Mar; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Roche, BMS, Genmab, Alligator. T. Tanos, C. Heichinger, I. Davydov, A. Boehnke, N. Kumpesa, C. Ooi, V. Karanikas, M. Cannarile: Financial Interests, Personal and Institutional, Full or part-time Employment: Roche. I. Baraibar Argota: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Other, Accommodation and travel expenses: Amgen, Merck, Sanofi, Servier. M. Martinez Garcia: Financial Interests, Personal, Advisory Board, speaker: Novocure; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Seagen; Financial Interests, Personal, Advisory Board, Honoraria: Eli Lilly; Financial Interests, Personal, Other, Honoraria, travel/accommodation expenses: AstraZeneca, Pfizer; Financial Interests, Personal, Advisory Board, Honoraria, travel/accommodation expenses: Gilead Science; Financial Interests, Personal, Other, Travel/accommodation expenses: Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria (public speaking): Reddy Pharma. 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 Ingelheim, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelixis, 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. C. Qvortrup: Financial Interests, Institutional, Coordinating PI: Roche, Miratis; Financial Interests, Institutional, Local PI: MSD, Pfizer, Servier, Amgen; Financial Interests, Institutional, Research Grant: Pierre Fabre; Non-Financial Interests, Leadership Role: Danish Multidisciplinary Cancer Goupgs, DCCG.dk (Danish Colorectal Cancer Group). T.W. Kim: Financial Interests, Institutional, Research Grant: Genentech, Genome insight. M.G. Van Dongen: Financial Interests, Institutional, Other, Author: Antoni van Leeuwenhoek ziekenhuis. E. Calvo: Financial Interests, Personal, Advisory Board: Adcendo, Amunix, Anaveon, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Diaccurate, Elevation Oncology, Ellipses Pharmacy, Genmab, Grey Wolf, Incyte, Janssen, MSD, Merus, MonTa, Nanobiotix, Nouscom, Novartis, Servier, SyneosHealth, T-knife, TargImmune, iTeos, Debio; Financial Interests, Personal, Invited Speaker: OncoDNA, PharmaMar, Roche/Genentech; Financial Interests, Personal, Full or part-time Employment, Director, Clinical Research: HM Hospitales Group; Financial Interests, Personal, Full or part-time Employment, Medical Oncologist. Clinical Investigator. Director, Clinical Research: START Madrid - CIOCC (Centro Integral Oncológico Clara Campal); Financial Interests, Personal, Member of Board of Directors, External Independent member of Board of Directors: PharmaMar; Financial Interests, Personal, Ownership Interest: START, Oncoart Associated; Financial Interests, Personal, Steering Committee Member, Member of Data Monitoring Committee: BeiGene, Sanofi, Merus, Shionogi; Financial Interests, Personal, Steering Committee Member: Novartis; Non-Financial Interests, Other, Non-for-profit Foundation. President and co-founder: INTHEOS (Investigational Therapeutics in Oncological Sciences) non-for-profit Foundation; Non-Financial Interests, Advisory Role: PsiOxus; Non-Financial Interests, Other, Chair of the Independent Data Monitoring Committee: EORTC IDMC; Non-Financial Interests, Member of Board of Directors, Non-for-profit Foundation, trustee member: Non-for-profit Foundation PharmaMar; Non-Financial Interests, Advisory Role, Non-for-profit foundation: CRIS Cancer Foundation, non-for-profit; Non-Financial Interests, Member: ASCO, ESMO, SEOM, EORTC. M.C. Riesco Martinez: Financial Interests, Personal, Invited Speaker: Servier, MSD; Financial Interests, Personal, Other, Travel expenses for medical conference: Merck; Financial Interests, Institutional, Coordinating PI: MSD, BMS. 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 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 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. V.K. Woodcock: Financial Interests, Institutional, Local PI: Novartis, Roche. All other authors have declared no conflicts of interest.