Search

Background: This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs)., Methods: Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients., Results: Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients., Conclusion: Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation., Competing Interests: Competing interests: CG-R: Invited Speaker: BMS, Eisai, Pierre Fabre, Roche/Genentech; Coordinating PI: BMS; Steering Committee Member: BMS; Local PI: Foundation Medicine; Steering Committee Member: Genentech; Research Grant: Roche/Genentech; AM: Stock ownership Pegascy, Hifibio Therapeutics, Shattuck Labs, Centessa Pharmaceuticals; Honoraria: BMS, AstraZeneca/MedImmune, Oncovir; Consulting and advisory activities: Lytix Biopharma, Eisai, Pierre Fabre, AstraZeneca, Servier, Roche, Redx Pharma, Sotio, Innate Pharma, ImCheck Therapeutics, MSD, OSE Immunotherapeutics, HIFIBIO Therapeutics, MedinCell, Centessa Pharmaceuticals; Speaker’s bureau: BMS; Research funding: BMS, Boehringer Ingelheim, Transgene, MSD; Travel expenses: MSD, AstraZeneca; SC: Honoraria: Amgen, AstraZeneca, BMS, EISAI, Janssen, MSD, Novartis and Roche; Principal Investigator of Clinical Trials for: Amgen, MSD, Sanofi Aventis, Transgene; Advisory Board: Alderaan Biotechnology, Amgen, AstraZeneca, Oncovita, Seagen, Ultrahuman; Travel and congress: AstraZeneca, MSD, Roche; Principal/sub-investigator of clinical trials for: Abbvie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Curevac, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Turning Point Therapeutics, Xencor; Research Grants from: Astrazeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, SanofiNon-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, GSK, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche; SA: Speakers bureau: Pfizer, Roche, Sanofi and BMSAdvisory board: Sanofi; PC: Honoraria: Novartis, Roche/Genentech, Amgen, Astra Zeneca, Merck Serono; Research Funding: Novartis, Roche/Genentech, Lilly, lueprint Medicines, Bayer, Astra Zeneca, Celgene, Plexxikon, Abbvie, BMS, Merck Serono, Merck Sharp and Dohme, Taiho Pharmaceutical, Toray Industries, Transgene, Loxo, GSK, Innate Pharma, Janssen; Travel expenses: Roche, Amgen, Novartis, BMS, MSD, Netris Pharma, Bayer, Merck Serono; DZ: Reports research support from: Roche, Astra Zeneca, and Plexxikon; Personal/consultancy fees from Synlogic Therapeutics, GSK, Roche, Xencor, Memgen, Immunos, Celldex, Calidi, and Agenus; J-PM: Advisory board member or speaker with honoraria: Pfizer, Roche, Astra/Zeneca, Bayer, Innate, Merck Serono, Boerhinger, BMS, Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, iTEOS, eTheRNATravel expenses: Amgen, BMS, Pfizer, MSDData safety monitoring board with honoraria: Debio, Nanobiotix, Psioxus; Uncompensated advisory role: MSD; JLPG; Research grants and support: Roche, BMS, MSD, Seattle Genetics. Speakers bureau and advisory boards: Roche, BMS, Ipsen, MSD, Seattle Genetics. Travel support: Roche, MSD, BMS; FSH: Consulting: BMS, Merck, EMD Serono, Novartis, Sanofi, Psioxus Therapeutics, Pieris Pharmacutical, Corner Therapeutics, Eisai, Idera, Takeda, Genentech/Roche; Advisory Board: Compass Therapeutics, Apricity Scientific, Pionyr, Torque, Rheos, Bicara, Checkpoint Therapeutics, Bioentre, Gossamer, Iovance; ATG: Personal fees from: Boehringer-Ingelheim, BMS, MSD, Roche, Pfizer, Astra Zeneca, Tesaro-GSK and non-financial support from Boehringer-Ingelheim, Lilly and RocheMaria Martinez Garcia; Research grants and support: Roche, BMS, MSD, Seattle Genetics; Speakers bureau and advisory boards: Roche, BMS, Ipsen, MSD, Seattle Genetics; Travel support: Roche, MSD, BMS; VB: Consulting or Advisory Role: Puma Biotechnology; Ideaya Biosciences; Loxo Therapeutics, CytomX Therapeutics; Guidepoint; Oncoart; Amunix; Institutional financial support for clinical trials from: Abbvie, ACEO, Adaptaimmune, Amcure, AMGEN, AstraZeneca, BMS, Cytomx, GSK, Genentech/Roche, H3, Incyte, Janssen, Kura, Lilly, Loxo, Nektar, Macrogenics, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, PUMA, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Takeda, Incyte, Innovio, MSD, PsiOxus, Seattle Genetics, Mersana, GSK, Daiichi, Nektar, Astellas, ORCA, Boston Therapeutics, Dynavax, DebioPharm, Boehringen Ingelheim, Regeneron, Millenium, Synthon, Spectrum, Rigontec, Zenith; JPE: The author declares no potential conflicts of interest. NH: The author declares no potential conflicts of interest. RS: Consultant/advisory boards: Asana Biosciences, AstraZeneca, Bristol-Myers Squibb, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, Replimune; Research funding: Amgen, Merck; DM: Consulting and honoraria: BMS, Pfizer, Merck, Alkermes Inc., EMD Serono, Eli Lilly and Company, Iovance, Eisai Inc., Werewolf Therapeutics, Calithera Biosciences; Research support: BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, Alkermes Inc; MAC: Sponsor employee and sponsor stock ownership; A-MJ: Former sponsor employee and has patent issued in the use of emactuzumab; WJ: Sponsor employee and sponsor stock ownership; CR: Former Roche employee and has patent issued in the use of emactuzumab. Consultant for Verseau Therapeutics, Ridgeline Discovery, iOmx Therapeutics AG; KK: Sponsor employee and Roche stocks; GB: Sponsor employee; FM: Sponsor employee; RC: Sponsor employee and Roche stocks; CW: Sponsor consultantGeorgina Meneses-LorenteSponsor employee; MW: Sponsor employee, stock options, and has patent issued in the use of emactuzumab; DR: Sponsor employee, sponsor stock ownership and has patent issued in the use of emactuzumab; J-PD: Consulting/Advisory: Novartis, Roche/Genentech, BMS, MSD; Research funding: Genentech, BMS, MSD, Astra Zeneca, Transgene; CT: Research funding GSK, travel expenses Mundipharma., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This phase Ib study evaluated the safety, clinical activity, pharmacokinetics, and pharmacodynamics (PD) of emactuzumab (anti-colony stimulating factor 1 receptor monoclonal antibody (mAb)) in combination with selicrelumab (agonistic cluster of differentiation 40 mAb) in patients with advanced solid tumors., Methods: Both emactuzumab and selicrelumab were administered intravenously every 3 weeks and doses were concomitantly escalated (emactuzumab: 500 to 1000 mg flat; selicrelumab: 2 to 16 mg flat). Dose escalation was conducted using the product of independent beta probabilities dose-escalation design. PD analyzes were performed on peripheral blood samples and tumor/skin biopsies at baseline and on treatment. Clinical activity was evaluated using investigator-based and Response Evaluation Criteria In Solid Tumors V.1.1-based tumor assessments., Results: Three dose-limiting toxicities (all infusion-related reactions (IRRs)) were observed at 8, 12 and 16 mg of selicrelumab together with 1000 mg of emactuzumab. The maximum tolerated dose was not reached at the predefined top doses of emactuzumab (1000 mg) and selicrelumab (16 mg). The most common adverse events were IRRs (75.7%), fatigue (54.1%), facial edema (37.8%), and increase in aspartate aminotransferase and creatinine phosphokinase (35.1% both). PD analyzes demonstrated an increase of Ki67 + -activated CD8 + T cells accompanied by a decrease of B cells and the reduction of CD14 Dim CD16 bright monocytes in peripheral blood. The best objective clinical response was stable disease in 40.5% of patients., Conclusion: Emactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses., Trialregistration Number: NCT02760797., Competing Interests: Competing interests: Jean-Pascal Machiels: Advisory board consulting for Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boerhinger, BMS, Novartis, Janssen, Incyte, Cue Biopharma and ALX Oncology; travel expenses from Amgen, BMS, Pfizer, MSD; data safety monitoring board support for Debio, Nanobiotix and PsiOxus. Carlos Gomez-Roca: Consultancy for AstraZeneca and BMS; travel grant from Boehringer Ingelheim, BMS, Pierre Fabre, Roche and Sanofi Aventis; honoraria from BMS, Pierre Fabre and Roche; Jean-Marie Michot: Consultancy from Celgene, Bristol Myers Squibb, AstraZeneca and Janssen; travel grant and non-financial support from AstraZeneca, Roche, Novartis, Gilead, Celgene and Bristol Myers Squibb; Dmitriy Zamarin: Consultancy fees from Merck, Synlogic Therapeutics, Biomed Valley Discoveries, Trieza Therapeutics, Tesaro, and Agenus; Tara Mitchell: Advisory board consulting for Merck, BMS and Array; Gaetan Catala: Travel grants from Roche, Pharmamar, MSD and AstraZeneca; advisory role for MSD. Lauriane Eberst: None. Wolfgang Jacob: Sponsor employee and sponsor stock ownership. Anna-Maria Jegg: Former sponsor employee and has patent issued in the use of emactuzumab. Michael A Cannarile: Sponsor employee and sponsor stock ownership. Carl Watson: Sponsor consultant. Galina Babitzki: Sponsor employee. Konstanty Korski: Sponsor employee. Irina Klaman: Sponsor employee. Priscila C Teixeira: Sponsor employee. Sabine Hoves: Sponsor employee, sponsor stock ownership and has patent issued in the use of emactuzumab. Carola Ries: Former sponsor employee and has patent issued in the use of emactuzumab. Georgina Meneses-Lorente: Sponsor employee. Francesca Michielin: Sponsor employee. Randolph Christen: Sponsor employee and sponsor stock ownership. Dominik Rüttinger: Sponsor employee, sponsor stock ownership and has patent issued in the use of emactuzumab. Martin Weisser: Sponsor employee and sponsor stock ownership. Jean-Pierre Delord: Consulting or advisory role for Novartis, Roche/Genentech, Bristol Myers Squibb, MSD Oncology; research funding from Genentech, Bristol Myers Squibb, MSD Oncology. Philippe Cassier: Honoraria from Novartis, Roche/Genentech, Blueprint Medicines, Amgen and AstraZeneca; research funding from Novartis, Roche/Genentech, Eli Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Taiho Pharmaceuticals, Toray Industries, Transgene, Loxo, GlaxoSmithKline, Innatre Pharma and Janssen; travel grants from Roche, Amgen, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme and Netris Pharma., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The tumor-permissive and immunosuppressive characteristics of tumor-associated macrophages (TAM) have fueled interest in therapeutically targeting these cells. In this context, the colony-stimulating factor 1 (CSF1)/colony-stimulating factor 1 receptor (CSF1R) axis has gained the most attention, and various approaches targeting either the ligands or the receptor are currently in clinical development. Emerging data on the tolerability of CSF1/CSF1R-targeting agents suggest a favorable safety profile, making them attractive combination partners for both standard treatment modalities and immunotherapeutic agents. The specificity of these agents and their potent blocking activity has been substantiated by impressive response rates in diffuse-type tenosynovial giant cell tumors, a benign connective tissue disorder driven by CSF1 in an autocrine fashion. In the malignant disease setting, data on the clinical activity of immunotherapy combinations with CSF1/CSF1R-targeting agents are pending. As our knowledge of macrophage biology expands, it becomes apparent that the complex phenotypic and functional properties of macrophages are heavily influenced by a continuum of survival, differentiation, recruitment, and polarization signals within their specific tissue environment. Thus, the role of macrophages in regulating tumorigenesis and the impact of depleting and/or reprogramming TAM as therapeutic approaches for cancer patients may vary greatly depending on organ-specific characteristics of these cells. We review the currently available clinical safety and efficacy data with CSF1/CSF1R-targeting agents and provide a comprehensive overview of ongoing clinical studies. Furthermore, we discuss the local tissue macrophage and tumor-type specificities and their potential impact on CSF1/CSF1R-targeting treatment strategies for the future.