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LY3022855, an anti–colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial

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Summary

Background Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti–CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non–weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non–weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4–6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non–weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov ID NCT01346358 (Registration Date: May 3, 2011).

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Data availability

Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once they are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data-sharing environment for up to 2 years per proposal. For details on submitting a request, see the instructions provided at www.clinicalstudydatarequest.com.

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Acknowledgements

We extend our gratitude to the patients and their families and caregivers for participating in this trial. Medical writing support was provided by Karan Sharma from Eli Lilly Services India Pvt. Ltd.

Funding

This trial was funded by Eli Lilly and Company.

Author information

Authors and Affiliations

  1. Department of Medicine Division of Hematology and Oncology, University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH, USA

    Afshin Dowlati

  2. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA

    R. Donald Harvey

  3. Department of Medicine, Division of Hematology/Oncology, Columbia University, College of Physicians and Surgeons New York, New York, NY, USA

    Richard D. Carvajal

  4. Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Cedars-Sinai Affiliate, Los Angeles, CA, USA

    Omid Hamid

  5. Department of Medicine and Oncology, Massachusetts General Hospital, Boston, MA, USA

    Samuel J. Klempner

  6. Medical Oncology, Hutchison MediPharma Inc., Florham Park, NJ, USA

    John Sae Wook Kauh

  7. Eli Lilly and Company, Indianapolis, IN, USA

    Daniel A. Peterson, Danni Yu, Anna M. Szpurka, Michelle Carlsen & Tonya Quinlan

  8. Eli Lilly and Company, Windlesham, Surrey, UK

    Sonya C. Chapman

  9. Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, 1310D Lincoln Tower, 1800 Cannon Drive, Columbus, OH, 43210, USA

    Robert Wesolowski

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  1. Afshin Dowlati
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Contributions

D. Yu, SC. Chapman, and AM. Szpurka contributed to study concept and design. D. Yu developed methodology. R. Wesolowski, SJ. Klempner, A. Dowlati, RH. Donald, and H. Omid contributed to patient and data acquisition. D. Yu, M. Carlsen, SC. Chapman, AM. Szpurka, R. Wesolowski, SJ. Klempner, A. Dowlati, RH. Donald, and H. Omid contributed to analysis and interpretation of data. All the authors contributed in writing, review, and revision of the manuscript.

Corresponding author

Correspondence to Robert Wesolowski.

Ethics declarations

Ethics approval

The study was performed in accordance with the International Conference on Harmonization guidelines and Declaration of Helsinki 1964 and its amendments. The Institutional review board of each study site approved the study protocol, information brochure and the informed consent form before study initiation.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent for publication

Patients provided informed consent to regarding publishing their data.

Conflict of interest

A. Dowlati reports other from Glaxo Smith Kline, non-financial support from Glaxo Smith Kline; grants from EMD Serono, Tesaro, Roche, Vertex, Regeneron; grants and personal fees from Abbvie, Astra Zeneca, Millenium, Seattle Genetics; grants from Eli Lilly, Takeda, Ipsen, United Therapeutics, Mirati, Bristol Myers Squibb, Incuron; personal fees from Ariad, grants from Bayer.

RD. Harvey has nothing to disclose.

R. Carvajal reports personal fees and other from BMS, Incyte, Immunocore, Merck Roche/Genentech; personal fees from Castle Biosciences, Compugen, Foundation Medicine, I-Mab, PureTech, Sanofi Genzyme, Sorrento Therapeutics, Aura Biosciences, Chimeron, Rgenix; other from Amgen, Novartis, Pfizer, AstraZeneca, Bellicum, Plexxikon, Mirati, Macrogenics, Corvus, Bayer, Eli Lilly, Astellis, outside the submitted work.

O. Hamid received personal fees from Aduro, Akeso, Amgen, Array, Beigene, BMS, Genentech, GSK, Immunocore, Incyte, Janssen, Merck, Nextcure, Novartis, Sanofi Regeneron, Seattle Genetics, Tempus, Zelluna, Array Pfizer, BMS, Novartis, Sanofi Regeneron; other from Arcus, Aduro, Akeso, Amgen, Array, BMS, CytomX, Exelixis, Genentech, GSK, Immunocore, Incyte, Iovance, Merck, Moderna, Merck Serono, Nextcure, Novartis, Sanofi Regeneron, Seattle Genetics, Torque, Zelluna.

SJ. Klempner received personal fees from Eli Lilly, Merck, Bristol Myers Squibb, Foundation Medicine, Inc., Pieris; Stock/equity from Turning Point Therapeutics.

JSW. Kauh is a former employee of Eli Lilly and Company and presently working at Hutchison MediPharma Inc.

R. Wesolowski reports other (Lilly covered the cost of conducting this study at our institution).

AM. Szpurka, DA. Peterson, D. Yu, M. Carlsen, SC. Chapman, and T. Quinlan, are employees and stockholder at Eli Lilly and Company.

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Dowlati, A., Harvey, R.D., Carvajal, R.D. et al. LY3022855, an anti–colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial. Invest New Drugs 39, 1057–1071 (2021). https://doi.org/10.1007/s10637-021-01084-8

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