First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors

  • Clin Cancer Res. 2022 Jan 1;28(1):57-70. doi: 10.1158/1078-0432.CCR-21-2160.
Lillian L Siu  1 ,  Ding Wang  2 ,  John Hilton  3 ,  Ravit Geva  4 ,  Drew Rasco  5 ,  Ruth Perets  6  7 ,  Anson K Abraham  8 ,  Douglas C Wilson  9 ,  Julia F Markensohn  8 ,  Jared Lunceford  8 ,  Leah Suttner  8 ,  Shabana Siddiqi  8 ,  Rachel A Altura  8 ,  Corinne Maurice-Dror  10
Affiliations
  • 1. Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 2. Department of Medical Oncology, Henry Ford Cancer Institute, Detroit, Michigan.
  • 3. Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, Ontario, Canada.
  • 4. Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
  • 5. Department of Clinical Research, START Center for Cancer Care, San Antonio, Texas.
  • 6. Division of Oncology, Clinical Research Institute at Rambam, Rambam Medical Center, Haifa, Israel.
  • 7. Department of Cancer and Cell Biology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
  • 8. Oncology Early Development, Merck & Co., Inc., Kenilworth, New Jersey.
  • 9. Department of Profiling and Expression, Genetics and Pharmacogenomics, Merck & Co., Inc., South San Francisco, California.
  • 10. Division of Oncology, Rambam Health Care Campus, Haifa, Israel.
PMID: 34598945 DOI: 10.1158/1078-0432.CCR-21-2160
Abstract

Purpose: In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.

Patients and methods: Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated.

Results: Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti-PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation.

Conclusions: This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti-PD-1/PD-L1 agent.

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