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  • 850 Interim results for phase 1b dose expansion of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumour malignancies

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Regular and Young Investigator Award Abstracts
Combination Immunotherapies
850 Interim results for phase 1b dose expansion of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumour malignancies
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  1. Ruth Plummer1,
  2. Mikael Sodergren2,
  3. Brid Ryan3,
  4. Ilian Tachkov3,
  5. Vikash Reebye3,
  6. Tim Meyer4,
  7. David Pinato2,
  8. Debashis Sarker5,
  9. Bristi Basu6,
  10. Sarah Blagden7,
  11. Natalie Cook8,
  12. Jeff Evans9,
  13. Jeffrey Yachnin10,
  14. Cheng-Ean Chee11,
  15. Daneng Li12,
  16. Anthony El-Khoueiry13,
  17. Maria Diab14,
  18. Kai-Wen Huang15,
  19. Antonio D'Alessio2,
  20. Claudia Fulgenzi2,
  21. Marcus Noel16,
  22. Bridget Keenan17,
  23. Devalingam Mahalingam18,
  24. Nina Raulf3,
  25. Rose Hogson3,
  26. Choon Ping Tan3,
  27. Joanna Nicholls2,
  28. Alison Adderkin3,
  29. Julia Vassiliadou3,
  30. Robert Habib3,
  31. John Rossi19 and
  32. Nagy Habib3
  1. 1Newcastle University, Newcastle-upon-Tyne, UK
  2. 2Imperial College London, London, UK
  3. 3MiNA Therapeutics Ltd, London, UK
  4. 4University College London, London, UK
  5. 5Kings College London, London, UK
  6. 6University of Cambridge, Cambridge, UK
  7. 7Univeristy of Oxford, Oxford, UK
  8. 8The Christie NHS Foundation Trust, Manchester, UK
  9. 9University of Glasgow, Glasgow, UK
  10. 10Karolinska University Hospital, Stockholm, Sweden
  11. 11National University Cancer Institute, Singapore, Singapore
  12. 12City of Hope Comprehensive Cancer Center, Duarte, CA, United States
  13. 13University of Southern California, Los Angeles, CA, United States
  14. 14Emory University, Atlanta, GA, United States
  15. 15National Taiwan University Hospital, Taipei, Taiwan
  16. 16Medstar Georgetown University Hospital, Washington, WA, United States
  17. 17University of California San Francisco, San Francisco, CA, United States
  18. 18Northwestern University, Chicago, IL, United States
  19. 19Beckman Research Institute, City of Hope, CA, United States

Abstract

Background Most cancer patients do not benefit from currently approved immune checkpoint inhibitors (ICI), suggesting that additional immunomodulation is required to improve outcomes. MTL-CEBPA is a novel immunotherapy targeting the myeloid cell lineage that has shown promising clinical activity in hepatocellular carcinoma, and preclinical activity in models of solid tumour cancers in combination with ICIs. We previously reported dose escalation data for MTL-CEBPA in combination with ICI from TIMEPOINT, an ongoing multi-centre phase 1/1b study (NCT-04105335) evaluating the safety, PK, immunomodulation and clinical activity of MTL-CEBPA in combination with pembrolizumab in patients with anti-PD(L)1 naïve advanced solid tumours for whom no standard therapy is available.1

Methods In the dose expansion part of TIMEPOINT, patients were treated at RP2D 130mg/m2 MTL-CEBPA QW for 3 consecutive weeks and 1 week off (28-day cycle) and 200mg pembrolizumab Q3W. Analysis was undertaken of plasma cytokine and complement profiles; gene expression (qPCR and Nanostring I/O 360) and immune landscape (multiplex IHC) from core tumour biopsies taken at baseline and cycle 2. Adverse events (AEs) were assessed by CTCAEv5.0. Clinical activity was assessed by RECIST v1.1/iRECIST.

Results At data cut-off 15 March 2022, 50 patients across a wide range of tumour types reported to have primary resistance to anti-PD(L)1 therapy have been enrolled. Patient demographics, clinical characteristics are in table 1. The most frequent AEs in at least 5 patients (10%) are listed in table 2. 20 patients (40%) experienced an AE Gr 33 , 1 pt (2%) had a Gr4 AE, and there were no Gr 5 AEs. 7 pts (14%) had a SAE, however there were no AEs leading to dose modification or treatment discontinuation of MTL-CEBPA. Pharmacokinetic profile of MTL-CEBPA was not affected by pembrolizumab. Cytokine/complement analysis did not suggest cytokine release syndrome. Paired tumour biopsies during treatment suggested significant increase in Immunosign21 (figure 1) and proliferation of granzyme-producing T cells. 4 (10%) patients had confirmed PR (table 1). A 30-year-old NET patient with primarily lung involvement (failed 3 prior lines of therapy) achieved PR (43% reduction) in cycle 4, associated with a transformation from cold to hot TME (Immunosign21 from 2/21 to 19/21).

Conclusions MTL-CEBPA in combination with pembrolizumab is safe and well tolerated, with encouraging early signs of activity in heavily pre-treated patients across multiple tumour types. Treatment was associated with intratumoural changes supporting the hypothesis of immunomodulation by MTL-CEBPA and further investigation in combination with ICI is warranted.

Reference

  1. Plummer R, Sodergren M, Pinato D, et al. 515 A phase 1 study of myeloid modulating agent MTL-CEBPA in combination with pembrolizumab in adult patients with advanced solid tumours Journal for ImmunoTherapy of Cancer 2021;9:doi: 10.1136/jitc-2021-SITC2021.515.

Ethics Approval The study was approved by the North East – Newcastle & North Tyneside 2 Research Ethics Committee, approval number 19/NE/0312.

View this table:
Abstract 850 Table 1

Demographics, clinical characteristics and clinical response

View this table:
Abstract 850 Table 2

Most common AEs in order of decreasing incidence in at least 5 patients (10%)

Abstract 850 Figure 1
Abstract 850 Figure 1

Change in Immunosign21 score (Veracyte) following combination treatment with MTL-CEBPA and pembrolizumab

https://doi.org/10.1136/jitc-2022-SITC2022.0850

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