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A phase I study of IMC-001, a PD-L1 blocker, in patients with metastatic or locally advanced solid tumors

Investigational New Drugs volume 39, pages 1624–1632 (2021)Cite this article

Summary

Introduction IMC-001 is a fully human IgG1 monoclonal antibody that binds to human PD-L1 (programmed death-ligand 1). This study evaluated the safety, pharmacokinetics, and pharmacodynamics of IMC-001 in patients with advanced solid tumors. Materials and Methods This open-labeled phase I study used a standard 3 + 3 dose-escalation design, with doses ranging from 2 to 20 mg/kg. IMC-001 was administered intravenously every 2 weeks until disease progression or unacceptable toxicity. The dose-limiting toxicity window was defined as 21 days from the first dose. Results Fifteen subjects were included in 5 dose-escalation cohorts. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. The most common adverse events (AEs) were general weakness, decreased appetite, fever, and cough. No grade 4 or 5 treatment emergent AEs were reported during the study. One subject in the 2 mg/kg cohort showed grade 2 immune-induced thyroiditis and diabetes mellitus suspected to be related to IMC-001. Over the dose range of 2–20 mg/kg IMC-001, the AUC0–14d, AUC0—∞, and Cmax generally increased in a dose-proportional manner for each step of dose escalation. Of the 15 enrolled patients, 1 subject with rectal cancer showed a partial response, and the disease control rate was 33.3%. Conclusions IMC-001 demonstrated a favorable safety profile up to 20 mg/kg administered intravenously every 2 weeks and showed preliminary efficacy in patients with advanced solid tumors. Based on pharmacokinetic and pharmacodynamic data, 20 mg/kg was selected as the recommended phase II dose. Clinical trial identification NCT03644056 (date of registration: August 23, 2018).

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Data availability

The data that support the findings of this study are available on request from the corresponding author Dr. Park. The data are not publicly available due to information that could compromise research participant consent.

References

  1. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25:9543–9553. https://doi.org/10.1128/MCB.25.21.9543-9553.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Patsoukis N, Brown J, Petkova V et al (2012) Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal 5:ra46. https://doi.org/10.1126/scisignal.2002796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151. https://doi.org/10.1016/s1074-7613(00)80089-8

    Article  CAS  PubMed  Google Scholar 

  4. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322. https://doi.org/10.1126/science.291.5502.319

    Article  CAS  PubMed  Google Scholar 

  5. Wang Q, Liu F, Liu L (2017) Prognostic significance of PD-L1 in solid tumor: an updated meta-analysis. Medicine (Baltimore) 96:e6369. https://doi.org/10.1097/MD.0000000000006369

    Article  CAS  Google Scholar 

  6. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800. https://doi.org/10.1038/nm730

    Article  CAS  PubMed  Google Scholar 

  7. Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y (2010) Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116:1757–1766. https://doi.org/10.1002/cncr.24899

    Article  PubMed  Google Scholar 

  8. Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465. https://doi.org/10.1056/NEJMoa1200694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Park J-E, Kim S-E, Keam B, Park HR, Kim S, Kim M, Kim TM, Doh J, Kim DW, Heo DS (2020) Anti-tumor effects of NK cells and anti-PD-L1 antibody with antibody-dependent cellular cytotoxicity in PD-L1-positive cancer cell lines. J Immunother Cancer 8(2):e000873. https://doi.org/10.1136/jitc-2020-000873

  10. Schwartz LH, Litière S, de Vries E, Ford R, Gwyther S, Mandrekar S, Shankar L, Bogaerts J, Chen A, Dancey J, Hayes W, Hodi FS, Hoekstra OS, Huang EP, Lin N, Liu Y, Therasse P, Wolchok JD, Seymour L (2016) RECIST 1.1 – update and clarification: from the RECIST committee. Eur J Cancer 62:132–137. https://doi.org/10.1016/j.ejca.2016.03.081

    Article  PubMed  PubMed Central  Google Scholar 

  11. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litière S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EGE, RECIST working group (2017) iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 18:e143–e152. https://doi.org/10.1016/S1470-2045(17)30074-8

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kim H, Kwon HJ, Han YB, Park SY, Kim ES, Kim SH, Kim YJ, Lee JS, Chung JH (2019) Increased CD3+ T cells with a low FOXP3+/CD8+ T cell ratio can predict anti-PD-1 therapeutic response in non-small cell lung cancer patients. Mod Pathol 32:367–375. https://doi.org/10.1038/s41379-018-0142-3

    Article  CAS  PubMed  Google Scholar 

  13. Buder-Bakhaya K, Hassel JC (2018) Biomarkers for clinical benefit of immune checkpoint inhibitor treatment-a review from the melanoma perspective and beyond. Front Immunol 9:1474. https://doi.org/10.3389/fimmu.2018.01474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gibney GT, Weiner LM, Atkins MB (2016) Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 17:e542–e551. https://doi.org/10.1016/S1470-2045(16)30406-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gulley JL, Kelly K (2017) Infusion-related reactions with administration of avelumab: mild and manageable side effects. Transl Cancer Res 6:S1296–S1298. https://doi.org/10.21037/tcr.2017.09.44

    Article  CAS  PubMed  Google Scholar 

  16. Dillman RO, Hendrix CS (2003) Unique aspects of supportive care using monoclonal antibodies in cancer treatment. Support Cancer Ther 1:38–48. https://doi.org/10.3816/SCT.2003.n.003

    Article  PubMed  Google Scholar 

  17. BAVENCIO® (avelumab) | For Healthcare Professionals. https://www.bavencio.com/en_US/hcp.html

  18. Upadhaya S, Neftelino ST, Hodge JP, Oliva C, Campbell JR, Yu JX (2021) Combinations take Centre stage in PD1/PDL1 inhibitor clinical trials. Nat Rev Drug Discov 20:168–169. https://doi.org/10.1038/d41573-020-00204-y

  19. Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, Sznol M, Long GV, Li H, Waxman IM, Jiang J, Robert C (2017) Safety profile of Nivolumab Monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 35:785–792. https://doi.org/10.1200/JCO.2015.66.1389

    Article  CAS  PubMed  Google Scholar 

  20. Patel SP, Kurzrock R (2015) PD-L1 expression as a predictive biomarker in Cancer immunotherapy. Mol Cancer Ther 14:847–856. https://doi.org/10.1158/1535-7163.MCT-14-0983

    Article  CAS  PubMed  Google Scholar 

  21. Matulonis UA, Shapira-Frommer R, Santin AD, Lisyanskaya AS, Pignata S, Vergote I, Raspagliesi F, Sonke GS, Birrer M, Provencher DM, Sehouli J, Colombo N, González-Martín A, Oaknin A, Ottevanger PB, Rudaitis V, Katchar K, Wu H, Keefe S, Ruman J, Ledermann JA (2019) Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol 30:1080–1087. https://doi.org/10.1093/annonc/mdz135

    Article  CAS  PubMed  Google Scholar 

  22. Nosaki K, Saka H, Hosomi Y, Baas P, de Castro G Jr, Reck M, Wu YL, Brahmer JR, Felip E, Sawada T, Noguchi K, Han SR, Piperdi B, Kush DA, Lopes G (2019) Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1-positive advanced non-small-cell lung cancer: pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies. Lung Cancer 135:188–195. https://doi.org/10.1016/j.lungcan.2019.07.004

    Article  PubMed  Google Scholar 

  23. González-González L, Alonso J (2018) Periostin: a Matricellular protein with multiple functions in Cancer development and progression. Front Oncol 8:225. https://doi.org/10.3389/fonc.2018.00225

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zhao H, Chen Q, Alam A, Cui J, Suen KC, Soo AP, Eguchi S, Gu J, Ma D (2018) The role of osteopontin in the progression of solid organ tumour. Cell Death Dis 9:356. https://doi.org/10.1038/s41419-018-0391-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pang X, Gong K, Zhang X, Wu S, Cui Y, Qian BZ (2019) Osteopontin as a multifaceted driver of bone metastasis and drug resistance. Pharmacol Res 144:235–244. https://doi.org/10.1016/j.phrs.2019.04.030

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the participating patients, their family members, and all researchers involved in this study.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea

    Bhumsuk Keam, Chan-Young Ock, Tae Min Kim & Do-Youn Oh

  2. Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea

    Bhumsuk Keam, Tae Min Kim & Do-Youn Oh

  3. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea

    Won Ki Kang, Yeon Hee Park, Jeeyun Lee & Young Suk Park

  4. ImmuneOncia Therapeutics Inc., Seongnam, South Korea

    Ji Hye Lee, Yoen Hee Ahn, Hyeon Ju Kim, Sook Kyung Chang, Jihyun Park, Ji Yea Choi & Yun Jeong Song

Authors
  1. Bhumsuk Keam
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  15. Young Suk Park
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Contributions

This study was directed and coordinated by B Keam and YS Park, as the principal investigators, provided conceptual and technical guidance for all aspects of the study and drafted the manuscript. C-Y Ock, TM Kim, D-Y Oh, WK Kang, YH Park, J LEE participated the study as the co-investigators and helped to draft the manuscript. JH Lee, YH Ahn, HJ Kim and YJ Song planned and managed the study operation and analyzed clinical data and drafted the manuscript. SK Chang, J Park, JY Choi carried out the biomarker studies and drafted biomarker part of the manuscript. All authors reviewed the final manuscript.

Corresponding author

Correspondence to Young Suk Park.

Ethics declarations

Ethics approval

1. H-1801-042-913

2. SMC 2018–01–007-001

Consent to participate

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

Consent for publication

Informed consent for the publication of any associated data was obtained from all individual participants in the study.

Conflict of interest

Ji Hye Lee, Yoen Hee Ahn, Hyeon Ju Kim, Sook Kyung Chang, Jihyun Park, Ji Yea Choi and Yun Jeong Song are full-time employees of ImmuneOncia Therapeutics Inc.

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Keam, B., Ock, CY., Kim, T.M. et al. A phase I study of IMC-001, a PD-L1 blocker, in patients with metastatic or locally advanced solid tumors. Invest New Drugs 39, 1624–1632 (2021). https://doi.org/10.1007/s10637-021-01078-6

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