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).
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
BAVENCIO® (avelumab) | For Healthcare Professionals. https://www.bavencio.com/en_US/hcp.html
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
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
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
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
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
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
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
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
We thank the participating patients, their family members, and all researchers involved in this study.
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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