CEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials.
Humans
Antibodies, Bispecific
/ therapeutic use
Antibodies, Monoclonal, Humanized
/ therapeutic use
Female
Male
Middle Aged
Aged
CD3 Complex
/ immunology
Adult
Carcinoembryonic Antigen
/ immunology
Neoplasms
/ drug therapy
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 May 2024
15 May 2024
Historique:
received:
30
01
2023
accepted:
02
05
2024
medline:
16
5
2024
pubmed:
16
5
2024
entrez:
15
5
2024
Statut:
epublish
Résumé
Cibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as a T-cell engager. Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation and -expansion studies: as a single agent with or without obinutuzumab in S1 (NCT02324257) and with atezolizumab in S2 (NCT02650713). Primary endpoints were safety, dose finding, and pharmacokinetics in S1; safety and dose finding in S2. Secondary endpoints were anti-tumour activity (including overall response rate, ORR) and pharmacodynamics in S1; anti-tumour activity, pharmacodynamics and pharmacokinetics in S2. S1 and S2 enrolled a total of 149 and 228 patients, respectively. Grade ≥3 cibisatamab-related adverse events occurred in 36% of S1 and 49% of S2 patients. The ORR was 4% in S1 and 7% in S2. In S2, patients with microsatellite stable colorectal carcinoma (MSS-CRC) given flat doses of cibisatamab and atezolizumab demonstrated an ORR of 14%. In S1 and S2, 40% and 52% of patients, respectively, developed persistent anti-drug antibodies (ADAs). ADA appearance could be mitigated by obinutuzumab-pretreatment, with 8% of patients having persistent ADAs. Overall, cibisatamab warrants further exploration in immunotherapy combination strategies for MSS-CRC.
Identifiants
pubmed: 38750034
doi: 10.1038/s41467-024-48479-8
pii: 10.1038/s41467-024-48479-8
doi:
Types de publication
Journal Article
Clinical Trial, Phase I
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
4091Informations de copyright
© 2024. The Author(s).
Références
Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).
doi: 10.1038/nature21349
pubmed: 28102259
Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).
doi: 10.1126/science.aar4060
pubmed: 29567705
pmcid: 7391259
Ochoa de Olza, M., Navarro Rodrigo, B., Zimmermann, S. & Coukos, G. Turning up the heat on non-immunoreactive tumours: opportunities for clinical development. Lancet Oncol. 21, e419–e430 (2020).
doi: 10.1016/S1470-2045(20)30234-5
pubmed: 32888471
Zappasodi, R., Wolchok, J. D. & Merghoub, T. Strategies for Predicting Response to Checkpoint Inhibitors. Curr. Hematol. Malig. Rep. 13, 383–395 (2018).
doi: 10.1007/s11899-018-0471-9
pubmed: 30159703
pmcid: 6719799
Darvin, P., Toor, S. M., Sasidharan Nair, V. & Elkord, E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp. Mol. Med 50, 1–11 (2018).
doi: 10.1038/s12276-018-0191-1
pubmed: 30546008
Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133–150 (2019).
doi: 10.1038/s41568-019-0116-x
pubmed: 30755690
pmcid: 6705396
McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).
doi: 10.1126/science.aaf1490
pubmed: 26940869
pmcid: 4984254
Huehls, A. M., Coupet, T. A. & Sentman, C. L. Bispecific T-cell engagers for cancer immunotherapy. Immunol. Cell Biol. 93, 290–296 (2015).
doi: 10.1038/icb.2014.93
pubmed: 25367186
Bacac, M. et al. A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors. Clin. Cancer Res 22, 3286–3297 (2016).
doi: 10.1158/1078-0432.CCR-15-1696
pubmed: 26861458
Beauchemin, N. & Arabzadeh, A. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev. 32, 643–671 (2013).
doi: 10.1007/s10555-013-9444-6
pubmed: 23903773
Hammarstrom, S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol. 9, 67–81 (1999).
doi: 10.1006/scbi.1998.0119
pubmed: 10202129
Tiernan, J. P. et al. Carcinoembryonic antigen is the preferred biomarker for in vivo colorectal cancer targeting. Br. J. Cancer 108, 662–667 (2013).
doi: 10.1038/bjc.2012.605
pubmed: 23322207
pmcid: 3593555
Hefta, S. A., Hefta, L. J., Lee, T. D., Paxton, R. J. & Shively, J. E. Carcinoembryonic antigen is anchored to membranes by covalent attachment to a glycosylphosphatidylinositol moiety: identification of the ethanolamine linkage site. Proc. Natl Acad. Sci. USA 85, 4648–4652 (1988).
doi: 10.1073/pnas.85.13.4648
pubmed: 3387431
pmcid: 280492
Shimada, H., Noie, T., Ohashi, M., Oba, K. & Takahashi, Y. Clinical significance of serum tumor markers for gastric cancer: a systematic review of literature by the Task Force of the Japanese Gastric Cancer Association. Gastric Cancer 17, 26–33 (2014).
doi: 10.1007/s10120-013-0259-5
pubmed: 23572188
Bacac, M., Klein, C. & Umana, P. CEA TCB: A novel head-to-tail 2:1 T cell bispecific antibody for treatment of CEA-positive solid tumors. Oncoimmunology 5, e1203498 (2016).
doi: 10.1080/2162402X.2016.1203498
pubmed: 27622073
pmcid: 5007959
Sam, J. et al. Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity. Front. Oncol. 10, 575737 (2020).
doi: 10.3389/fonc.2020.575737
pubmed: 33330050
pmcid: 7735156
Teijeira, A. et al. Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers. Theranostics 12, 1373–1387 (2022).
doi: 10.7150/thno.63359
pubmed: 35154495
pmcid: 8771540
Cartron, G. et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood 124, 2196–2202 (2014).
doi: 10.1182/blood-2014-07-586610
pubmed: 25143487
Salles, G. et al. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood 119, 5126–5132 (2012).
doi: 10.1182/blood-2012-01-404368
pubmed: 22431570
ClinicalTrials.gov. A study of RO6958688 in participants with locally advanced and/or metastatic carcinoembryonic antigen positive solid tumors, < https://clinicaltrials.gov/ct2/show/NCT02324257 > (2022).
ClinicalTrials.gov. A study of the safety, pharmacokinetics, and therapeutic activity of RO6958688 in combination with atezolizumab in participants with locally advanced and/or metastatic carcinoembryonic antigen (CEA)-positive solid tumors, < https://clinicaltrials.gov/ct2/show/NCT02650713 > (2022).
Bai, S. et al. A guide to rational dosing of monoclonal antibodies. Clin. Pharmacokinet. 51, 119–135 (2012).
doi: 10.2165/11596370-000000000-00000
pubmed: 22257150
Lehmann, S. et al. In Vivo Fluorescence Imaging of the Activity of CEA TCB, a Novel T-Cell Bispecific Antibody, Reveals Highly Specific Tumor Targeting and Fast Induction of T-Cell-Mediated Tumor Killing. Clin. Cancer Res 22, 4417–4427 (2016).
doi: 10.1158/1078-0432.CCR-15-2622
pubmed: 27117182
Tabernero, J., Homicsko, K. & JH., S. Clinical evidence of intra-tumoral immune activation and tumor targeting with RG2813, a CEA-targeted engineered IL-2 immunocytokine. Eur. J. Cancer 51, S104–S105 (2015).
Dudal, S. et al. Application of a MABEL Approach for a T-Cell-Bispecific Monoclonal Antibody: CEA TCB. J. Immunother. 39, 279–289 (2016).
doi: 10.1097/CJI.0000000000000132
pubmed: 27404941
Shankar, G. et al. Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations. AAPS J. 16, 658–673 (2014).
doi: 10.1208/s12248-014-9599-2
pubmed: 24764037
pmcid: 4070270