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Current Treatment Options in Oncology
Published in: Current Treatment Options in Oncology 9/2023

05-07-2023 | Cystectomy

Antibody Drug Conjugates in Bladder Cancer: Current Milestones and Future Perspectives

Authors: Raafat Alameddine, MD, Patrick Mallea, MD, Farhan Shahab, MD, Yousef Zakharia, MD

Published in: Current Treatment Options in Oncology | Issue 9/2023

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Opinion Statement

Over the last several years, the treatment landscape of urothelial carcinoma has witnessed an unprecedented expansion of therapeutic options including checkpoint inhibitors, tyrosine kinase inhibitors, and antibody drug conjugates (ADC). Early trial data has shown that ADCs are safer and potentially effective treatment options in advanced bladder cancer as well as in the early disease. In particular, enfortumab–vedotin (EV) has shown promising results with a recent cohort of a clinical trial demonstrating that EV is effective as neoadjuvant monotherapy as well as in combination with pembrolizumab in metastatic setting. Similar promising results have been shown by other classes of ADC in other trials including sacituzumab–govitecan (SG) and oportuzumab monatox (OM). ADCs are likely to become a mainstay treatment option in the urothelial carcinoma playbook as either a monotherapy or combination therapy. The cost of the drug presents a real challenge, but further trial data may justify the use of the drug as mainstay treatment.
Literature
1.
2.
3.
4.
Cumberbatch MGK, et al. Epidemiology of bladder cancer: a systematic review and contemporary update of risk factors in 2018. Eur Urol. 2018;74(6):784–95.PubMedCrossRef
5.
Kirkali Z, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urol. 2005;66(6 Suppl 1):4–34.PubMedCrossRef
6.
7.
Ennis RD, et al. The effect of cystectomy, and perioperative methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy on the risk and pattern of relapse in patients with muscle invasive bladder cancer. J Urol. 2000;163(5):1413–8.PubMedCrossRef
8.
Grossman HB, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859–66.PubMedCrossRef
9.
• Pfister, C., et al., Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine and cisplatin as perioperative chemotherapy for patients with nonmetastatic muscle-invasive bladder cancer: results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol., 2022: p. JCO2102051. Randomized phase 3 trial comparing two historical standard platinum-based regimens in the neoadjuvant setting for bladder cancer
10.
11.
• Powles T, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(7):931–45. Phase 3 trial demonstrating efficicacy of first-line pembrolizumab monotherapyPubMedCrossRef
12.
• Galsky MD, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547–57. Negative results of phase 3 trial of first-line atezolizumabPubMedCrossRef
13.
Necchi A, et al. Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: post-progression outcomes from the phase II IMvigor210 study. Ann Oncol. 2017;28(12):3044–50.PubMedPubMedCentralCrossRef
14.
Powles T, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748–57.PubMedCrossRef
15.
• Powles T, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218–30. Registratrion trial of avelumab maintenance for metastatic diseasePubMedCrossRef
16.
Rowe JM, Lowenberg B. Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug. Blood. 2013;121(24):4838–41.PubMedCrossRef
17.
18.
Ungaro, A., et al., Antibody-drug conjugates in urothelial carcinoma: a new therapeutic opportunity moves from bench to bedside. Cells., 2022. 11(5).
19.
Choi W, et al. A molecular inquiry into the role of antibody-drug conjugates in Bacillus Calmette-Guerin-exposed non-muscle-invasive bladder cancer. Eur Urol. 2022;81(2):138–42.PubMedCrossRef
20.
Tsuchikama K, An Z. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell. 2018;9(1):33–46.PubMedCrossRef
21.
Gerber HP, Koehn FE, Abraham RT. The antibody-drug conjugate: an enabling modality for natural product-based cancer therapeutics. Nat Prod Rep. 2013;30(5):625–39.PubMedCrossRef
22.
Lianos GD, et al. Potential of antibody-drug conjugates and novel therapeutics in breast cancer management. Onco Targets Ther. 2014;7:491–500.PubMedPubMedCentral
23.
Sliwkowski MX, Mellman I. Antibody therapeutics in cancer. Sci. 2013;341(6151):1192–8.CrossRef
24.
Sun Y, Yu F, Sun BW. Antibody-drug conjugates as targeted cancer therapeutics. Yao Xue Xue Bao. 2009;44(9):943–52.PubMed
25.
Zhan J, Han Q, Wang K. Development of antibody therapeutics for small cell lung cancer. Expert Opin Investig Drugs. 2013;22(2):235–44.PubMedCrossRef
26.
Drake PM, Rabuka D. An emerging playbook for antibody-drug conjugates: lessons from the laboratory and clinic suggest a strategy for improving efficacy and safety. Curr Opin Chem Biol. 2015;28:174–80.PubMedCrossRef
27.
Hedrich WD, et al. Antibody-drug conjugates: pharmacokinetic/pharmacodynamic modeling, preclinical characterization, clinical studies, and lessons learned. Clin Pharmacokinet. 2018;57(6):687–703.PubMedPubMedCentralCrossRef
28.
Krieckaert C, Rispens T, Wolbink G. Immunogenicity of biological therapeutics: from assay to patient. Curr Opin Rheumatol. 2012;24(3):306–11.PubMedCrossRef
29.
Rosenberg AS. Immunogenicity of biological therapeutics: a hierarchy of concerns. Dev Biol (Basel). 2003;112:15–21.PubMed
30.
Ponziani, S., et al., Antibody-drug conjugates: the new frontier of chemotherapy. Int J Mol Sci., 2020. 21(15).
31.
Dragovich PS, et al. Antibody-mediated delivery of chimeric BRD4 degraders. Part 1: exploration of antibody linker, payload loading, and payload molecular properties. J Med Chem. 2021;64(5):2534–75.PubMedCrossRef
32.
Hamilton JZ, et al. Improving antibody-tubulysin conjugates through linker chemistry and site-specific conjugation. Chem Med Chem. 2021;16(7):1077–81.PubMedCrossRef
33.
Shao T, et al. Construction of paclitaxel-based antibody-drug conjugates with a PEGylated linker to achieve superior therapeutic index. Signal Transduct Target Ther. 2020;5(1):132.PubMedPubMedCentralCrossRef
34.
Wang Y, et al. Antibody-drug conjugate using ionized cys-linker-MMAE as the potent payload shows optimal therapeutic safety. Cancers (Basel). 2020;12(3)
35.
Alley SC, et al. Contribution of linker stability to the activities of anticancer immunoconjugates. Bioconjug Chem. 2008;19(3):759–65.PubMedCrossRef
36.
Laguzza BC, et al. New antitumor monoclonal antibody-vinca conjugates LY203725 and related compounds: design, preparation, and representative in vivo activity. J Med Chem. 1989;32(3):548–55.PubMedCrossRef
37.
Dal Corso A, et al. Protease-cleavable linkers modulate the anticancer activity of noninternalizing antibody-drug conjugates. Bioconjug Chem. 2017;28(7):1826–33.PubMedPubMedCentralCrossRef
38.
39.
Matsuda Y, Mendelsohn BA. Recent advances in drug-antibody ratio determination of antibody-drug conjugates. Chem Pharm Bull (Tokyo). 2021;69(10):976–83.PubMedCrossRef
40.
Li F, et al. Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res. 2016;76(9):2710–9.PubMedCrossRef
41.
Hafeez U, et al. Antibody-drug conjugates for cancer therapy. Molecules. 2020;25:20.CrossRef
42.
43.
Chen H, et al. Tubulin inhibitor-based antibody-drug conjugates for cancer therapy. Molecules. 2017;22(8)
44.
45.
Mantaj J, et al. Covalent bonding of pyrrolobenzodiazepines (PBDs) to terminal guanine residues within duplex and hairpin DNA fragments. PLoS One. 2016;11(4):e0152303.PubMedPubMedCentralCrossRef
46.
47.
Khera E, et al. Quantifying ADC bystander payload penetration with cellular resolution using pharmacodynamic mapping. Neoplasia. 2021;23(2):210–21.PubMedCrossRef
48.
Heath EI, Rosenberg JE. The biology and rationale of targeting nectin-4 in urothelial carcinoma. Nat Rev Urol. 2021;18(2):93–103.PubMedCrossRef
49.
Reymond N, et al. Nectin4/PRR4, a new afadin-associated member of the nectin family that trans-interacts with nectin1/PRR1 through V domain interaction. J Biol Chem. 2001;276(46):43205–15.PubMedCrossRef
50.
Calandrella ML, et al. Nectin-4 and DNA mismatch repair proteins expression in upper urinary tract urothelial carcinoma (UTUC) as a model for tumor targeting approaches: an ImGO pilot study. BMC Cancer. 2022;22(1):168.PubMedPubMedCentralCrossRef
51.
Tomiyama E, et al. Expression of Nectin-4 and PD-L1 in upper tract urothelial carcinoma. Int J Mol Sci. 2020;21(15)
52.
Ueki H, et al. Expressions of PD-L1 and Nectin-4 in urothelial cancer patients treated with pembrolizumab. Clin Transl Oncol. 2022;24(3):568–77.PubMedCrossRef
53.
Bouleftour W, Guillot A, Magne N. The anti-Nectin 4: a promising tumor cells target. A systematic review. Mol Cancer Ther. 2022;21(4):493–501.PubMedCrossRef
54.
Targeting Nectin-4 in bladder cancer. Cancer Discov. 2017;7(8):OF3.
55.
Athanassiadou AM, et al. The significance of Survivin and Nectin-4 expression in the prognosis of breast carcinoma. Folia Histochem Cytobiol. 2011;49(1):26–33.PubMedCrossRef
56.
Fan Y, et al. Head-to-head comparison of the expression differences of NECTIN-4, TROP-2, and HER2 in urothelial carcinoma and its histologic variants. Front Oncol. 2022;12:858865.PubMedPubMedCentralCrossRef
57.
Hoffman-Censits JH, et al. Expression of Nectin-4 in bladder urothelial carcinoma, in morphologic variants, and nonurothelial histotypes. Appl Immunohistochem Mol Morphol. 2021;29(8):619–25.PubMedPubMedCentralCrossRef
58.
59.
Miao X, et al. Nectin-2 and DDX3 are biomarkers for metastasis and poor prognosis of squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder. Int J Clin Exp Pathol. 2013;6(2):179–90.PubMedPubMedCentral
60.
Deng H, et al. Over-expression of Nectin-4 promotes progression of esophageal cancer and correlates with poor prognosis of the patients. Cancer Cell Int. 2019;19:106.PubMedPubMedCentralCrossRef
61.
Wong JL, Rosenberg JE. Targeting nectin-4 by antibody-drug conjugates for the treatment of urothelial carcinoma. Expert Opin Biol Ther. 2021;21(7):863–73.PubMedPubMedCentralCrossRef
62.
Boylan KL, et al. The expression of Nectin-4 on the surface of ovarian cancer cells alters their ability to adhere, migrate, aggregate, and proliferate. Oncotarget. 2017;8(6):9717–38.PubMedCrossRef
63.
• Rosenberg JE, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol. 2019;37(29):2592–600. Results of phaseIII trial of EV after progression on platinum and PD1 inhibitorPubMedPubMedCentralCrossRef
64.
• Powles T, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125–35. Results of phaseIII trial of EV after progression on platinum and PD1 inhibitorPubMedPubMedCentralCrossRef
65.
• Rosenberg, J.E., et al., Long-term outcomes in EV-301: 24-month findings from the phase 3 trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. 2022, A Soc Clin Oncol.. Results of phaseIII trial of EV after progression on platinum and PD1 inhibitor
66.
Smoking and cancers of the bladder and kidney. Lancet, 1971. 1(7700): p. 635-6
67.
Petrylak, D.P., et al., EV-201: Results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. 2019, Am Soc Clin Oncol.
68.
• Rosenberg J, et al. LBA73 Study EV-103 Cohort K: antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Annals Oncol. 2022;33:S1441. Results of EV monotherapy or in combination with pembrolizumab in the first-line setting in platinum-ineligible patientsCrossRef
69.
Hoimes CJ, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol. 2023;41(1):22–31.PubMedCrossRef
70.
Chou, J., et al., TROP2 expression across molecular subtypes of urothelial carcinoma and enfortumab vedotin-resistant cells. Eur Urol Oncol., 2022.
71.
72.
Tagawa ST, et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2474–85. Phase 3 trial of antiTROP2 ADC after progression on platinum and checkpoint inhibitorPubMedPubMedCentralCrossRef
73.
Aruga J. Slitrk6 expression profile in the mouse embryo and its relationship to that of Nlrr3. Gene Expr Patterns. 2003;3(6):727–33.PubMedCrossRef
74.
75.
Sanford T, Porten S, Meng MV. Molecular analysis of upper tract and bladder urothelial carcinoma: results from a microarray comparison. PLoS One. 2015;10(8):e0137141.PubMedPubMedCentralCrossRef
76.
Tan R, et al. HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis. BMC Med. 2022;20(1):105.PubMedPubMedCentralCrossRef
77.
Soysal SD, et al. EpCAM expression varies significantly and is differentially associated with prognosis in the luminal B HER2(+), basal-like, and HER2 intrinsic subtypes of breast cancer. Br J Cancer. 2013;108(7):1480–7.PubMedPubMedCentralCrossRef
78.
Ochs AM, et al. Expression of vascular endothelial growth factor and HER2/neu in stage II colon cancer and correlation with survival. Clin Colorectal Cancer. 2004;4(4):262–7.PubMedCrossRef
79.
Junker K, et al. HER2/neu expression and amplification in non-small cell lung cancer prior to and after neoadjuvant therapy. Lung Cancer. 2005;48(1):59–67.PubMedCrossRef
80.
81.
Indini A, Rijavec E, Grossi F. Trastuzumab deruxtecan: changing the destiny of HER2 expressing solid tumors. Int J Mol Sci. 2021;22(9)
82.
83.
• Sheng X, et al. Open-label, multicenter, phase II study of RC48-ADC, a HER2-targeting antibody-drug conjugate, in patients with locally advanced or metastatic urothelial carcinoma. Clin Cancer Res. 2021;27(1):43–51. Results of phase II basket trial of anti HER2 ADC including urothelial carcinomaPubMedCrossRef
84.
Schmelzer E, Reid LM. EpCAM expression in normal, non-pathological tissues. Front Biosci. 2008;13:3096–100.PubMedCrossRef
85.
van der Fels, C.A.M., S. Rosati, and I.J. de Jong, EpCAM expression in lymph node metastases of urothelial cell carcinoma of the bladder: a pilot study. Int J Mol Sci., 2017. 18(8).
86.
Fitsialos D, et al. Phase I/II study of vicinium given by intravesical administration in patients with superficial transitional cell carcinoma of the bladder: phase I results. J Clin Oncol. 2006;24(18_suppl):4580–0.CrossRef
87.
Kowalski M, et al. A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guerin. J Urol. 2012;188(5):1712–8.PubMedCrossRef
88.
Dickstein R, et al. LBA27 Phase 3 study of Vicinium in BCG-unresponsive non-muscle invasive bladder cancer: initial results. The J Urol. 2018;199(4S):e1167–7.CrossRef
Metadata
Title
Antibody Drug Conjugates in Bladder Cancer: Current Milestones and Future Perspectives
Authors
Raafat Alameddine, MD
Patrick Mallea, MD
Farhan Shahab, MD
Yousef Zakharia, MD
Publication date
05-07-2023
Publisher
Springer US
Published in
Current Treatment Options in Oncology / Issue 9/2023
Print ISSN: 1527-2729
Electronic ISSN: 1534-6277
DOI
https://doi.org/10.1007/s11864-023-01114-y

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Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
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