Skip to main content

Advertisement

SpringerLink
Log in

Progress in Gynecologic Cancers with Antibody Drug Conjugates

  • Gynecologic Cancers (J Brown and RW Naumann, Section Editors)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of review

This article provides a comprehensive review of antibody-drug conjugates (ADCs) under investigation in gynecologic cancers. The structure and function of ADCs are reviewed with a focus on clinical benefit as well as toxicity profiles.

Recent findings

Several ADCs with various target antigens have been investigated in ovarian, cervical, and endometrial cancer. ADCs have consistently demonstrated favorable safety/tolerability profiles both as monotherapy and in combination therapy. In ovarian cancer, response rates have ranged from 9 to 46% for monotherapy with response rates as high as 83% in combination therapy. In patients with cervical cancer with progressive disease despite doublet therapy and bevacizumab, response rates as high as 24% have been observed.

Summary

ADCs represent a rapidly evolving field of targeted therapy which have demonstrated notable clinical benefit both as monotherapy but also in combination therapy with an overall favorable toxicity profile. With continued refinement of the target biomarkers utilized, improved clinical benefit is likely to be observed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Sievers EL, Larson RA, Stadtmauer EA, Estey E, Löwenberg B, Dombret H, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001;19(13):3244–54. https://doi.org/10.1200/JCO.2001.19.13.3244.

    Article  CAS  PubMed  Google Scholar 

  2. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783–91. https://doi.org/10.1056/NEJMoa1209124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617–28. https://doi.org/10.1056/NEJMoa1814017.

    Article  Google Scholar 

  4. Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610–21. https://doi.org/10.1056/NEJMoa1914510.

    Article  CAS  PubMed  Google Scholar 

  5. Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, et al. Sacituzumab Govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 2019;380(8):741–51. https://doi.org/10.1056/NEJMoa1814213.

    Article  CAS  PubMed  Google Scholar 

  6. Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, 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. https://doi.org/10.1200/jco.19.01140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Carter PJ, Lazar GA. Next generation antibody drugs: pursuit of the 'high-hanging fruit'. Nat Rev Drug Discov. 2018;17(3):197–223. https://doi.org/10.1038/nrd.2017.227.

    Article  CAS  PubMed  Google Scholar 

  8. Elias DJ, Hirschowitz L, Kline LE, Kroener JF, Dillman RO, Walker LE, et al. Phase I clinical comparative study of monoclonal antibody KS1/4 and KS1/4-methotrexate immunconjugate in patients with non-small cell lung carcinoma. Cancer Res. 1990;50(13):4154–9.

    CAS  PubMed  Google Scholar 

  9. Tolcher AW, Sugarman S, Gelmon KA, Cohen R, Saleh M, Isaacs C, et al. Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer. J Clin Oncol. 1999;17(2):478–84. https://doi.org/10.1200/jco.1999.17.2.478.

    Article  CAS  PubMed  Google Scholar 

  10. Ritchie M, Tchistiakova L, Scott N. Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates. MAbs. 2013;5(1):13–21. https://doi.org/10.4161/mabs.22854.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hoffmann RM, Coumbe BGT, Josephs DH, Mele S, Ilieva KM, Cheung A, et al. Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs). Oncoimmunology. 2018;7(3):e1395127. https://doi.org/10.1080/2162402x.2017.1395127.

    Article  CAS  PubMed  Google Scholar 

  12. Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs. 2016;8(4):659–71. https://doi.org/10.1080/19420862.2016.1156829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Birrer MJ, Moore KN, Betella I, Bates RC. Antibody-drug conjugate-based therapeutics: state of the science. J Natl Cancer Inst. 2019;111(6):538–49. https://doi.org/10.1093/jnci/djz035.

    Article  CAS  PubMed  Google Scholar 

  14. Lee EK, Liu JF. Antibody-drug conjugates in gynecologic malignancies. Gynecol Oncol. 2019;153(3):694–702. https://doi.org/10.1016/j.ygyno.2019.03.245.

    Article  CAS  PubMed  Google Scholar 

  15. Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10(20):7063–70. https://doi.org/10.1158/1078-0432.CCR-04-0789.

    Article  CAS  PubMed  Google Scholar 

  16. Sun X, Ponte JF, Yoder NC, Laleau R, Coccia J, Lanieri L, et al. Effects of drug-antibody ratio on pharmacokinetics, biodistribution, efficacy, and tolerability of antibody-maytansinoid conjugates. Bioconjug Chem. 2017;28(5):1371–81. https://doi.org/10.1021/acs.bioconjchem.7b00062.

    Article  CAS  PubMed  Google Scholar 

  17. Remillard S, Rebhun LI, Howie GA, Kupchan SM. Antimitotic activity of the potent tumor inhibitor maytansine. Science. 1975;189(4207):1002–5. https://doi.org/10.1126/science.1241159.

    Article  CAS  PubMed  Google Scholar 

  18. Kalli KR, Oberg AL, Keeney GL, Christianson TJ, Low PS, Knutson KL, et al. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008;108(3):619–26. https://doi.org/10.1016/j.ygyno.2007.11.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Moore KN, Martin LP, O'Malley DM, Matulonis UA, Konner JA, Vergote I, et al. A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer. Future Oncol. 2018;14(2):123–36. https://doi.org/10.2217/fon-2017-0379.

    Article  CAS  PubMed  Google Scholar 

  20. Brown Jones M, Neuper C, Clayton A, Mariani A, Konecny G, Thomas MB, et al. Rationale for folate receptor alpha targeted therapy in "high risk" endometrial carcinomas. Int J Cancer. 2008;123(7):1699–703. https://doi.org/10.1002/ijc.23686.

    Article  CAS  PubMed  Google Scholar 

  21. Moore KN, Borghaei H, O'Malley DM, Jeong W, Seward SM, Bauer TM, et al. Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors. Cancer. 2017;123(16):3080–7. https://doi.org/10.1002/cncr.30736.

    Article  CAS  PubMed  Google Scholar 

  22. Moore KN, Martin LP, O'Malley DM, Matulonis UA, Konner JA, Perez RP, et al. Safety and activity of Mirvetuximab Soravtansine (IMGN853), a folate receptor alpha-targeting antibody-drug conjugate, in platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a phase I expansion study. J Clin Oncol. 2017;35(10):1112–8. https://doi.org/10.1200/JCO.2016.69.9538.

    Article  CAS  PubMed  Google Scholar 

  23. Moore K, Matulonis U, O'Malley D, Konner J, Martin L, Perez R, et al. Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): activity and safety analyses in phase I pooled expansion cohorts. Journal of Clinical Oncology 2017. p. 5547.

  24. Moore KN, Vergote I, Oaknin A, Colombo N, Banerjee S, Oza A, et al. FORWARD I: a phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer. Future Oncol. 2018;14(17):1669–78. https://doi.org/10.2217/fon-2017-0646.

    Article  CAS  PubMed  Google Scholar 

  25. Moore K, Oza A, Colombo N, Oaknin A, Scambia G, Lorusso D, et al. FORWARD I (GOG3011): a phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients with platinum-resistant ovarian cancer (PROC). Ann Oncol. 2019;30:v403–34.

    Article  Google Scholar 

  26. Moore KN, O'Malley DM, Vergote I, Martin LP, Gonzalez-Martin A, Malek K, et al. Safety and activity findings from a phase 1b escalation study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with carboplatin in patients with platinum-sensitive ovarian cancer. Gynecol Oncol. 2018;151(1):46–52. https://doi.org/10.1016/j.ygyno.2018.07.017.

    Article  CAS  PubMed  Google Scholar 

  27. O'Malley DM, Matulonis UA, Birrer MJ, Castro CM, Gilbert L, Vergote I, et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2020;157:379–85. https://doi.org/10.1016/j.ygyno.2020.01.037.

    Article  CAS  PubMed  Google Scholar 

  28. Gilbert L, Oaknin A, Matulonis U, Mantia-Smaldone G, Lim P, Castro C, et al. Mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), in combination with bevaciziumab in patients with platinum-agnostic ovarian cancer. J Clin Oncol. 2020;38:6004.

    Article  Google Scholar 

  29. O'Malley D, Richardson D, Vergote I, Gilbert L, Martin L, Mantia-Smaldone G, et al. Mirvetuximab soravtaninse, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), in combination with carboplatin and bevacizumab: initial results from a phase 1b study in patients with ovarian cancer. Ann Oncol. 2019:v403–34.

  30. Matulonis U, Moore K, Martin L, Vergote I, Castro C, Gilbert L, et al. Mirvetuximab soravtaninse, a folate receptor alpha (FRalpha)-targeting antibody-drug conjugate (ADC), with pembrolizumab, in platinum-resistant ovarian cancer (PROC): Initial results of an expansion cohort from FORWARD II, a phase Ib study. Abstracts Gynaecological Cancers: Annals of Oncology; 2018.

  31. Hassan R, Blumenschein GR Jr, Moore KN, Santin AD, Kindler HL, Nemunaitis JJ, et al. First-in-human, multicenter, phase I dose-escalation and expansion study of anti-mesothelin antibody-drug conjugate anetumab ravtansine in advanced or metastatic solid tumors. J Clin Oncol. 2020;38(16):1824–35. https://doi.org/10.1200/jco.19.02085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bulat I, Moore K, Haceatrean A, Chung J, Rajagopalan P, Xia C, et al. Phase Ib study of anti-mesothelin antibody drug conjugate anetumab ravtansine in combination with pegylated liposomal doxorubicin in platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer. J Clin Oncol. 2018;36:5571.

    Article  Google Scholar 

  33. Coleman R, Lorusso D, Gennigens C, Gonzalez-Martin A, Randall L, Cibula D, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase II innovaTV 204/GOG-3023/ENGOT-cx6 study. Ann Oncol. 2020:S1142–S215.

  34. Hong DS, Concin N, Vergote I, de Bono JS, Slomovitz BM, Drew Y, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer. Clin Cancer Res. 2020;26(6):1220–8. https://doi.org/10.1158/1078-0432.ccr-19-2962.

    Article  CAS  PubMed  Google Scholar 

  35. de Bono JS, Concin N, Hong DS, Thistlethwaite FC, Machiels JP, Arkenau HT, et al. Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(3):383–93. https://doi.org/10.1016/s1470-2045(18)30859-3.

    Article  CAS  PubMed  Google Scholar 

  36. Banerjee S, Oza AM, Birrer MJ, Hamilton EP, Hasan J, Leary A, et al. Anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer in a randomized, open-label, phase II study. Ann Oncol. 2018;29(4):917–23. https://doi.org/10.1093/annonc/mdy023.

    Article  CAS  PubMed  Google Scholar 

  37. Moore KN, Birrer MJ, Marsters J, Wang Y, Choi Y, Royer-Joo S, et al. Phase 1b study of anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol. 2020;158(3):631–9. https://doi.org/10.1016/j.ygyno.2020.05.039.

    Article  CAS  PubMed  Google Scholar 

  38. Lim SI. Site-specific bioconjugation and self-assembly technologies for multi-functional biologics: on the road to the clinic. Drug Discov Today. 2020;25(1):168–76. https://doi.org/10.1016/j.drudis.2019.10.002.

    Article  CAS  PubMed  Google Scholar 

  39. Li X, Abrahams C, Zhou S, Krimm S, Henningsen R, Stephenson H, et al. Discovery and activity of STRO-002, a novel ADC targeting folate receptor alpha for ovarian and endometrial cancer. Cancer Res 2018. p. 1782.

  40. Naumann R, Braiteh F, Diaz J, Hamilton E, Diab S, Schilder R, et al. Phase 1 dose-escalation study of STRO-002, an anti-folate receptor alpha (FRalpha) antibody drug conjugate (ADC), in patients with advanced, platinum-resistant/refractory epithelial ovarian cancer. IGSC Annual Meeting 2020.

  41. Shimizu T, Fujiwara Y, Yonemori K, Koyama T, Shimomura A, Tamura K, et al. First-in-human (FIH) phase 1 (Ph1) study of MORAb-202 in patients (pts) with advanced folate receptor alpha (FRA)-positive solid tumors. J Clin Oncol. 2019;37:5544.

    Article  Google Scholar 

  42. Tolcher A, Ulahannan S, Papadopoulos K, Edenfield W, Matulonis U, Burns T, et al. Phase 1 dose escalation study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC), in patients with solid tumors likely to express NaPi2b. J Clin Oncol. 2019;37:3010.

    Article  Google Scholar 

  43. Hamilton E, Barve M, Tolcher A, Buscema J, Papadopoulos K, Zarwan C, et al. Safety and efficacy of XMT-1536 in ovarian cancer: a subgroup analysis from the Phase I expansion study of XMT-1536, a NaPi2b antibody-drug conjugate. European Society of Medical Oncology (ESMO) Virtual Congress 2020.

  44. Weekes CD, Lamberts LE, Borad MJ, Voortman J, McWilliams RR, Diamond JR, et al. Phase I study of DMOT4039A, an antibody-drug conjugate targeting mesothelin, in patients with unresectable pancreatic or platinum-resistant ovarian cancer. Mol Cancer Ther. 2016;15(3):439–47. https://doi.org/10.1158/1535-7163.mct-15-0693.

    Article  CAS  PubMed  Google Scholar 

  45. Clarke J, Chu S, Siu L, Machiels J, Markman B, Heinhuis K, et al. BMS-986128, an anti-mesothelin antibody-drug conjugate (ADC), alone or in combination with nivolumab demonstrates clinical activity in patients with select advanced tumors. Molecular Cancer Therapeutics 2019. B057.

  46. Moore K, Hamilton E, Burris H, Barroilhet L, Gutierrez M, Wang J, et al. Abstract CT036: targeting MUC16 with the THIOMABTM-drug conjugate DMUC4064A in patients with platinum-resistant ovarian cancer: a phase I expansion study. Cancer Res 2018. CT036.

  47. Calo CA, O'Malley DM. Antibody-drug conjugates for the treatment of ovarian cancer. Expert Opin Biol Ther. 2020:1–13. https://doi.org/10.1080/14712598.2020.1776253.

  48. Eaton JS, Miller PE, Mannis MJ, Murphy CJ. Ocular adverse events associated with antibody-drug conjugates in human clinical trials. J Ocul Pharmacol Ther. 2015;31(10):589–604. https://doi.org/10.1089/jop.2015.0064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Naumann RW, Coleman RL, Burger RA, Sausville EA, Kutarska E, Ghamande SA, et al. PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2013;31(35):4400–6. https://doi.org/10.1200/jco.2013.49.7685.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Ohio State University, M210 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH, 43210, USA

    David M. O’Malley & Corinne A. Calo

Authors
  1. David M. O’Malley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Corinne A. Calo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David M. O’Malley.

Ethics declarations

Conflict of Interest

David M. O'Malley has received institutional support for clinical trials from AstraZeneca, Tesaro/GlaxoSmithKline, ImmunoGen, Janssen/Johnson & Johnson, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, VentiRx, Array BioPharma, EMD Serono, Ergomed, Ajinomoto, Inc., Ludwig Cancer Research, Stemcentrx, Inc., Cerulean Pharma, Gynecologic Oncology Group (GOG) Foundation, Bristol-Myers Squibb, Serono, Inc., TRACON Pharmaceuticals, Yale University, New Mexico Cancer Care Alliance, INC Research, Inc., inVentiv Health Clinical, Iovance Biotherapeutics, Inc., PRA International, Eisai, Agenus, Merck, Genmab, Seagen, Mersana Therapeutics, and Clovis Oncology; and has received compensation for service as a consultant/advisory board participant from AstraZeneca, Tesaro/GlaxoSmithKline, ImmunoGen, Ambry, Janssen/Johnson & Johnson, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, GOG Foundation, Iovance Biotherapeutics, Myriad Genetics, Eisai, Agenus, Tarveda, Merck, Seagen, Novartis, Mersana Therapeutics, Clovis Oncology, Rubius Therapeutics, and Elevar Therapeutics. Corinne A. Calo declares that she has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Gynecologic Cancers

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

O’Malley, D.M., Calo, C.A. Progress in Gynecologic Cancers with Antibody Drug Conjugates. Curr Oncol Rep 23, 89 (2021). https://doi.org/10.1007/s11912-021-01080-4

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11912-021-01080-4

Keywords

Search

Navigation