Skip to main content

Advertisement

SpringerLink
Log in

A phase II study of Mirvetuximab Soravtansine in triple-negative breast cancer

  • PHASE II STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Folate receptor alpha (FRα) has been reported to be expressed in up to 80% of triple-negative breast cancers (TNBC) with limited expression in normal tissues, making it a promising therapeutic target. Mirvetuximab soravtansine (mirvetuximab-s) is an antibody drug conjugate which has shown promise in the treatment of FRα-positive solid tumors in early phase clinical trials. Herein, are the results of the first prospective phase II trial evaluating mirvetuximab-s in metastatic TNBC. Patients with advanced, FRα-positive TNBC were enrolled on this study. Mirvetuximab-s was administered at a dose of 6.0 mg/kg every 3 weeks. 96 patients with advanced TNBC consented for screening. FRα staining was performed on tumor tissue obtained from 80 patients. The rate of FRα positivity by immunohistochemistry was 10.0% (8/80). Two patients were treated on study, with best overall responses of stable disease in one and progressive disease in the other. Adverse events were consistent with earlier studies. The study was terminated early due to the low rate of FRα positivity in the screened patient population and lack of disease response in the two patients treated. The observed rate of FRα positivity was considerably lower than previously reported and none of the patients had a partial or complete response. Treatment with mirvetuximab-s should only be further explored in TNBC if an alternate biomarker strategy is developed for patient selection on the basis of additional preclinical data.

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
Fig. 2

Similar content being viewed by others

References

  1. Lopus M, Oroudjev E, Wilson L, Wilhelm S, Widdison W, Chari R, Jordan MA (2010) Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther 9(10):2689–2699. https://doi.org/10.1158/1535-7163.MCT-10-0644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ab O, Whiteman KR, Bartle LM, Sun X, Singh R, Tavares D, LaBelle A, Payne G, Lutz RJ, Pinkas J, Goldmacher VS, Chittenden T, Lambert JM (2015) IMGN853, a Folate Receptor-alpha (FRalpha)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRalpha-Expressing Tumors. Mol Cancer Ther 14(7):1605–1613. https://doi.org/10.1158/1535-7163.MCT-14-1095

    Article  CAS  PubMed  Google Scholar 

  3. Erickson HK, Widdison WC, Mayo MF, Whiteman K, Audette C, Wilhelm SD, Singh R (2010) Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody-maytansinoid conjugates. Bioconjug Chem 21(1):84–92. https://doi.org/10.1021/bc900315y

    Article  CAS  PubMed  Google Scholar 

  4. Moore KN, Borghaei H, O'Malley DM, Jeong W, Seward SM, Bauer TM, Perez RP, Matulonis UA, Running KL, Zhang X, Ponte JF, Ruiz-Soto R, Birrer MJ (2017) Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor alpha-targeting antibody-drug conjugate, in patients with solid tumors. Cancer 123(16):3080–3087. https://doi.org/10.1002/cncr.30736

    Article  CAS  PubMed  Google Scholar 

  5. Morris GJ, Naidu S, Topham AK, Guiles F, Xu Y, McCue P, Schwartz GF, Park PK, Rosenberg AL, Brill K, Mitchell EP (2007) Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: a single-institution compilation compared with the National Cancer Institute's surveillance, epidemiology, and end results database. Cancer 110(4):876–884. https://doi.org/10.1002/cncr.22836

    Article  PubMed  Google Scholar 

  6. Onitilo AA, Engel JM, Greenlee RT, Mukesh BN (2009) Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res 7(1–2):4–13. https://doi.org/10.3121/cmr.2009.825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V (2007) Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer registry. Cancer 109(9):1721–1728. https://doi.org/10.1002/cncr.22618

    Article  PubMed  Google Scholar 

  8. Thike AA, Cheok PY, Jara-Lazaro AR, Tan B, Tan P, Tan PH (2010) Triple-negative breast cancer: clinicopathological characteristics and relationship with basal-like breast cancer. Mod Pathol 23(1):123–133. https://doi.org/10.1038/modpathol.2009.145

    Article  CAS  PubMed  Google Scholar 

  9. Yam C, Mani SA, Moulder SL (2017) Targeting the molecular subtypes of triple negative breast Cancer: understanding the diversity to Progress the field. Oncologist 22(9):1086–1093. https://doi.org/10.1634/theoncologist.2017-0095

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1):4429–4434. https://doi.org/10.1158/1078-0432.CCR-06-3045

    Article  PubMed  Google Scholar 

  11. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13(8):2329–2334. https://doi.org/10.1158/1078-0432.CCR-06-1109

    Article  CAS  PubMed  Google Scholar 

  12. Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, Harris L, Hait W, Toppmeyer D (2006) Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24(36):5652–5657. https://doi.org/10.1200/JCO.2006.06.5664

    Article  PubMed  Google Scholar 

  13. Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M, Walls A, Bousamra A, Ramineni M, Sinn B, Hunt K, Buchholz TA, Valero V, Buzdar AU, Yang W, Brewster AM, Moulder S, Pusztai L, Hatzis C, Hortobagyi GN (2017) Long-term prognostic risk after Neoadjuvant chemotherapy associated with residual Cancer burden and breast Cancer subtype. J Clin Oncol 35(10):1049–1060. https://doi.org/10.1200/JCO.2015.63.1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ginter PS, McIntire PJ, Cui X, Irshaid L, Liu Y, Chen Z, Shin SJ (2017) Folate receptor alpha expression is associated with increased risk of recurrence in triple-negative breast Cancer. Clin Breast Cancer 17(7):544–549. https://doi.org/10.1016/j.clbc.2017.03.007

    Article  CAS  PubMed  Google Scholar 

  15. Norton N, Youssef B, Hillman DW, Nassar A, Geiger XJ, Necela BM, Liu H, Ruddy KJ, Polley MC, Ingle JN, Couch FJ, Perez EA, Liu MC, Carter JM, Leon-Ferre RA, Boughey JC, Somers EB, Kalari KR, Visscher DW, Goetz MP, Knutson KL (2020) Folate receptor alpha expression associates with improved disease-free survival in triple negative breast cancer patients. NPJ Breast Cancer 6:4. https://doi.org/10.1038/s41523-020-0147-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cheung A, Opzoomer J, Ilieva KM, Gazinska P, Hoffmann RM, Mirza H, Marlow R, Francesch-Domenech E, Fittall M, Dominguez Rodriguez D, Clifford A, Badder L, Patel N, Mele S, Pellizzari G, Bax HJ, Crescioli S, Petranyi G, Larcombe-Young D, Josephs DH, Canevari S, Figini M, Pinder S, Nestle FO, Gillett C, Spicer JF, Grigoriadis A, Tutt ANJ, Karagiannis SN (2018) Anti-Folate receptor alpha-directed antibody therapies restrict the growth of triple-negative breast Cancer. Clin Cancer Res 24(20):5098–5111. https://doi.org/10.1158/1078-0432.CCR-18-0652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang Z, Wang J, Tacha DE, Li P, Bremer RE, Chen H, Wei B, Xiao X, Da J, Skinner K, Hicks DG, Bu H, Tang P (2014) Folate receptor alpha associated with triple-negative breast cancer and poor prognosis. Arch Pathol Lab Med 138(7):890–895. https://doi.org/10.5858/arpa.2013-0309-OA

    Article  PubMed  Google Scholar 

  18. O'Shannessy DJ, Somers EB, Maltzman J, Smale R, Fu YS (2012) Folate receptor alpha (FRA) expression in breast cancer: identification of a new molecular subtype and association with triple negative disease. Springerplus 1:22. https://doi.org/10.1186/2193-1801-1-22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Elnakat H, Ratnam M (2004) Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev 56(8):1067–1084. https://doi.org/10.1016/j.addr.2004.01.001

    Article  CAS  PubMed  Google Scholar 

  20. Salazar MD, Ratnam M (2007) The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer Metastasis Rev 26(1):141–152. https://doi.org/10.1007/s10555-007-9048-0

    Article  CAS  PubMed  Google Scholar 

  21. Frontera ED, Khansa RM, Schalk DL, Leakan LE, Guerin-Edbauer TJ, Ratnam M, Gorski DH, Speyer CL (2018) IgA fc-folate conjugate activates and recruits neutrophils to directly target triple-negative breast cancer cells. Breast Cancer Res Treat 172(3):551–560. https://doi.org/10.1007/s10549-018-4941-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026

    Article  CAS  PubMed  Google Scholar 

  23. Moore K, Oza A, Colombo N, Oaknin A, Scambia G, Lorusso D, Farias-Eisner R, Banerjee S, Murphy C, Tanyi J, Hirte H, Konner J, Lim P, Hayes M, Monk B, Kim S, Wang J, Pautier P, Vergote I, Birrer M (2019) 992OFORWARD I (GOG 3011): a phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC). Ann Oncol 30:v403. https://doi.org/10.1093/annonc/mdz250

    Article  Google Scholar 

  24. Martin LP, Konner JA, Moore KN, Seward SM, Matulonis UA, Perez RP, Su Y, Berkenblit A, Ruiz-Soto R, Birrer MJ (2017) Characterization of folate receptor alpha (FRalpha) expression in archival tumor and biopsy samples from relapsed epithelial ovarian cancer patients: a phase I expansion study of the FRalpha-targeting antibody-drug conjugate mirvetuximab soravtansine. Gynecol Oncol 147(2):402–407. https://doi.org/10.1016/j.ygyno.2017.08.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Heo GS, Detering L, Luehmann HP, Primeau T, Lee YS, Laforest R, Li S, Stec J, Lim KH, Lockhart AC, Liu Y (2019) Folate receptor alpha-targeted (89)Zr-M9346A Immuno-PET for image-guided intervention with Mirvetuximab Soravtansine in triple-negative breast Cancer. Mol Pharm 16(9):3996–4006. https://doi.org/10.1021/acs.molpharmaceut.9b00653

    Article  CAS  PubMed  Google Scholar 

  26. Moore KN, Martin LP, O'Malley DM, Matulonis UA, Konner JA, Perez RP, Bauer TM, Ruiz-Soto R, Birrer MJ (2017) 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 35(10):1112–1118. https://doi.org/10.1200/JCO.2016.69.9538

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by ImmunoGen, Inc., the National Institutes of Health/National Cancer Institute (N01-CM-2011-00039), and generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program. Dr. Yam is supported by the Allison and Brian Grove Endowed Fellowship for Breast Medical Oncology, the Susan Papizan Dolan Fellowship in Breast Oncology, and the 2018 Gianni Bonadonna Breast Cancer Research Fellowship. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the sponsors.

Author information

Authors and Affiliations

  1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Dan L. Duncan Building CPB5.3542, 1515 Holcombe Blvd. Unit 1354, Houston, TX, 77030, USA

    Clinton Yam, Meghan Karuturi, Elizabeth Ravenberg, Jason White, Alyson Clayborn, Pamela McCarthy, Sausan Abouharb, Bora Lim, Jennifer K. Litton, David L. Ramirez, Sadia Saleem, Senthil Damodaran & Stacy L. Moulder

  2. Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Gaiane M. Rauch

  3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Tanbin Rahman & Ryan Sun

  4. ImmunoGen, Inc, Waltham, MA, USA

    James Stec

  5. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    W. Fraser Symmans

  6. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Lei Huo

Authors
  1. Clinton Yam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gaiane M. Rauch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tanbin Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meghan Karuturi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elizabeth Ravenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jason White
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alyson Clayborn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pamela McCarthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sausan Abouharb
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bora Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jennifer K. Litton
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. David L. Ramirez
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sadia Saleem
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. James Stec
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. W. Fraser Symmans
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Lei Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Senthil Damodaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Ryan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Stacy L. Moulder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stacy L. Moulder.

Ethics declarations

Conflict of interest

J.K.L. has received grant or research support from Novartis, Medivation/Pfizer, Genentech, GSK, EMD-Serono, Astra-Zeneca, Medimmune, Zenith, Jounce; participated in Speaker’s Bureau for MedLearning, Physician’s Education Resource, Prime Oncology, Medscape, Clinical Care Options; received honoraria from UpToDate; served on advisory committees or review panels for Astra-Zeneca, Ayala, Pfizer (all uncompensated), NCCN, ASCO, NIH, PDQ, SITC Breast Committee, SWOG Breast Committee. J.S. is a full-time employee and shareholder of ImmunoGen, Inc. S.L.M. has received research support from the NCCN for the clinical trial. All other authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

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

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yam, C., Rauch, G.M., Rahman, T. et al. A phase II study of Mirvetuximab Soravtansine in triple-negative breast cancer. Invest New Drugs 39, 509–515 (2021). https://doi.org/10.1007/s10637-020-00995-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-020-00995-2

Keywords

Search

Navigation