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Drug EvaluationFree Access

A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer

    Kathleen N Moore

    *Author for correspondence:

    E-mail Address: kathleen-moore@ouhsc.edu

    Department of Obstetrics & Gynecology, Stephenson Oklahoma Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA

    ,
    Lainie P Martin

    Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA

    ,
    David M O'Malley

    Department of Obstetrics & Gynecology, The Ohio State University, Columbus, OH 43210, USA

    ,
    Ursula A Matulonis

    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA

    ,
    Jason A Konner

    Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

    ,
    Ignace Vergote

    Gynaecological Oncology, Leuven Cancer Institute, Leuven 3000, Belgium

    ,
    Jose F Ponte

    Pharmacology, ImmunoGen, Inc, Waltham, MA 02451, USA

    &
    Michael J Birrer

    Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, Boston, MA 02114, USA

    Published Online:https://doi.org/10.2217/fon-2017-0379

    Resistance to platinum-based therapy poses a significant clinical challenge for the management of advanced ovarian cancer, a leading cause of cancer mortality among women. Mirvetuximab soravtansine is a novel antibody–drug conjugate that targets folate receptor-α, a validated molecular target for therapeutic intervention in this disease. Here, we examine mirvetuximab soravtansine's mechanism of action and pharmacology, and review its clinical evaluation in ovarian cancer to date. We focus on the favorable tolerability and encouraging signals of efficacy that have emerged, most notably in patients with platinum-resistant disease. Ongoing Phase III monotherapy and Phase Ib/II combination trials evaluating its activity in the setting of platinum resistance are emphasized, which will help define its role in the evolving landscape of ovarian cancer therapy.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136(5), E359–E386 (2015).
    • 2 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J. Clin. 67(1), 7–30 (2017).
    • 3 Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. Nature 474(7353), 609–615 (2011).
    • 4 Liu J, Matulonis UA. New strategies in ovarian cancer: translating the molecular complexity of ovarian cancer into treatment advances. Clin. Cancer Res. 20(20), 5150–5156 (2014).
    • 5 Lacey JV, Sherman ME. Ovarian neoplasia. In: Robboy's Pathology of the Female Reproductive Tract. Robboy SL, Mutter GL, Prat J (Eds). Churchill Livingstone Elsevier, Oxford, UK, 601 (2009).
    • 6 Desai A, Xu J, Aysola K et al. Epithelial ovarian cancer: an overview. World J. Transl. Med. 3(1), 1–8 (2014).
    • 7 Luvero D, Milani A, Ledermann JA. Treatment options in recurrent ovarian cancer: latest evidence and clinical potential. Ther. Adv. Med. Oncol. 6(5), 229–239 (2014).
    • 8 Della Pepa C, Tonini G, Pisano C et al. Ovarian cancer standard of care: are there real alternatives? Chin. J. Cancer 34(1), 17–27 (2015).
    • 9 Davis A, Tinker AV, Friedlander M. “Platinum resistant” ovarian cancer: what is it, who to treat and how to measure benefit? Gynecol. Oncol. 133(3), 624–631 (2014).
    • 10 Tapia G, Diaz-Padilla I. Molecular mechanisms of platinum resistance in ovarian cancer. In: Ovarian Cancer - A Clinical And Translational Update. Diaz-Padilla I (Ed.). InTech (2013).
    • 11 Cooke SL, Brenton JD. Evolution of platinum resistance in high-grade serous ovarian cancer. Lancet Oncol. 12(12), 1169–1174 (2011).
    • 12 Stuart GC, Kitchener H, Bacon M et al. 2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference. Int. J. Gynecol. Cancer 21(4), 750–755 (2011).
    • 13 Markman M, Bookman MA. Second-line treatment of ovarian cancer. Oncologist 5(1), 26–35 (2000).
    • 14 Rose PG, Fusco N, Fluellen L, Rodriguez M. Second-line therapy with paclitaxel and carboplatin for recurrent disease following first-line therapy with paclitaxel and platinum in ovarian or peritoneal carcinoma. J. Clin. Oncol. 16(4), 1494–1497 (1998).
    • 15 Hoekstra AV, Hurteau JA, Kirschner CV, Rodriguez GC. The combination of monthly carboplatin and weekly paclitaxel is highly active for the treatment of recurrent ovarian cancer. Gynecol. Oncol. 115(3), 377–381 (2009).
    • 16 Wagner U, Marth C, Largillier R et al. Final overall survival results of Phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients. Br. J. Cancer 107(4), 588–591 (2012).
    • 17 Herzog TJ, Armstrong DK, Brady MF et al. Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper. Gynecol. Oncol. 132, 8–17 (2014).
    • 18 Oronsky B, Ray CM, Spira AI, Trepel JB, Carter CA, Cottrill HM. A brief review of the management of platinum-resistant-platinum-refractory ovarian cancer. Med. Oncol. 34(6), 103 (2017).
    • 19 Bookman MA, Brady MF, Mcguire WP et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III trial of the gynecologic cancer intergroup. J. Clin. Oncol. 27(9), 1419–1425 (2009).
    • 20 Du Bois A, Weber B, Rochon J et al. Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens. J. Clin. Oncol. 24(7), 1127–1135 (2006).
    • 21 Lheureux S, Karakasis K, Kohn EC, Oza AM. Ovarian cancer treatment: the end of empiricism? Cancer 121(18), 3203–3211 (2015).
    • 22 Korkmaz T, Seber S, Basaran G. Review of the current role of targeted therapies as maintenance therapies in first and second line treatment of epithelial ovarian cancer; In the light of completed trials. Crit. Rev. Oncol. Hematol. 98, 180–188 (2016).
    • 23 Symeonides S, Gourley C. Ovarian cancer molecular stratification and tumor heterogeneity: a necessity and a challenge. Front. Oncol. 5, 229 (2015).
    • 24 Colombo N, Conte PF, Pignata S, Raspagliesi F, Scambia G. Bevacizumab in ovarian cancer: focus on clinical data and future perspectives. Crit. Rev. Oncol. Hematol. 97, 335–348 (2016).
    • 25 Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br. J. Cancer 115(10), 1157–1173 (2016).
    • 26 Banerjee S, Kaye S. The role of targeted therapy in ovarian cancer. Eur. J. Cancer 47(Suppl. 3), S116–S130 (2011).
    • 27 Aravantinos G, Pectasides D. Bevacizumab in combination with chemotherapy for the treatment of advanced ovarian cancer: a systematic review. J. Ovarian Res. 7, 57 (2014).
    • 28 Yoshida H, Yabuno A, Fujiwara K. Critical appraisal of bevacizumab in the treatment of ovarian cancer. Drug Des. Devel. Ther. 9, 2351–2358 (2015).
    • 29 Choi SW, Mason JB. Folate and carcinogenesis: an integrated scheme. J. Nutr. 130(2), 129–132 (2000).
    • 30 Assaraf YG, Leamon CP, Reddy JA. The folate receptor as a rational therapeutic target for personalized cancer treatment. Drug Resist. Updat. 17(4–6), 89–95 (2014).
    • 31 Zhao R, Diop-Bove N, Visentin M, Goldman ID. Mechanisms of membrane transport of folates into cells and across epithelia. Annu. Rev. Nutr. 31, 177–201 (2011).
    • 32 Desmoulin SK, Hou Z, Gangjee A, Matherly LH. The human proton-coupled folate transporter: biology and therapeutic applications to cancer. Cancer Biol. Ther. 13(14), 1355–1373 (2012).
    • 33 Elnakat H, Ratnam M. Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv. Drug Deliv. Rev. 56(8), 1067–1084 (2004).
    • 34 Salazar MD, Ratnam M. The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer Metastasis Rev. 26(1), 141–152 (2007).
    • 35 Ledermann JA, Canevari S, Thigpen T. Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments. Ann. Oncol. 26(10), 2034–2043 (2015).
    • 36 Kalli KR, Oberg AL, Keeney GL et al. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol. Oncol. 108(3), 619–626 (2008).
    • 37 Vergote IB, Marth C, Coleman RL. Role of the folate receptor in ovarian cancer treatment: evidence, mechanism, and clinical implications. Cancer Metastasis Rev. 34(1), 41–52 (2015). • Summarizes the role of folate receptor in ovarian cancer, and provides a rationale for targeting this receptor in the development of new therapeutic agents.
    • 38 Markert S, Lassmann S, Gabriel B et al. Alpha-folate receptor expression in epithelial ovarian carcinoma and non-neoplastic ovarian tissue. Anticancer Res. 28(6A), 3567–3572 (2008).
    • 39 O'shannessy DJ, Somers EB, Smale R, Fu YS. Expression of folate receptor-alpha (FRA) in gynecologic malignancies and its relationship to the tumor type. Int. J. Gynecol. Pathol. 32(3), 258–268 (2013).
    • 40 Chen YL, Chang MC, Huang CY et al. Serous ovarian carcinoma patients with high alpha-folate receptor had reducing survival and cytotoxic chemo-response. Mol. Oncol. 6(3), 360–369 (2012).
    • 41 Toffoli G, Russo A, Gallo A et al. Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer. Int. J. Cancer 79(2), 121–126 (1998).
    • 42 Marchetti C, Palaia I, Giorgini M et al. Targeted drug delivery via folate receptors in recurrent ovarian cancer: a review. Onco. Targets Ther. 7, 1223–1236 (2014).
    • 43 Spannuth WA, Sood AK, Coleman RL. Farletuzumab in epithelial ovarian carcinoma. Expert Opin. Biol. Ther. 10(3), 431–437 (2010).
    • 44 Gokhale M, Thakur A, Rinaldi F. Degradation of BMS-753493, a novel epothilone folate conjugate anticancer agent. Drug Dev. Ind. Pharm. 39(9), 1315–1327 (2013).
    • 45 Ambrosio AJ, Suzin D, Palmer EL, Penson RT. Vintafolide (EC145) for the treatment of folate-receptor-alpha positive platinum-resistant ovarian cancer. Expert Rev. Clin. Pharmacol. 7(4), 443–450 (2014).
    • 46 Lutz RJ. Targeting the folate receptor for the treatment of ovarian cancer. Transl. Cancer Res. 4(1), 118–126 (2015).
    • 47 Vergote I, Armstrong D, Scambia G et al. A randomized, double-blind, placebo-controlled, Phase III study to assess efficacy and safety of weekly farletuzumab in combination with carboplatin and taxane in patients with ovarian cancer in first platinum-sensitive relapse. J. Clin. Oncol. 34(19), 2271–2278 (2016).
    • 48 Merck and Endocyte announce independent DSMB recommends vintafolide proceed Phase III trial be stopped for futility following interim analysis (2014). http://investor.endocyte.com/releasedetail.cfm?releaseid=844838.
    • 49 Naumann RW, Coleman RL, Burger RA 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. 31(35), 4400–4406 (2013).
    • 50 Kline JB, Kennedy RP, Albone E et al. Tumor antigen CA125 suppresses antibody-dependent cellular cytotoxicity (ADCC) via direct antibody binding and suppressed Fc-gamma receptor engagement. Oncotarget 8(32), 52045–52060 (2017).
    • 51 Chari RV, Miller ML, Widdison WC. Antibody–drug conjugates: an emerging concept in cancer therapy. Angew. Chem. Int. Ed. Engl. 53(15), 3796–3827 (2014).
    • 52 Parslow AC, Parakh S, Lee FT, Gan HK, Scott AM. Antibody–drug conjugates for cancer therapy. Biomedicines 4(3), 14 (2016).
    • 53 Thomas A, Teicher BA, Hassan R. Antibody–drug conjugates for cancer therapy. Lancet Oncol. 17(6), e254–e262 (2016).
    • 54 Lambert JM, Morris CQ. Antibody–drug conjugates (ADCs) for personalized treatment of solid tumors: a review. Adv. Ther. 34(5), 1015–1035 (2017). • Provides a comprehensive review of the current status of antibody–drug conjugates undergoing advanced clinical testing, with emphasis on solid tumors.
    • 55 Lambert JM. Drug-conjugated antibodies for the treatment of cancer. Br. J. Clin. Pharmacol. 76(2), 248–262 (2013).
    • 56 Lutz RJ. Targeting the folate receptor for the treatment of ovarian cancer. Transl. Cancer Res. 4, 118–126 (2015).
    • 57 Oroudjev E, Lopus M, Wilson L et al. Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol. Cancer Ther. 9(10), 2700–2713 (2010).
    • 58 Goldmacher VS, Audette CA, Guan Y et al. High-affinity accumulation of a maytansinoid in cells via weak tubulin interaction. PLoS ONE 10(2), e0117523 (2015).
    • 59 Ab O, Whiteman KR, Bartle LM et al. 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 (2015). • Preclinical development and characterization of mirvetuximab soravtansine.
    • 60 Erickson HK, Park PU, Widdison WC et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 66(8), 4426–4433 (2006).
    • 61 Kovtun YV, Audette CA, Ye Y et al. Antibody–drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 66(6), 3214–3221 (2006).
    • 62 Drewinko B, Patchen M, Yang LY, Barlogie B. Differential killing efficacy of twenty antitumor drugs on proliferating and nonproliferating human tumor cells. Cancer Res. 41(6), 2328–2333 (1981).
    • 63 Gunderson CC, Moore KN. Mirvetuximab soravtansine. FRα-targeting ADC, treatment of epithelial ovarian cancer. Drugs of the Future 41(9), 539–545 (2016).
    • 64 Moore KN, Borghaei H, O'malley DM et al. 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 (2017).
    • 65 Konner JA, Bell-Mcguinn KM, Sabbatini P et al. Farletuzumab, a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian cancer: a Phase I study. Clin. Cancer. Res. 16(21), 5288–5295 (2010).
    • 66 Sasaki Y, Miwa K, Yamashita K et al. A Phase I study of farletuzumab, a humanized anti-folate receptor alpha monoclonal antibody, in patients with solid tumors. Invest. New Drugs 33(2), 332–340 (2015).
    • 67 Gomez-Roca CA, Boni V, Moreno V et al. A Phase I study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs) (NCT01156870). J. Clin. Oncol. 34(Suppl.), Abstract 2511 (2016).
    • 68 Parslow AC, Parakh S, Lee F, Gan HK, Scott AM. Antibody–drug conjugates for cancer therapy. Biomedicines 4(3), 14 (2016).
    • 69 Eaton JS, Miller PE, Mannis MJ, Murphy CJ. Ocular adverse events associated with antibody–drug conjugates in human clinical trials. J. Ocul. Pharmacol. Ther. 31(10), 589–604 (2015).
    • 70 Sega EI, Low PS. Tumor detection using folate receptor-targeted imaging agents. Cancer Metastasis Rev. 27(4), 655–664 (2008).
    • 71 Despierre E, Lambrechts S, Leunen K et al. Folate receptor alpha (FRA) expression remains unchanged in epithelial ovarian and endometrial cancer after chemotherapy. Gynecol. Oncol. 130(1), 192–199 (2013).
    • 72 Rubinsak LA, Cohen C, Khanna N, Horowitz IR, Hanley KZ. Folate receptor alpha expression in platinum resistant/refractory ovarian carcinomas and primary endocervical adenocarcinomas. Appl. Immunohistochem. Mol. Morphol. doi:10.1097/PAI.0000000000000476 (2016) (Epub ahead of print).
    • 73 Martin LP, Konner J, Moore KN et al. Characterization of folate receptor alpha (FRα) expression in archival tumor and biopsy samples in a Phase I study of mirvetuximab soravtansine, a FRα-targeting antibody–drug conjugate (ADC), in relapsed epithelial ovarian cancer patients. Gynecol. Oncol. 145, 34 (2017).
    • 74 Moore KN, Martin LP, O'malley DM 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. 35(10), 1112–1118 (2017). •• Data from a Phase I expansion cohort study indicating that mirvetuximab soravtansine is clinically active in patients with platinum-resistant epithelial ovarian cancer.
    • 75 Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized Phase III study of pegylated liposomal doxorubicin versus topotecan. J. Clin. Oncol. 19(14), 3312–3322 (2001).
    • 76 Ferrandina G, Ludovisi M, Lorusso D et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J. Clin. Oncol. 26(6), 890–896 (2008).
    • 77 Pujade-Lauraine E, Hilpert F, Weber B et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized Phase III trial. J. Clin. Oncol. 32(13), 1302–1308 (2014). •• Results of a pivotal Phase III trial that resulted in approval of bevacizumab for the treatment of ovarian cancer.
    • 78 Moore KN, Matulonis UA, O'malley DM et al. Mirvetuximab soravtansine (IMGN853), a folate alpha (FRα)-targeting antibody–drug conjugate (ADC), in platinum-resistant epithelial ovarian caner (EOC) patients (pts): Activity and safety analyses in Phase I pooled expansion cohorts. J. Clin. Oncol. 35(Suppl.), Abstract 5547 (2017).
    • 79 Ponte JF, Ab O, Lanieri L et al. Mirvetuximab soravtansine (IMGN853), a folate receptor alpha-targeting antibody–drug conjugate, potentiates the activity of standard of care therapeutics in ovarian cancer models. Neoplasia 18(12), 775–784 (2016). • Preclinical studies demonstrating combinatorial benefit conferred by the addition of mirvetuximab soravtansine to established therapeutic agents used in the treatment of epithelial ovarian cancer.
    • 80 Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706), 58–62 (2005).
    • 81 Arjaans M, Schroder CP, Oosting SF, Dafni U, Kleibeuker JE, De Vries EG. VEGF pathway targeting agents, vessel normalization and tumor drug uptake: from bench to bedside. Oncotarget 7(16), 21247–21258 (2016).
    • 82 O'malley DM, Moore KN, Vergote I et al. Safety findings from FORWARD II: a Phase Ib study evaluating the folate recepotr alpha (FRα)-targeting antibody–drug conjugate (ADC) mirvetuximab soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin (PLD), or pembrolizumab in patients (pts) with ovarian cancer. J. Clin. Oncol. 35(Suppl.), Abstract 5553 (2017).
    • 83 Ye H, Karim AA, Loh XJ. Current treatment options and drug delivery systems as potential therapeutic agents for ovarian cancer: a review. Mater. Sci. Eng. C Mater. Biol. Appl. 45, 609–619 (2014).
    • 84 Garon EB, Rizvi NA, Hui R et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372(21), 2018–2028 (2015).
    • 85 Weiss L, Huemer F, Mlineritsch B, Greil R. Immune checkpoint blockade in ovarian cancer. Memo 9, 82–84 (2016).
    • 86 Mittica G, Genta S, Aglietta M, Valabrega G. Immune checkpoint inhibitors: a new opportunity in the treatment of ovarian cancer? Int. J. Mol. Sci. 17(7), pii:E1169 (2016).
    • 87 Varga A, Piha-Paul SA, Ott PA et al. Pembrolizumab in patients (pts) with PD-L1–positive (PD-L1+) advanced ovarian cancer: updated analysis of KEYNOTE-028. J. Clin. Oncol. 35(15 Suppl.), 5513–5513 (2017).
    • 88 Skaletskaya A, Ponte JF, Chittenden T, Setiady J. Treatment of tumor cells with mirvetuximab soravtansine, a FRα-targeting antibody–drug conjugate (ADC), activates monocytes through Fc-FcgR interaction and immunogenic cell death. J. ImmunoTher. Cancer 4(Suppl. 1), 73 (2016).
    • 89 Muller P, Kreuzaler M, Khan T et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci. Transl. Med. 7(315), 315ra188 (2015).