Skip to main content

Advertisement

SpringerLink
Log in

A phase II trial of trabectedin in triple-negative and HER2-overexpressing metastatic breast cancer

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Trabectedin is an alkylating agent that binds to the minor groove of DNA. Early studies with trabectedin suggested efficacy in triple-negative and HER2-overexpressing metastatic breast cancer (MBC). The efficacy and safety of trabectedin in pretreated patients with these tumors were evaluated in this parallel-cohort phase II trial. Patients received a 3-h infusion of trabectedin 1.3 mg/m2 intravenously every 3 weeks until progression or unmanageable/unacceptable toxicity. The primary objective was to evaluate the efficacy using the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives comprised time-to-event endpoints and safety assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. Patients with heavily pretreated triple-negative (n = 50) or HER2-overexpressing (n = 37) MBC were enrolled. No confirmed responses were found in triple-negative MBC patients, with median progression-free survival (PFS) of 2.2 months (95 % CI 1.3–2.7 months). Confirmed partial responses occurred in 4 of 34 evaluable HER2-overexpressing MBC patients (ORR = 12 %; 95 % CI 3–27 %) and lasted a median of 12.5 months (95 % CI, 6.2–14.7 months); median PFS was 3.8 months (95 % CI, 1.8–5.5 months). Most trabectedin-related adverse events were mild or moderate, and the most frequent were fatigue, nausea, vomiting, constipation, and anorexia. Severe neutropenia and transaminase increases were non-cumulative and transient and were mostly managed by infusion delays or dose reductions. Single-agent trabectedin is well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Further studies are warranted to evaluate trabectedin combined with HER2-targeted treatments in this subtype.

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. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093

    Article  CAS  PubMed  Google Scholar 

  2. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874. doi:10.1073/pnas.191367098

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Aristei C, Leonardi C, Stracci F, Palumbo I, Luini A, Viale G, Cristallini EG, Cavaliere A, Orecchia R (2011) Risk factors for relapse after conservative treatment in T1–T2 breast cancer with one to three positive axillary nodes: results of an observational study. Ann Oncol 22(4):842–847. doi:10.1093/annonc/mdq470

    Article  CAS  PubMed  Google Scholar 

  4. Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, Symmans WF, Pusztai L, Bloom KJ (2003) The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 8(4):307–325

    Article  CAS  PubMed  Google Scholar 

  5. Kast K, Link T, Friedrich K, Petzold A, Niedostatek A, Schoffer O, Werner C, Klug SJ, Werner A, Gatzweiler A, Richter B, Baretton G, Wimberger P (2015) Impact of breast cancer subtypes and patterns of metastasis on outcome. Breast Cancer Res Treat 150(3):621–629. doi:10.1007/s10549-015-3341-3

    Article  CAS  PubMed  Google Scholar 

  6. Minuzzo M, Marchini S, Broggini M, Faircloth G, D’Incalci M, Mantovani R (2000) Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci USA 97(12):6780–6784

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Erba E, Bergamaschi D, Bassano L, Damia G, Ronzoni S, Faircloth GT, D’Incalci M (2001) Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. Eur J Cancer 37(1):97–105

    Article  CAS  PubMed  Google Scholar 

  8. Marco E, Garcia-Nieto R, Mendieta J, Manzanares I, Cuevas C, Gago F (2002) A 3. (ET743)-DNA complex that both resembles an RNA-DNA hybrid and mimicks zinc finger-induced DNA structural distortions. J Med Chem 45(4):871–880

    Article  CAS  PubMed  Google Scholar 

  9. D’Incalci M, Zambelli A (2015) Trabectedin for the treatment of breast cancer. Expert Opin Investig Drugs (in press)

  10. Zelek L, Yovine A, Brain E, Turpin F, Taamma A, Riofrio M, Spielmann M, Jimeno J, Misset JL (2006) A phase II study of Yondelis (trabectedin, ET-743) as a 24-h continuous intravenous infusion in pretreated advanced breast cancer. Br J Cancer 94(11):1610–1614

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Goldstein LJ, Gurtler J, Del Prete SA, Tjulandin S, Semiglazov VF, Bayever E, Michiels B (2014) Trabectedin as a single-agent treatment of advanced breast cancer after anthracycline and taxane treatment: a multicenter, randomized, phase II study comparing 2 administration regimens. Clin Breast Cancer 14(6):396–404. doi:10.1016/j.clbc.2014.06.006

    Article  CAS  PubMed  Google Scholar 

  12. Takebayashi Y, Pourquier P, Zimonjic DB, Nakayama K, Emmert S, Ueda T, Urasaki Y, Kanzaki A, Akiyama SI, Popescu N, Kraemer KH, Pommier Y (2001) Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 7(8):961–966

    Article  CAS  PubMed  Google Scholar 

  13. Damia G, Silvestri S, Carrassa L, Filiberti L, Faircloth GT, Liberi G, Foiani M, D’Incalci M (2001) Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int J Cancer 92(4):583–588

    Article  CAS  PubMed  Google Scholar 

  14. Schöffski P, Casali PG, Taron M, van Oosterom AT, Judson I, Grosso F, Blay JY, Maki B, Tercero JC, Jimeno J, Rosell R (2006) DNA repair functionality appears to modulate the clinical outcome of advanced sarcoma patients treated with Yondelis (ET-743). J Clin Oncol 24(18S):9522

    Google Scholar 

  15. Delaloge S, Wolp-Diniz R, Byrski T, Blum JL, Goncalves A, Campone M, Lardelli P, Kahatt C, Nieto A, Cullell-Young M, Lubinski J (2014) Activity of trabectedin in germline BRCA1/2-mutated metastatic breast cancer: results of an international first-in-class phase II study. Ann Oncol 25(6):1152–1158. doi:10.1093/annonc/mdu134

    Article  CAS  PubMed  Google Scholar 

  16. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  CAS  PubMed  Google Scholar 

  17. O’Brien PC, Fleming TR (1979) A multiple testing procedure for clinical trials. Biometrics 35(3):549–556

    Article  PubMed  Google Scholar 

  18. Lan KKG, DeMets DL (1983) Discrete sequential boundaries for clinical trials. Biometrika 70(3):659–663

    Article  Google Scholar 

  19. 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. doi:10.1002/cncr.22618

    Article  PubMed  Google Scholar 

  20. Lin NU, Vanderplas A, Hughes ME, Theriault RL, Edge SB, Wong YN, Blayney DW, Niland JC, Winer EP, Weeks JC (2012) Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. Cancer 118(22):5463–5472. doi:10.1002/cncr.27581

    Article  PubMed Central  PubMed  Google Scholar 

  21. Gabos Z, Thoms J, Ghosh S, Hanson J, Deschenes J, Sabri S, Abdulkarim B (2010) The association between biological subtype and locoregional recurrence in newly diagnosed breast cancer. Breast Cancer Res Treat 124(1):187–194. doi:10.1007/s10549-010-1135-1

    Article  PubMed  Google Scholar 

  22. Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA (2009) Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat 115(2):423–428. doi:10.1007/s10549-008-0086-2

    Article  PubMed  Google Scholar 

  23. O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, Koo IC, Sherman BM, Bradley C (2011) Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364(3):205–214. doi:10.1056/NEJMoa1011418

    Article  PubMed  Google Scholar 

  24. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792. doi:10.1056/NEJM200103153441101

    Article  CAS  PubMed  Google Scholar 

  25. Olson EM, Najita JS, Sohl J, Arnaout A, Burstein HJ, Winer EP, Lin NU (2013) Clinical outcomes and treatment practice patterns of patients with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast 22(4):525–531. doi:10.1016/j.breast.2012.12.006

    Article  PubMed Central  PubMed  Google Scholar 

  26. Lowery AJ, Kell MR, Glynn RW, Kerin MJ, Sweeney KJ (2012) Locoregional recurrence after breast cancer surgery: a systematic review by receptor phenotype. Breast Cancer Res Treat 133(3):831–841. doi:10.1007/s10549-011-1891-6

    Article  PubMed  Google Scholar 

  27. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J, Group CS (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372(8):724–734. doi:10.1056/NEJMoa1413513

    Article  CAS  PubMed  Google Scholar 

  28. Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J (2015) Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 33(6):594–601. doi:10.1200/JCO.2013.52.4892

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743. doi:10.1056/NEJMoa064320

    Article  CAS  PubMed  Google Scholar 

  30. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S (2009) Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03–05 study. J Clin Oncol 27(12):1999–2006. doi:10.1200/JCO.2008.19.6618

    Article  Google Scholar 

  31. Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O’Shaughnessy J (2012) Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol 30(21):2585–2592. doi:10.1200/JCO.2011.35.6725

    Article  CAS  PubMed  Google Scholar 

  32. Demetri GD, Chawla SP, von Mehren M, Ritch P, Baker LH, Blay JY, Hande KR, Keohan ML, Samuels BL, Schuetze S, Lebedinsky C, Elsayed YA, Izquierdo MA, Gomez J, Park YC, Le Cesne A (2009) Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol 27(25):4188–4196

    Article  CAS  PubMed  Google Scholar 

  33. Schoffski P, Dumez H, Wolter P, Stefan C, Wozniak A, Jimeno J, Van Oosterom AT (2008) Clinical impact of trabectedin (ecteinascidin-743) in advanced/metastatic soft tissue sarcoma. Expert Opin Pharmacother 9(9):1609–1618. doi:10.1517/14656566.9.9.1609

    Article  PubMed  Google Scholar 

  34. Garcia-Carbonero R, Supko JG, Maki RG, Manola J, Ryan DP, Harmon D, Puchalski TA, Goss G, Seiden MV, Waxman A, Quigley MT, Lopez T, Sancho MA, Jimeno J, Guzman C, Demetri GD (2005) Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study. J Clin Oncol 23(24):5484–5492

    Article  CAS  PubMed  Google Scholar 

  35. Michaelson MD, Bellmunt J, Hudes GR, Goel S, Lee RJ, Kantoff PW, Stein CA, Lardelli P, Pardos I, Kahatt C, Nieto A, Cullell-Young M, Lewis NL, Smith MR (2012) Multicenter phase II study of trabectedin in patients with metastatic castration-resistant prostate cancer. Ann Oncol 23(5):1234–1240. doi:10.1093/annonc/mdr399

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Massuti B, Cobo M, Camps C, Domine M, Provencio M, Alberola V, Vinolas N, Rosell R, Taron M, Gutierrez-Calderon V, Lardelli P, Alfaro V, Nieto A, Isla D (2012) Trabectedin in patients with advanced non-small-cell lung cancer (NSCLC) with XPG and/or ERCC1 overexpression and BRCA1 underexpression and pretreated with platinum. Lung Cancer 76(3):354–361. doi:10.1016/j.lungcan.2011.12.002

    Article  PubMed  Google Scholar 

  37. Gronchi A, Bui BN, Bonvalot S, Pilotti S, Ferrari S, Hohenberger P, Hohl RJ, Demetri GD, Le Cesne A, Lardelli P, Perez I, Nieto A, Tercero JC, Alfaro V, Tamborini E, Blay JY (2012) Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma. Ann Oncol 23(3):771–776. doi:10.1093/annonc/mdr265

    Article  CAS  PubMed  Google Scholar 

  38. Del Campo JM, Sessa C, Krasner CN, Vermorken JB, Colombo N, Kaye S, Gore M, Zintl P, Gomez J, Parekh T, Park YC, McMeekin S (2013) Trabectedin as single agent in relapsed advanced ovarian cancer: results from a retrospective pooled analysis of three phase II trials. Med Oncol 30(1):435. doi:10.1007/s12032-012-0435-1

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was sponsored by Pharma Mar, S.A.

Author information

Author notes

  1. Pierfranco Conte

    Present address: Istituto Oncologico Veneto, IRCCS, Università di Padova, Padua, Italy

Authors and Affiliations

  1. Baylor-Charles A. Sammons Cancer Center, Texas Oncology, US Oncology, 3410 Worth St., Suite 400, Dallas, TX, 75246, USA

    Joanne L. Blum

  2. Institut Paoli Calmettes, Marseille, France

    Anthony Gonçalves

  3. Kaplan Medical Center, Rehovot, Israel

    Noa Efrat

  4. Institute Bergonie, Bordeaux, France

    Marc Debled

  5. Azienda Ospedaliero, Università di Modena, Modena, Italy

    Pierfranco Conte

  6. Oncology/Hematology Associates of SW Virginia, US Oncology, Salem, VA, USA

    Paul D. Richards

  7. Texas Oncology - Tyler, US Oncology, Tyler, TX, USA

    Donald Richards

  8. Pharma Mar, S.A., Clinical R&D, Colmenar Viejo, Madrid, Spain

    Pilar Lardelli, Antonio Nieto & Martin Cullell-Young

  9. Gustave Roussy Cancer Campus, Villejuif, France

    Suzette Delaloge

Authors
  1. Joanne L. Blum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anthony Gonçalves
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noa Efrat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marc Debled
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pierfranco Conte
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul D. Richards
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Donald Richards
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pilar Lardelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Antonio Nieto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Martin Cullell-Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Suzette Delaloge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joanne L. Blum.

Ethics declarations

Conflict of interest

Pilar Lardelli, Antonio Nieto, and Martin Cullell-Young—remuneration and stock ownership (Pharma Mar, S.A.). All other authors declare that they have no conflict of interest.

Ethical approval

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blum, J.L., Gonçalves, A., Efrat, N. et al. A phase II trial of trabectedin in triple-negative and HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 155, 295–302 (2016). https://doi.org/10.1007/s10549-015-3675-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-015-3675-x

Keywords

Search

Navigation