Advertisement

Breast Cancer Research and Treatment

, Volume 165, Issue 3, pp 601–609 | Cite as

A randomized phase II trial of ridaforolimus, dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients with advanced breast cancer

  • Hope S. RugoEmail author
  • Olivier Trédan
  • Jungsil Ro
  • Serafin M. Morales
  • Mario Campone
  • Antonino Musolino
  • Noémia Afonso
  • Marta Ferreira
  • Kyong Hwa Park
  • Javier Cortes
  • Antoinette R. Tan
  • Joanne L. Blum
  • Lamar Eaton
  • Christine K. Gause
  • Zhen Wang
  • Ellie Im
  • David J. Mauro
  • Mary Beth Jones
  • Andrew Denker
  • José Baselga
Clinical trial

Abstract

Purpose

To evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor (ridaforolimus) plus aromatase inhibitor (exemestane) improves outcomes in patients with estrogen receptor (ER)-positive advanced/metastatic breast cancer.

Methods

This randomized, open-label, phase II trial enrolled 80 postmenopausal women with high-proliferation (Ki67 index staining ≥15%), ER-positive breast cancer that progressed after a non-steroidal aromatase inhibitor (NCT01605396). Randomly assigned patients were given oral ridaforolimus 10 mg QD 5 ×/week, intravenous dalotuzumab 10 mg/kg/week, and oral exemestane 25 mg/day (R/D/E, n = 40), or ridaforolimus 30 mg QD 5 ×/week and exemestane 25 mg/day (R/E; n = 40). Primary end point was progression-free survival (PFS).

Results

Median PFS was 23.3 weeks for R/D/E versus 31.9 weeks for R/E (hazard ratio 1.18; 80% CI 0.81–1.72; P = 0.565). Grade 3–5 adverse events were reported in 67.5% of patients in the R/E arm and 59.0% in the R/D/E arm. Stomatitis (95.0 vs. 76.9%; P = 0.021) and pneumonitis (22.5 vs. 5.1%; P = 0.027) occurred more frequently in the R/E than the R/D/E arm; hyperglycemia (27.5 vs. 28.2%) occurred at a similar rate.

Conclusions

R/D/E did not improve PFS compared with R/E. Because the PFS reported for R/E was similar to that reported for everolimus plus exemestane in patients with advanced breast cancer, it is possible that lower-dose ridaforolimus in the R/D/E arm (from overlapping toxicities with IGF1R inhibitor) contributed to lack of improved PFS.

Keywords

Breast cancer Ridaforolimus mTOR Dalotuzumab IGF1R Exemestane 

Notes

Acknowledgements

We thank the patients and their families for their participation and support during the study as well as the study center staff and principal investigators. Editorial support was provided by Tim Ibbotson, PhD, of ApotheCom and was funded by Merck & Co., Inc., Kenilworth, NJ.

Funding

This work was supported by a grant from Merck & Co., Inc.

Conflicts of interest

JC has received fees for lectures and consulting from Roche, Celgene, Novartis, and Eisai. HSR has received research support from Merck & Co., Inc. and Novartis. ART received grants from Merck & Co., Inc. for conducting this study. AD, CKG, EI, MBJ, DJM, and ZW are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ and may hold stock or stock options in the company. MF has received grants from Merck Sharp & Dohme Corp. and AstraZeneca, grants and non-financial support from Novartis, and F. Hoffmann-La Roche, and non-financial support from Merck Sharp & Dohme Corp. NA, JB, JLB, MC, LE, AM, JR, SMM, OT, and KHP have nothing to disclose.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Independent ethics committees reviewed and approved the protocol and applicable amendments for each institution.

Informed consent

Written informed consent was obtained from all participants.

References

  1. 1.
    Johnston SR (2006) Clinical efforts to combine endocrine agents with targeted therapies against epidermal growth factor receptor/human epidermal growth factor receptor 2 and mammalian target of rapamycin in breast cancer. Clin Cancer Res 12:1061s–1068sCrossRefGoogle Scholar
  2. 2.
    Burstein HJ (2011) Novel agents and future directions for refractory breast cancer. Semin Oncol 38(suppl 2):S17–S24CrossRefGoogle Scholar
  3. 3.
    Quek R, Wang Q, Morgan JA et al (2011) Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors. Clin Cancer Res 17:871–879CrossRefGoogle Scholar
  4. 4.
    Di Cosimo S, Sathyanarayanan S, Bendell JC et al (2015) Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical trial. Clin Cancer Res 21:49–59CrossRefGoogle Scholar
  5. 5.
    Elit L (2006) Drug evaluation: aP-23573—an mTOR inhibitor for the treatment of cancer. IDrugs 9:636–644PubMedGoogle Scholar
  6. 6.
    Rivera VM, Squillace RM, Miller D et al (2011) Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Mol Cancer Ther 10:1059–1071CrossRefGoogle Scholar
  7. 7.
    Sun SY, Rosenberg LM, Wang X et al (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65:7052–7058CrossRefGoogle Scholar
  8. 8.
    Baselga J, Semiglazov V, van Dam P et al (2009) Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27:2630–2637CrossRefGoogle Scholar
  9. 9.
    Kurmasheva RT, Dudkin L, Billups C, Debelenko LV, Morton CL, Houghton PJ (2009) The insulin-like growth factor-1 receptor-targeting antibody, CP-751,871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma. Cancer Res 69:7662–7671CrossRefGoogle Scholar
  10. 10.
    Broussas M, Dupont J, Gonzalez A et al (2009) Molecular mechanisms involved in activity of h7C10, a humanized monoclonal antibody, to IGF-1 receptor. Int J Cancer 124:2281–2293CrossRefGoogle Scholar
  11. 11.
    O’Reilly KE, Rojo F, She QB et al (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508CrossRefGoogle Scholar
  12. 12.
    Baselga J, Morales SM, Awada A et al (2013) A phase 2 study of ridaforolimus (RIDA) and dalotuzumab (DALO) in estrogen receptor positive (ER+) breast cancer [Abstract]. Cancer Res 73(24):TPS110Google Scholar
  13. 13.
    Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefGoogle Scholar
  14. 14.
    Ellis PM, Shepherd FA, Laurie SA et al (2014) NCIC CTG IND.190 phase I trial of dalotuzumab (MK-0646) in combination with cisplatin and etoposide in extensive-stage small-cell lung cancer. J Thorac Oncol 9:410–413CrossRefGoogle Scholar
  15. 15.
    Fierz Y, Novosyadlyy R, Vijayakumar A, Yakar S, LeRoith D (2010) Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes. Endocr Rel Cancer 17:941–951CrossRefGoogle Scholar
  16. 16.
    Ray-Coquard I, Haluska P, O’Reilly S et al (2013) A multicenter open-label phase II study of the efficacy and safety of ganitumab (AMG 479), a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R) as second-line therapy in patients with recurrent platinum-sensitive ovarian cancer. J Clin Oncol 31:5515Google Scholar
  17. 17.
    Ryan PD, Neven P, Dirix LY et al (2016) Safety of the anti-IGF-1R antibody CP-751,871 in combination with exemestane in patients with advanced breast cancer. Cancer Res 69(2):2136Google Scholar
  18. 18.
    Okusaka T, Ikeda M, Fukutomi A et al (2014) Safety, tolerability, pharmacokinetics and antitumor activity of ganitumab, an investigational fully human monoclonal antibody to insulin-like growth factor type 1 receptor, combined with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer: a phase 1b study. Jpn J Clin Oncol 44:442–447CrossRefGoogle Scholar
  19. 19.
    Miettinen O, Nurminen M (1985) Comparative analysis of two rates. Stat Med 4:213–226CrossRefGoogle Scholar
  20. 20.
    Haluska P, Shaw HM, Batzel GN et al (2007) Phase I dose escalation study of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors. Clin Cancer Res 13:5834–5840CrossRefGoogle Scholar
  21. 21.
    Yee D, Paoloni M, Van’t Veer L et al (2016) The evaluation of ganitumab/metformin plus standard neoadjuvant therapy in high-risk breast cancer: results from the I-SPY 2 trial. Presented at: San Antonio Breast Cancer Symposium; December 6–10, 2016; San Antonio, TX. Abstract P6-11-04Google Scholar
  22. 22.
    Gradishar WJ, Yardley DA, Layman R et al (2016) Clinical and translational results of a phase II, randomized trial of an anti-IGF-1R (cixutumumab) in women with breast cancer that progressed on endocrine therapy. Clin Cancer Res 22:301–309CrossRefGoogle Scholar
  23. 23.
    Yardley DA, Noguchi S, Pritchard KI et al (2013) Everolimus plus exemestane in postmenopausal patients with HR breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther 30:870–884CrossRefGoogle Scholar
  24. 24.
    National Comprehensive Cancer Network, Inc (2014) NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. version 1. 2014. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed 22 Nov 2016
  25. 25.
    Boers-Doets CB, Raber-Durlacher JE, Treister NS et al (2013) Mammalian target of rapamycin inhibitor-associated stomatitis. Future Oncol 9:1883–1892CrossRefGoogle Scholar
  26. 26.
    Martins F, de Oliveira MA, Wang Q et al (2013) A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients. Oral Oncol 49:293–298CrossRefGoogle Scholar
  27. 27.
    Pilotte AP, Hohos MB, Polson KM, Huftale TMn, Treister N (2011) Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors. Clin J Oncol Nurs 15:E83–E89CrossRefGoogle Scholar
  28. 28.
    Baselga J, Campone M, Piccart M et al (2012) Everolimus in postmenopausal hormone receptor-positive advanced breast cancer. N Engl J Med 366:520–529CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Hope S. Rugo
    • 1
    Email author
  • Olivier Trédan
    • 2
  • Jungsil Ro
    • 3
  • Serafin M. Morales
    • 4
  • Mario Campone
    • 5
  • Antonino Musolino
    • 6
  • Noémia Afonso
    • 7
  • Marta Ferreira
    • 7
  • Kyong Hwa Park
    • 8
  • Javier Cortes
    • 9
  • Antoinette R. Tan
    • 10
    • 15
  • Joanne L. Blum
    • 11
  • Lamar Eaton
    • 12
  • Christine K. Gause
    • 12
  • Zhen Wang
    • 12
  • Ellie Im
    • 12
  • David J. Mauro
    • 12
  • Mary Beth Jones
    • 12
    • 16
  • Andrew Denker
    • 12
    • 13
  • José Baselga
    • 14
  1. 1.UCSF Helen, Diller Family Comprehensive Cancer CenterSan FranciscoUSA
  2. 2.Centre Léon BérardLyonFrance
  3. 3.National Cancer CenterGoyangRepublic of Korea
  4. 4.H. de Lleida Arnau de VilanovaLeridaSpain
  5. 5.Institut de Cancérologie de l’OuestSt Herblain-NantesFrance
  6. 6.University Hospital of ParmaParmaItaly
  7. 7.Instituto Português de Oncologia Francisco GentilPortoPortugal
  8. 8.Korea University Medical CenterSeoulRepublic of Korea
  9. 9.Ramón y Cajal University HospitalMadrid and Vall d´Hebron Institute of Oncology (VHIO)BarcelonaSpain
  10. 10.Rutgers Cancer Institute of New JerseyNew BrunswickUSA
  11. 11.Baylor Sammons Cancer CenterTexas Oncology, US OncologyDallasUSA
  12. 12.Merck& Co., Inc.KenilworthUSA
  13. 13.Alexion PharmaceuticalsNew HavenUSA
  14. 14.Memorial Sloan Kettering Cancer CenterNew YorkUSA
  15. 15.Levine Cancer InstituteCarolinas HealthCare SystemCharlotteUSA
  16. 16.Checkmate PharmaceuticalsCambridgeUSA

Personalised recommendations