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A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer

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Abstract

Purpose

Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%).

Methods

This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] × 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus–dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd × 5 days/week. The primary endpoint was progression-free survival (PFS).

Results

Median PFS was 21.4 weeks for ridaforolimus 30 mg qd × 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy.

Conclusions

The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.

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Acknowledgements

Medical writing and editorial assistance was provided by Tim Ibbotson, PhD, of ApotheCom (Yardley, Pennsylvania, USA), with funding provided by Merck & Co., Inc., Kenilworth, New Jersey, USA.

Funding

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

Author information

Author notes

  1. Antoinette R. Tan

    Present address: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA

Authors and Affiliations

  1. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    José Baselga

  2. H. de Lleida Arnau de Vilanova, Lérida, Spain

    Serafin M. Morales

  3. Institut Jules Bordet, Brussels, Belgium

    Ahmad Awada

  4. Baylor Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX, USA

    Joanne L. Blum

  5. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Antoinette R. Tan

  6. Institute of Clinical Research, Odense University Hospital, University of Southern Denmark, Odense, Denmark

    Marianne Ewertz

  7. Ramon y Cajal University Hospital, Madrid and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

    Javier Cortes

  8. Massachusetts General Hospital, Boston, MA, USA

    Beverly Moy

  9. Mayo Clinic, Rochester, MN, USA

    Kathryn J. Ruddy

  10. University of Minnesota Masonic Clinical Cancer Center, Minneapolis, MN, USA

    Tufia Haddad

  11. Hospital 12 de Octubre, Madrid, Spain

    Eva M. Ciruelos

  12. Clinique Sainte Elisabeth, Namur, Belgium

    Peter Vuylsteke

  13. Merck & Co., Inc., Kenilworth, NJ, USA

    Scot Ebbinghaus, Ellie Im, Lamar Eaton, Kumudu Pathiraja, Christine Gause, David Mauro & Mary Beth Jones

  14. UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero St., San Francisco, CA, USA

    Hope S. Rugo

  15. Checkmate Pharmaceuticals, Cambridge, MA, USA

    David Mauro

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  1. José Baselga
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Corresponding author

Correspondence to Hope S. Rugo.

Ethics declarations

Informed consent

Written informed consent was obtained from all participants. 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.

Conflict of interest

AA has served on advisory boards for Bayer, Roche, and Lilly. JC has received personal fees for lectures and consulting from Roche, Celgene, Novartis, and Eisai. ME and ART received grants from Merck & Co., Inc., for the conduct of this study. HSR has received research support from Merck & Co., Inc., and Novartis. SE, CG, EI, MBJ, DM, and KP are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and may hold stock or stock options in the company. The other authors have nothing to disclose.

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Baselga, J., Morales, S.M., Awada, A. et al. A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer. Breast Cancer Res Treat 163, 535–544 (2017). https://doi.org/10.1007/s10549-017-4199-3

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  • DOI: https://doi.org/10.1007/s10549-017-4199-3

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