A randomized phase II trial of ridaforolimus, dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients with advanced breast cancer
- 347 Downloads
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.
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).
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.
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.
KeywordsBreast cancer Ridaforolimus mTOR Dalotuzumab IGF1R Exemestane
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.
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.
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.
Written informed consent was obtained from all participants.
- 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
- 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.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.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
- 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
- 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