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

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; Dalotuzumab; Exemestane; IGF1R; Ridaforolimus; mTOR.

Conflict of interest statement

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.

Figures

Fig. 1

CONSORT diagram of patient disposition through the trial. Each patient was counted once based on the latest corresponding disposition record. Patients for whom a disposition record did not exist at the time of reporting were recorded as unknown. R/D/E, ridaforolimus 10 mg qd 5 ×/week, dalotuzumab 10 mg/kg/week, and exemestane 25 mg/day; R/E, ridaforolimus 30 mg qd 5 ×/week and exemestane 25 mg/day

Fig. 2

Kaplan–Meier plot of progression-free survival (PFS) by independent radiology review in the intent-to-treat primary analysis population for patients receiving either ridaforolimus/dalotuzumab/exemestane (R/D/E) or ridaforolimus/exemestane (R/E)