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

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.

Keywords: Breast cancer; Dalotuzumab; IGF1R; Ridaforolimus; mTOR.

Conflict of interest statement

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.

Figures

Fig. 1

Kaplan-Meier estimate of progression-free survival by central radiologic review for the randomized arms of the study, ridaforolimus 30 mg qd × 5/week + dalotuzumab (n = 29) versus exemestane (n = 33) (a), and all 3 ridaforolimus + dalotuzumab dosing cohorts and exemestane (b)

Fig. 2. Overall survival for randomized population, ridaforolimus 30 mg + Dalotuzumab (n = 29) versus exemestane (n = 33)