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 dalo-tuzumab 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.

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…In a phase II study of temsirolimus with bevacizumab for patients with metastatic renal cell carcinoma previously treated with other VEGFR TKI, the combination treatment resulted in modest activity and dose reductions were needed due to toxicity [250]. Another phase II study of lower dose ridaforolimus with dalotuzumab, which inhibits autophosphorylation of IGF1R in ER+ advanced breast cancer had similar efficacy but with higher incidence of adverse events compared to treatment with the aromatase inhibitor, exemestane [251]. However, the combination of cixutumumab, an anti-IGF-1R antibody, with temsirolimus did not show objective responses in pediatric and young adults with refractory or recurrent sarcoma [252].…”

PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom

“…Basing on this evidence, 2 randomized phase II trials have evaluated the activity and efficacy of the potent mTOR inhibitor ridaforolimus, in combination with the anti-IGF1R dalotuzumab in patients with luminal MBC progressing after NSAIs [16,17]. Both trials were negative, showing neither survival improvement nor differences in response rate.…”

“…Both trials were negative, showing neither survival improvement nor differences in response rate. Furthermore, the association of dalotuzumab with ridaforolimus was always associated with high rates of adverse events [16,17].…”

A unifying biology of sex steroid-induced apoptosis in prostate and breast cancers

“…everolimus, temsirolimus, deforolimus) show promise in the ER-positive and/or HER2-positive breast cancer ( Fasolo & Sessa 2008 , Vicier et al . 2014 , Baselga et al . 2017 ).…”