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.

Overcoming cancer therapeutic bottleneck by drug repurposing

“…For instance, the combination of insulin like growth factor 1 receptor (IGF1R) inhibitors with semisynthetic rapamycin analogs inhibits the proliferation of breast and prostate cancers and myelomas. 60,[75][76][77] Similar encouraging results come from other growth factor receptor antagonists, including the epidermal growth factor receptor (EGFR). 78 Recently, an AKT inhibitor, perifosine, was used to treat multiple myeloma cells and potentiate the anticancer activity by combination with nanoparticle bound rapamycin.…”

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…The PFS of the R/D/E did not improve compared to R/E, likely due to lower doses of ridaforolimus in the R/D/E arm. While there was less toxicity, the efficacy of the R/D/E regimen was poorer [280]. Taken together, rapalogs in combination with growth factor receptor inhibitors have limited efficacy.…”

Role of the IGF-1 Axis in Overcoming Resistance in Breast Cancer

“…Di Cosimo et al (2010), in a phase 1 clinical trial, have demonstrated clinical benefit in 21.7% of BC patients combining ridaforolimus (a small molecule inhibitor of mTOR) and IGF-1R antibody dalotuzumab. The combination was feasible and well tolerated and a phase 2 was initiated, but accrual was prematurely interrupted due to a higher than expected incidence of stomatitis in the treated patients (Rugo et al, 2017). Vlahovic et al have evaluated the clinical benefits of combining ganitumab, a monoclonal antibody directed versus IGF-1R, with everolimus (Ev) and panitumumab in patients with advanced cancers.…”