Supplementary Figure 2 from Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial

Di Cosimo, Serena; Sathyanarayanan, Sriram; Bendell, Johanna C.; Cervantes, Andrés; Stein, Mark N.; Braña, Irene; Roda, Desamparados; Haines, Brian B.; Zhang, Theresa; Winter, Christopher G.; Jha, Sharda; Xu, Youyuan; Frazier, Jason; Klinghoffer, Richard A.; Leighton-Swayze, Ann; Song, Yang; Ebbinghaus, Scot; Baselga, José

doi:10.1158/1078-0432.22454823.v1

Supplementary Figure 2 from Combination of the mTOR Inhibitor Ridaforolimus and the Anti-IGF1R Monoclonal Antibody Dalotuzumab: Preclinical Characterization and Phase I Clinical Trial

journal contribution

posted on 2023-03-31, 18:08 authored by Serena Di Cosimo, Sriram Sathyanarayanan, Johanna C. Bendell, Andrés Cervantes, Mark N. Stein, Irene Braña, Desamparados Roda, Brian B. Haines, Theresa Zhang, Christopher G. Winter, Sharda Jha, Youyuan Xu, Jason Frazier, Richard A. Klinghoffer, Ann Leighton-Swayze, Yang Song, Scot Ebbinghaus, José Baselga

Supplementary Figure 2. Combination therapy with ridaforolimus and dalotuzumab potentiates PI3K pathway inhibition and blocks cancer cell proliferation

History

ARTICLE ABSTRACT

Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin–like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination.Experimental Design:In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10–40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored.Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER+/high-proliferative breast cancer showed antitumor activity.Conclusions: Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER+/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379). Clin Cancer Res; 21(1); 49–59. ©2014 AACR.