Abstract PD5-1: Results from the phase 2 trial of ridaforolimus, dalotuzumab, and exemestane compared to ridaforolimus and exemestane in advanced breast cancer
Authors: Rugo Hope S , Tredan Olivier , Ro Jungsil , Morales Serafin , Musolino Antonino , Afonso Noemia , Ferreira Marta , Park Kyong Hwa , Cortes Javier , Tan Antoinette R , Blum Joanne L , Eaton Lamar , Gause Christine K , Wang Adelle (Zhen) , Im Ellie , Mauro David J , Baselga José 
Published: May 2015

Abstract
Introduction: The combination of a mammalian target of rapamycin (mTOR) inhibitor and an aromatase inhibitor has been shown to significantly increase progression-free survival (PFS) in patients with estrogen receptor-positive (ER+) advanced or metastatic breast cancer. Ridaforolimus is an alternative mTOR inhibitor with high potency and specificity. We hypothesized that triplet therapy with ridaforolimus, dalotuzumab (a humanized monoclonal antibody targeting the IGF-1 receptor [IGFR]), and exemestane (R/D/E) would be more effective than doublet therapy with ridaforolimus and exemestane (R/E).
Methods: This phase 2, randomized, open-label trial enrolled 80 postmenopausal patients who had high-proliferation (KI67 staining) ER+ breast cancer that had progressed following treatment with a nonsteroidal aromatase inhibitor. Patients received either triplet therapy, at the previously determined maximum tolerated dose of oral ridaforolimus 10 mg QD×5, dalotuzumab 10 mg/kg/week IV, and oral exemestane 25 mg/day (R/D/E, n=40), or doublet therapy with R 30 mg QD×5 and E 25 mg/day (R/E, n=40). Dose increases of R to 20 or 40 mg QD×5 were permitted in the R/D/E or R/E arms, respectively, in the absence of grade ≥2 stomatitis after cycle 1. The R dose could be reduced in either arm for toxicity. The primary endpoint was PFS in the ITT population by central review. Adverse events (AE) of clinical interest (Tier 1) included stomatitis, pneumonitis, hearing loss, and hyperglycemia.
Results: Baseline characteristics were balanced between treatment groups. The median PFS was 23.3 (95% CI, 8.71, 38.43) weeks for R/D/E versus 31.9 (95% CI, 16.00, 39.29) weeks in the R/E arm (hazard ratio, 1.18; 80% CI, 0.81-1.72; P=0.565). All patients experienced at least one AE. 5 (12.8%) and 3 (7.5%) patients in the R/D/E and R/E arms, respectively, discontinued the study because of AE. Serious drug-related AE occurred in 2.6% of the R/D/E arm and 15% of the R/E arm. Dose modifications due to AE occurred in 10.3% and 50% in the R/D/E and R/E arms, respectively (difference -39.7%; 95% CI, -56.7, -20.4). Tier 1 AE were primarily grade 1-2 in severity. Stomatitis occurred in 76.9% (30/39 patients) in the R/D/E arm vs 95.0% (38/40 patients) in the R/E arm (P=0.021), and grade 3-4 stomatitis was similar between arms (23.1% vs 25%). Pneumonitis occurred in 5.1% vs 22.5% (P=0.027) and hearing loss occurred in 1 patient in each treatment arm (2.6% vs 2.5%), all grade 1-2. Hyperglycemia occurred at a similar rate in both treatment arms (28.2% vs 27.5%), with grade 3-4 events in 4 (10.3%) and 3 (7.5%) patients in the R/D/E and R/E arms, respectively.
Conclusions: The combination of R 10 mg QD×5, D, and E did not improve PFS when compared to R 30 mg QD×5 plus E. The incidence rates of AE were lower in the R/D/E arm than the R/E arm for most categories of adverse events, likely because of the higher dose of R in the R/E arm. The efficacy reported for R/E in this study is similar to that reported in previous studies evaluating mTOR inhibitors in combination with exemestane in ABC. Overlapping toxicities and lower doses likely contributed to the lack of improved PFS with the addition of the IGFR inhibitor to this combination.
Citation Format: Hope S Rugo, Olivier Tredan, Jungsil Ro, Serafin Morales, Antonino Musolino, Noemia Afonso, Marta Ferreira, Kyong Hwa Park, Javier Cortes, Antoinette R Tan, Joanne L Blum, Lamar Eaton, Christine K Gause, Adelle (Zhen) Wang, Ellie Im, David J Mauro, José Baselga. Results from the phase 2 trial of ridaforolimus, dalotuzumab, and exemestane compared to ridaforolimus and exemestane in advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-1.