Abstract P6-21-01: Xentuzumab (BI 836845), an insulin-like growth factor (IGF)-neutralizing antibody (Ab), combined with exemestane and everolimus in hormone receptor-positive (HR+) locally advanced/metastatic breast cancer (LA/mBC): Randomized phase 2 results
Authors: Crown J , Sablin M-P , Cortés J , Bergh J , Im S-A , Lu Y-S , Martínez N , Neven P , Lee KS , Morales S , Pérez-Fidalgo JA , Adamson D , Goncalves A , Prat A , Jerusalem G , Schlieker L , Espadero R-M , Bogenrieder T , Chin-Lun Huang D , Schmid P 
Published: May 2019

Abstract
Background:
Xentuzumab (Xen), an IGF-1/-2-neutralizing Ab, binds IGF-1 and IGF-2, inhibits their growth-promoting signaling, and suppresses AKT activation by everolimus (Ev). This Phase 1b/2 trial evaluates Xen in combination with Ev and exemestane (Ex) in HR+/HER2− LA/mBC.
Methods:
The two-arm, open-label, randomized Phase 2 part enrolled female patients (pts) with HR+/HER2− LA/mBC not amenable to curative therapy and refractory to nonsteroidal aromatase inhibitors. Pts were randomized (1:1) to: oral Ev (10 mg/d) + Ex (25 mg/d); or Xen (1000 mg/wk iv) + Ev (10 mg/d) + Ex (25 mg/d). Randomization was stratified by visceral metastases (VM; Y vs N). Treatment continued in 28-day cycles until progression, intolerable adverse events (AEs) or other reasons for discontinuation. Primary endpoint was progression-free survival (PFS), with an interim futility analysis incorporated in the study design.
Results:
Following the results of the interim analysis, the Data Monitoring Committee (DMC) advised early termination of the trial and discontinuation of Xen treatment. Thus, Xen treatment exposure time and time-to-event data for the Xen+Ev+Ex arm are limited. Of the 139 women treated (Xen+Ev+Ex 70; Ev+Ex 69), 77% had VM. Median PFS was not significantly different between arms (Xen+Ev+Ex vs Ev+Ex, 7.3 vs 5.6 months; HR [95% CI] 0.97 [0.57–1.65]; p=0.91). In a pre-specified subgroup of pts without VM, Xen+Ev+Ex showed favorable PFS vs Ev+Ex (HR 0.21 [0.05–0.98]; Pint=0.0141). Pint values &lt;0.05 were also observed for ad hoc subgroups: measurable disease at baseline; bone-only metastases. Rates of total AEs/grade ≥3 AEs/drug-related AEs were similar between arms (Xen+Ev+Ex, 100/60/96%; Ev+Ex, 99/58/96%). The most common AEs overall were diarrhea (44 vs 33%), mucosal inflammation (39 vs 32%), rash (34 vs 33%) and stomatitis (34 vs 38%); most were grade 1/2. 6% of pts in the Xen+Ev+Ex arm discontinued Xen due to AEs. Ev/Ex discontinuations (Xen+Ev+Ex vs Ev+Ex) occurred in 13/6% vs 23/6%; 1 pt each in the Xen+Ev+Ex arm died from pneumonitis and liver injury and 1 pt each in the Ev+Ex arm died from Burkitt's lymphoma, acute kidney injury and metastases to the peritoneum.
Conclusion:
In the overall population, PFS did not improve with the addition of Xen to Ev+Ex and the trial was therefore discontinued early. Nevertheless, a favorable signal was observed in the pre-specified subgroup of pts without VM when treated with Xen+Ev+Ex, which warrants additional investigation. The safety profile was comparable between arms.
Citation Format: Crown J, Sablin M-P, Cortés J, Bergh J, Im S-A, Lu Y-S, Martínez N, Neven P, Lee KS, Morales S, Pérez-Fidalgo JA, Adamson D, Goncalves A, Prat A, Jerusalem G, Schlieker L, Espadero R-M, Bogenrieder T, Chin-Lun Huang D, Schmid P. Xentuzumab (BI 836845), an insulin-like growth factor (IGF)-neutralizing antibody (Ab), combined with exemestane and everolimus in hormone receptor-positive (HR+) locally advanced/metastatic breast cancer (LA/mBC): Randomized phase 2 results [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-01.