Xentuzumab (BI 836845), an IGF-neutralizing antibody, combined with exemestane and everolimus in hormone receptor-positive (HR+) locally advanced/metastatic breast cancer: Randomized Phase 2 results
Session type: Poster / e-Poster / Silent Theatre session
Xentuzumab (Xen), an IGF-1/-2-neutralizing antibody, binds IGF-1 and IGF-2, inhibits their growth-promoting signaling, and suppresses AKT activation by everolimus (Ev). This Phase 1b/2 trial evaluated Xen + Ev + exemestane (Ex) in HR+/HER2− LA/mBC.
The open-label, Phase 2 part enrolled female patients with HR+/HER2− locally advanced/metastatic BC refractory to nonsteroidal aromatase inhibitors. Patients 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). Primary endpoint: PFS. Interim futility analysis was incorporated in the study design.
Following results of the interim analysis, the Data Monitoring Committee advised early termination of the trial; Xen was discontinued. Of 139 women treated (Xen+Ev+Ex 70; Ev+Ex 69), 76% 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 patients without VM, Xen+Ev+Ex showed favourable PFS vs Ev+Ex (HR 0.21 [0.05–0.98]; Pint=0.0141). Pint values <0.05 were also observed for ad hoc subgroups: non-measurable disease at baseline; bone-only metastases. Rates of total AEs/grade ≥3 AEs/drug-related AEs were similar between arms (Xen+Ev+Ex, 100/56/94%; Ev+Ex, 99/45/96%). The most common AEs overall were diarrhoea (41 vs 29%), mucosal inflammation (39 vs 30%), rash (33 vs 30%) and stomatitis (34 vs 35%); most were grade 1/2. 6% of patients 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 17/6%.
Addition of Xen to Ev+Ex did not improve PFS in the overall population and the trial was discontinued early. A favourable signal was observed in patients without VM when treated with Xen+Ev+Ex, leading to initiation of XENERATM-1 (NCT03659136). Safety profile was comparable between arms.