Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2019

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 (#323)

John Crown 1 , Marie-Paule Sablin 2 , Javier Cortés 3 4 , Jonas Bergh 5 , Seock-Ah Im 6 , Yen-Shen Lu 7 , Noelia Martínez 8 , Patrick Neven 9 , Keun Seok Lee 10 , Serafín Morales 11 , J. Alejandro Pérez-Fidalgo 12 , Douglas Adamson 13 , Anthony Goncalves 14 , Aleix Prat 15 , Guy Jerusalem 16 , Laura Schlieker 17 , Rosa-Maria Espadero 18 , Thomas Bogenrieder 19 , Dennis Chin-Lun Huang 20 , Peter Schmid 21
  1. St Vincent's University Hospital, Dublin, Ireland
  2. Institut Curie, Paris, France
  3. IOB Institute of Oncology, Quironsalud Group, Madrid and Barcelona, Spain
  4. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
  5. Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
  6. Seoul National University Hospital, Seoul, Korea
  7. National Taiwan University Hospital, Taipei, Taiwan
  8. Ramon y Cajal University Hospital, Madrid, Spain
  9. UZ Leuven, Campus Gasthuisberg, Leuven, Belgium
  10. National Cancer Center, Goyang, Korea
  11. Hospital Universitario Arnau de Vilanova de Lleida, Lleida, Spain
  12. Hospital Clinico Universitario Valencia, Biomedical Research Institute INCLIVA, CIBERONC, Valencia, Spain
  13. Ninewells Hospital, Tayside Cancer Centre, Dundee, UK
  14. Institut Paoli Calmettes, Marseille, France
  15. Hospital Clínic de Barcelona Servicio de Oncología Médica, Barcelona, Spain
  16. Centre Hospitalier Universitaire de Liège, and Liège University, Liège, Belgium
  17. External statistician on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG, Staburo GmbH & Co. KG. Staburo GmbH, Munich, Germany
  18. Boehringer Ingelheim España S.A, Barcelona, Spain
  19. Boehringer Ingelheim RCV, Vienna, Austria
  20. Boehringer Ingelheim Taiwan Limited, Taipei, Taiwan
  21. Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK

Background: 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.

Methods: The open-label, Phase 2 part enrolled female patients with HR+/HER2− LA/mBC 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.

Results: 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%.

Conclusions: 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.