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


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John Crown1,Marie-Paule Sablin2,Javier Cortés3,Jonas Bergh4,Seock-Ah Im5,Yen-Shen Lu6,Noelia Martínez7,Patrick Neven8,Keun Seok Lee9,Serafín Morales10,J. Alejandro Pérez-Fidalgo11,Douglas Adamson12,Anthony Goncalves13,Aleix Prat14,Guy Jerusalem15,Laura Schlieker16,Rosa-Maria Espadero17,Thomas Bogenrieder18,Dennis Chin-Lun Huang19,Peter Schmid20
1St Vincent University Hospital, Dublin, Ireland,2Institut Curie, Paris, France,3IOB Institute of Oncology, Quironsalud Group, Madrid and Barcelona, Spain, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain,4Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden,5Seoul National University Hospital, Seoul, South Korea,6National Taiwan University Hospital, Taipei, Taiwan,7IOB Institute of Oncology, Quironsalud Group, Madrid and Barcelona, Spain,8UZ Leuven, Campus Gasthuisberg, Lueven, Belgium,9National Cancer Center, Goyang, South Korea,10Hospital Universitario Arnau de Vilanova de Lleida, Lleida, Spain,11Hospital Clinico Universitario Valencia, Spain, Biomedical Research Institute INCLIVA, Valencia, Spain, el Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain,12Tayside Cancer Centre, Ninewells Hospital, Dundee, UK,13Institut Paoli Calmettes, Marseille, France,14Hospital Clínic de Barcelona Servicio de Oncología Médica, Barcelona, Spain,15Centre Hospitalier Universitaire de Liège, Belgium, Liège University, Liège, Belgium,16External statistician on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG, Bracknell, UK, Staburo GmbH & Co. KG. Staburo GmbH, Munich, Germany,17Boehringer Ingelheim España S.A, Barcelona, Spain,18Boehringer Ingelheim RCV, Vienna, Austria,19Boehringer Ingelheim Taiwan Limited, Taipei, Taiwan,20Centre for Experimental Cancer Medicine, Barts Cancer Institute, London, UK, Queen Mary University of London, London, UK

Abstract

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.

Method

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.

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%.

Conclusion

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.