John Crown1, Javier Cortés2,3, Peter Schmid4, Marie-Paule Sablin5, Jonas Bergh6, Seock-Ah Im7, Yen-Shen Lu8, Noelia Martínez9, Patrick Neven10, Keun Seok Lee11, Serafín Morales12, J Alejandro Pérez-Fidalgo13, Douglas Adamson14, Anthony Gonçalves15, Aleix Prat16, Guy Jerusalem17, Laura Schlieker18, Rosa-Maria Espadero19, Thomas Bogenrieder20,21, Dennis Chin-Lun Huang22,23. 1. Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland. 2. Breast Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 3. Department of Oncology, IOB Institute of Oncology, Quironsalud Group, Madrid and Barcelona, Spain. 4. Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK. p.schmid@qmul.ac.uk. 5. Department of Drug Development and Innovation, Institut Curie, Paris, France. 6. Department of Oncology-Pathology, Karolinska Institutet and Breast Cancer Centre, Cancer Theme, Karolinska University Hospital, Stockholm, Sweden. 7. Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. 8. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. 9. Department of Oncology, Ramon y Cajal University Hospital, Madrid, Spain. 10. Department of Oncology, UZ Leuven, Campus Gasthuisberg, Leuven, Belgium. 11. Department of Internal Medicine, National Cancer Center, Goyang, South Korea. 12. Department of Medical Oncology, Hospital Universitario Arnau de Vilanova de Lleida, Lleida, Spain. 13. Medical Oncology Unit, Hospital Clinico Universitario Valencia, Biomedical Research Institute INCLIVA, CIBERONC, Valencia, Spain. 14. Department of Medical Oncology, Ninewells Hospital, Tayside Cancer Centre, Dundee, UK. 15. Department of Medical Oncology, Institut Paoli Calmettes, Aix-Marseille University, CRCM, CNRS, INSERM, Marseille, France. 16. Translational Genomics and Targeted Therapeutics in Solid Tumors, IDIBAPS, Hospital Clínic of Barcelona, Barcelona, Spain. 17. Department of Medical Oncology, Centre Hospitalier Universitaire de Liège, and Liège University, Liège, Belgium. 18. External statistician on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG., Staburo GmbH & Co. KG., Munich, Germany. 19. Medical Department (Clinical Operations), Boehringer Ingelheim España S.A, Barcelona, Spain. 20. Medical Department, Boehringer Ingelheim, RCV, Vienna, Austria. 21. Present Address: Amal Therapeutics SA, Geneva, Switzerland. 22. Medical Department, Boehringer Ingelheim Taiwan Limited, Taipei, Taiwan. 23. Present Address: MSD Taiwan, Taipei, Taiwan.
Abstract
BACKGROUND: Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). METHODS: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). RESULTS: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). CONCLUSIONS: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). TRIAL REGISTRATION: ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.
BACKGROUND: Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). METHODS: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). RESULTS: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). CONCLUSIONS: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). TRIAL REGISTRATION: ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.
Entities:
Keywords:
Breast cancer; HER2-negative; Hormone receptor-positive; Insulin-like growth factor; Xentuzumab
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