A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer
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, l...
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| Format: | Article |
| Language: | English |
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BMC
2021-01-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13058-020-01382-8 |
| _version_ | 1828892974594916352 |
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| author | Peter Schmid Marie-Paule Sablin Jonas Bergh Seock-Ah Im Yen-Shen Lu Noelia Martínez Patrick Neven Keun Seok Lee Serafín Morales J. Alejandro Pérez-Fidalgo Douglas Adamson Anthony Gonçalves Aleix Prat Guy Jerusalem Laura Schlieker Rosa-Maria Espadero Thomas Bogenrieder Dennis Chin-Lun Huang John Crown Javier Cortés |
| author_facet | Peter Schmid Marie-Paule Sablin Jonas Bergh Seock-Ah Im Yen-Shen Lu Noelia Martínez Patrick Neven Keun Seok Lee Serafín Morales J. Alejandro Pérez-Fidalgo Douglas Adamson Anthony Gonçalves Aleix Prat Guy Jerusalem Laura Schlieker Rosa-Maria Espadero Thomas Bogenrieder Dennis Chin-Lun Huang John Crown Javier Cortés |
| author_sort | Peter Schmid |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T13:45:29Z |
| format | Article |
| id | doaj.art-1117dc67dd994a8f8f4c31719c73a41f |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-12-13T13:45:29Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-1117dc67dd994a8f8f4c31719c73a41f2022-12-21T23:43:25ZengBMCBreast Cancer Research1465-542X2021-01-0123111110.1186/s13058-020-01382-8A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancerPeter Schmid0Marie-Paule Sablin1Jonas Bergh2Seock-Ah Im3Yen-Shen Lu4Noelia Martínez5Patrick Neven6Keun Seok Lee7Serafín Morales8J. Alejandro Pérez-Fidalgo9Douglas Adamson10Anthony Gonçalves11Aleix Prat12Guy Jerusalem13Laura Schlieker14Rosa-Maria Espadero15Thomas Bogenrieder16Dennis Chin-Lun Huang17John Crown18Javier Cortés19Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of LondonDepartment of Drug Development and Innovation, Institut CurieDepartment of Oncology-Pathology, Karolinska Institutet and Breast Cancer Centre, Cancer Theme, Karolinska University HospitalDepartment of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of MedicineDepartment of Oncology, National Taiwan University HospitalDepartment of Oncology, Ramon y Cajal University HospitalDepartment of Oncology, UZ LeuvenDepartment of Internal Medicine, National Cancer CenterDepartment of Medical Oncology, Hospital Universitario Arnau de Vilanova de LleidaMedical Oncology Unit, Hospital Clinico Universitario Valencia, Biomedical Research Institute INCLIVA, CIBERONCDepartment of Medical Oncology, Ninewells Hospital, Tayside Cancer CentreDepartment of Medical Oncology, Institut Paoli Calmettes, Aix-Marseille University, CRCM, CNRS, INSERMTranslational Genomics and Targeted Therapeutics in Solid Tumors, IDIBAPS, Hospital Clínic of BarcelonaDepartment of Medical Oncology, Centre Hospitalier Universitaire de Liège, and Liège UniversityExternal statistician on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG., Staburo GmbH & Co. KG.Medical Department (Clinical Operations), Boehringer Ingelheim España S.AMedical Department, Boehringer Ingelheim, RCVMedical Department, Boehringer Ingelheim Taiwan LimitedDepartment of Medical Oncology, St Vincent’s University HospitalBreast Cancer Group, Vall d’Hebron Institute of Oncology (VHIO)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.https://doi.org/10.1186/s13058-020-01382-8Breast cancerHER2-negativeHormone receptor-positiveInsulin-like growth factorXentuzumab |
| spellingShingle | Peter Schmid Marie-Paule Sablin Jonas Bergh Seock-Ah Im Yen-Shen Lu Noelia Martínez Patrick Neven Keun Seok Lee Serafín Morales J. Alejandro Pérez-Fidalgo Douglas Adamson Anthony Gonçalves Aleix Prat Guy Jerusalem Laura Schlieker Rosa-Maria Espadero Thomas Bogenrieder Dennis Chin-Lun Huang John Crown Javier Cortés A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer Breast Cancer Research Breast cancer HER2-negative Hormone receptor-positive Insulin-like growth factor Xentuzumab |
| title | A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer |
| title_full | A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer |
| title_fullStr | A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer |
| title_full_unstemmed | A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer |
| title_short | A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer |
| title_sort | phase ib ii study of xentuzumab an igf neutralising antibody combined with exemestane and everolimus in hormone receptor positive her2 negative locally advanced metastatic breast cancer |
| topic | Breast cancer HER2-negative Hormone receptor-positive Insulin-like growth factor Xentuzumab |
| url | https://doi.org/10.1186/s13058-020-01382-8 |
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