Khalil Zaman1, Ralph Winterhalder2, Christoph Mamot3, Ursula Hasler-Strub4, Christoph Rochlitz5, Andreas Mueller6, Catherine Berset7, Hans Wiliders8, Lucien Perey9, Christine Biaggi Rudolf10, Hanne Hawle11, Stephanie Rondeau12, Patrick Neven13. 1. Breast Center Medical Oncology, University Hospital CHUV, Lausanne, Switzerland. Electronic address: Khalil.Zaman@chuv.ch. 2. Division of Medical Oncology, Luzerner Kantonsspital, Lucerne, Switzerland. Electronic address: ralph.winterhalder@onkologie.ch. 3. Medical Oncology, Kantonsspital Aarau, Aarau, Switzerland. Electronic address: christoph.mamot@ksa.ch. 4. Breast Center, Kantonsspital, St Gallen, Switzerland. Electronic address: ursula.hasler-strub@kssg.ch. 5. Breast Center, Universitätsspital, Basel, Switzerland. Electronic address: crochlitz@uhbs.ch. 6. Medical Oncology and Breast Center, Kantonsspital, Winterthur, Switzerland. Electronic address: andreas.mueller@ksw.ch. 7. SAKK Coordinating Center, Bern, Switzerland. Electronic address: catherine.berset@sakk.ch. 8. Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Belgium. Electronic address: hans.wildiers@uz.kuleuven.ac.be. 9. Medical Oncology, Morges Hospital, Switzerland. Electronic address: lucien.perey@ehc.vd.ch. 10. SAKK Coordinating Center, Bern, Switzerland. Electronic address: Christine.Biaggi@sakk.ch. 11. SAKK Coordinating Center, Bern, Switzerland. Electronic address: hanne.hawle@sakk.ch. 12. SAKK Coordinating Center, Bern, Switzerland. Electronic address: stephanie.rondeau@sakk.ch. 13. University Hospital Gasthuisberg, Leuven, Belgium. Electronic address: patrick.neven@uz.kuleuven.ac.be.
Abstract
BACKGROUND: Second line endocrine therapy has limited antitumour activity. Fulvestrant inhibits and downregulates the oestrogen receptor. The mitogen-activated protein kinase (MAPK) pathway is one of the major cascades involved in resistance to endocrine therapy. We assessed the efficacy and safety of fulvestrant with selumetinib, a MEK 1/2 inhibitor, in advanced stage breast cancer progressing after aromatase inhibitor (AI). PATIENTS AND METHODS: This randomised phase II trial included postmenopausal patients with endocrine-sensitive breast cancer. They were ramdomised to fulvestrant combined with selumetinib or placebo. The primary endpoint was disease control rate (DCR) in the experimental arm. ClinicalTrials.gov Indentifier: NCT01160718. RESULTS: Following the planned interim efficacy analysis, recruitment was interrupted after the inclusion of 46 patients (23 in each arm), because the selumetinib-fulvestrant arm did not reach the pre-specified DCR. DCR was 23% (95% confidence interval (CI) 8-45%) in the selumetinib arm and 50% (95% CI 27-75%) in the placebo arm. Median progression-free survival was 3.7months (95% CI 1.9-5.8) in the selumetinib arm and 5.6months (95% CI 3.4-13.6) in the placebo arm. Median time to treatment failure was 5.1 (95% CI 2.3-6.7) and 5.6 (95% CI 3.4-10.2) months, respectively. The most frequent treatment-related adverse events observed in the selumetinib-fulvestrant arm were skin disorders, fatigue, nausea/vomiting, oedema, diarrhoea, mouth disorders and muscle disorders. CONCLUSIONS: The addition of selumetinib to fulvestrant did not show improving patients' outcome and was poorly tolerated at the recommended monotherapy dose. Selumetinib may have deteriorated the efficacy of the endocrine therapy in some patients.
RCT Entities:
BACKGROUND: Second line endocrine therapy has limited antitumour activity. Fulvestrant inhibits and downregulates the oestrogen receptor. The mitogen-activated protein kinase (MAPK) pathway is one of the major cascades involved in resistance to endocrine therapy. We assessed the efficacy and safety of fulvestrant with selumetinib, a MEK 1/2 inhibitor, in advanced stage breast cancer progressing after aromatase inhibitor (AI). PATIENTS AND METHODS: This randomised phase II trial included postmenopausal patients with endocrine-sensitive breast cancer. They were ramdomised to fulvestrant combined with selumetinib or placebo. The primary endpoint was disease control rate (DCR) in the experimental arm. ClinicalTrials.gov Indentifier: NCT01160718. RESULTS: Following the planned interim efficacy analysis, recruitment was interrupted after the inclusion of 46 patients (23 in each arm), because the selumetinib-fulvestrant arm did not reach the pre-specified DCR. DCR was 23% (95% confidence interval (CI) 8-45%) in the selumetinib arm and 50% (95% CI 27-75%) in the placebo arm. Median progression-free survival was 3.7months (95% CI 1.9-5.8) in the selumetinib arm and 5.6months (95% CI 3.4-13.6) in the placebo arm. Median time to treatment failure was 5.1 (95% CI 2.3-6.7) and 5.6 (95% CI 3.4-10.2) months, respectively. The most frequent treatment-related adverse events observed in the selumetinib-fulvestrant arm were skin disorders, fatigue, nausea/vomiting, oedema, diarrhoea, mouth disorders and muscle disorders. CONCLUSIONS: The addition of selumetinib to fulvestrant did not show improving patients' outcome and was poorly tolerated at the recommended monotherapy dose. Selumetinib may have deteriorated the efficacy of the endocrine therapy in some patients.
Authors: Katarzyna A Ludwik; J Preston Campbell; Mingzong Li; Yu Li; Zachary M Sandusky; Lejla Pasic; Miranda E Sowder; David R Brenin; Jennifer A Pietenpol; George A O'Doherty; Deborah A Lannigan Journal: Mol Cancer Ther Date: 2016-08-15 Impact factor: 6.261
Authors: Ze-Yi Zheng; Meenakshi Anurag; Jonathan T Lei; Jin Cao; Purba Singh; Jianheng Peng; Hilda Kennedy; Nhu-Chau Nguyen; Yue Chen; Philip Lavere; Jing Li; Xin-Hui Du; Burcu Cakar; Wei Song; Beom-Jun Kim; Jiejun Shi; Sinem Seker; Doug W Chan; Guo-Qiang Zhao; Xi Chen; Kimberly C Banks; Richard B Lanman; Maryam Nemati Shafaee; Xiang H-F Zhang; Suhas Vasaikar; Bing Zhang; Susan G Hilsenbeck; Wei Li; Charles E Foulds; Matthew J Ellis; Eric C Chang Journal: Cancer Cell Date: 2020-03-05 Impact factor: 31.743
Authors: Andrea Rocca; Roberta Maltoni; Sara Bravaccini; Caterina Donati; Daniele Andreis Journal: Cancer Manag Res Date: 2018-08-30 Impact factor: 3.989