Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ERD/HER2L breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2

被引:18
作者
Damodaran, S. [1 ,11 ]
O'Sullivan, C. C. [2 ]
Elkhanany, A. [3 ]
Anderson, I. C. [4 ]
Barve, M. [5 ]
Blau, S. [6 ]
Cherian, M. A. [7 ]
Peguero, J. A. [8 ]
Goetz, M. P. [2 ]
Plourde, P., V [9 ]
Portman, D. J. [9 ]
Moore, H. C. F. [10 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX USA
[2] Mayo Clin, Dept Oncol, Rochester, MN USA
[3] Baylor Coll Med, Duncan Canc Ctr Breast, Houston, TX USA
[4] Providence Med Grp, Santa Rosa, CA USA
[5] Mary Crowley Canc Res, Dallas, TX USA
[6] PPLC, Northwest Med Specialties, Oncol Div, Puyallup, WA USA
[7] Ohio State Univ, Comprehens Canc Ctr, Div Med Oncol, Columbus, OH USA
[8] Oncol Consultants, Dept Res, Houston, TX USA
[9] Sermonix Pharmaceut, Columbus, OH USA
[10] Cleveland Clin, Taussig Canc Inst, Cleveland, OH USA
[11] Univ Texas MD Anderson Canc Ctr, Breast Medtigat Canc Therapeut, 1515 Holcombe Blvd,Unit 1354, Houston, TX 77030 USA
关键词
abemaciclib; breast cancer; ctDNA; ESR1; mutation; lasofoxifene; selective estrogen receptor modulator; CIRCULATING TUMOR DNA; POSTMENOPAUSAL WOMEN; ESR1; MUTATIONS; VENOUS THROMBOEMBOLISM; CARDIOVASCULAR EVENTS; FULVESTRANT; RALOXIFENE; INHIBITOR; TAMOXIFEN; ALPELISIB;
D O I
10.1016/j.annonc.2023.09.3103
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1-mutated mBC.Patients and methods: In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1-mutated, ER+/ human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR).Results: Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifeneeabemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; w13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1-mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients.Conclusions: Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.
引用
收藏
页码:1131 / 1140
页数:10
相关论文
共 75 条
[1]   The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance [J].
Abdelmalak, Mary ;
Singh, Rajanbir ;
Anwer, Mohammed ;
Ivanchenko, Pavel ;
Randhawa, Amritdeep ;
Ahmed, Myra ;
Ashton, Anthony W. ;
Du, Yanming ;
Jiao, Xuanmao ;
Pestell, Richard .
CANCERS, 2022, 14 (21)
[2]   Real world outcomes with alpelisib in metastatic hormone receptor-positive breast cancer patients: A single institution experience [J].
Alaklabi, Sabah ;
Roy, Arya Mariam ;
Attwood, Kristopher ;
George, Anthony ;
O'Connor, Tracey ;
Early, Amy ;
Levine, Ellis G. ;
Gandhi, Shipra .
FRONTIERS IN ONCOLOGY, 2022, 12
[3]   Palbociclib Rechallenge for Hormone Receptor- Positive/HER-Negative Advanced Breast Cancer: Findings from the Phase II BioPER Trial [J].
Albanell, Joan ;
Manuel Perez-Garcia, Jose ;
Gil-Gil, Miguel ;
Curigliano, Giuseppe ;
Ruiz-Borrego, Manuel ;
Comerma, Laura ;
Gibert, Joan ;
Bellet, Meritxell ;
Bermejo, Begona ;
Calvo, Lourdes ;
de la Haba, Juan ;
Espinosa, Enrique ;
Marco Minisini, Alessandro ;
Quiroga, Vanesa ;
Santaballa Bertran, Ana ;
Mina, Leonardo ;
Bellosillo, Beatriz ;
Rojo, Federico ;
Menendez, Silvia ;
Sampayo-Cordero, Miguel ;
Popa, Crina ;
Malfettone, Andrea ;
Cortes, Javier ;
Llombart-Cussac, Antonio .
CLINICAL CANCER RESEARCH, 2022, 29 (01) :67-80
[4]   Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer [J].
Andre, Fabrice ;
Ciruelos, Eva ;
Rubovszky, Gabor ;
Campone, Mario ;
Loibl, Sibylle ;
Rugo, Hope S. ;
Iwata, Hiroji ;
Conte, Pierfranco ;
Mayer, Ingrid A. ;
Kaufman, Bella ;
Yamashita, Toshinari ;
Lu, Yen-Shen ;
Inoue, Kenichi ;
Takahashi, Masato ;
Papai, Zsuzsanna ;
Longin, Anne-Sophie ;
Mills, David ;
Wilke, Celine ;
Hirawat, Samit ;
Juric, Dejan .
NEW ENGLAND JOURNAL OF MEDICINE, 2019, 380 (20) :1929-1940
[5]   The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor [J].
Andreano, Kaitlyn J. ;
Baker, Jennifer G. ;
Park, Sunghee ;
Safi, Rachid ;
Artham, Sandeep ;
Oesterreich, Steffi ;
Jeselsohn, Rinath ;
Brown, Myles ;
Sammons, Sarah ;
Wardell, Suzanne E. ;
Chang, Ching-yi ;
Norris, John D. ;
McDonnell, Donald P. .
MOLECULAR CANCER THERAPEUTICS, 2020, 19 (07) :1395-1405
[6]  
[Anonymous], 2023, ORSERDUTM (elacestrant) tablets, for oral use
[7]  
[Anonymous], 2022, KISQALI (ribociclib) tablets, for oral use Prescribing Information
[8]  
[Anonymous], 2021, VERZENIO ABEMACICLIB
[9]  
[Anonymous], Verzenios (abemaciclib) 50, 100, 150 mg film-coated tablets Summary of Product Characteristics
[10]  
[Anonymous], 2019, IBRANCE PALBOCICLIB