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Clinical Trial
. 2023 Dec;34(12):1131-1140.
doi: 10.1016/j.annonc.2023.09.3103.

Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2

S Damodaran  1 , C C O'Sullivan  2 , A Elkhanany  3 , I C Anderson  4 , M Barve  5 , S Blau  6 , M A Cherian  7 , J A Peguero  8 , M P Goetz  2 , P V Plourde  9 , D J Portman  9 , H C F Moore  10
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Free article
Clinical Trial

Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2

S Damodaran et al. Ann Oncol. 2023 Dec.
Free article

Abstract

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 lasofoxifene-abemaciclib 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; ∼13 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.

Keywords: ESR1 mutation; abemaciclib; breast cancer; ctDNA; lasofoxifene; selective estrogen receptor modulator.

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Conflict of interest statement

Disclosure SD has received research funding from EMD Serono, Guardant Health, Taiho Pharmaceuticals, Novartis, and Sermonix. CCOS has received research funding (paid to institution) from Eli Lilly, Sermonix, AstraZeneca, SeaGen Inc, Bavarian Nordic, Minnemarita Therapeutics, Biovica, and nFerence. AE has received research funding (paid to institution) from Novartis; and has done consulting for AstraZeneca, Stemline, and Pfizer. ICA has received research funding (paid to institution) from AbbVie, Apollomics, AstraZeneca, EMD Serono, Hutchison MediPharma, Merck, Seattle Genetics, and Turning Point Therapeutics. SB reports consulting fees from Bristol Myers Squibb, Exelexis, Eisai, Pfizer, Myovant, and SeaGen; payment or honoraria from Exelexis, Eisai, and Bristol Myers Squibb; participation on a Data Safety Monitoring; Board or Advisory Board from SeaGen, Pfizer, and Myovant; and stock or stock options in Natera; outside of the submitted work. JAP received research funds and consultant fees from TerSera Therapeutics. MPG has CME activities from Research to Practice, Clinical Education Alliance, and Medscape; was a panelist for Total Health Conferencing and a moderator for Curio Science; has done consulting for AstraZeneca, Biovica, Biotheranostics, Blueprint Medicines, Eagle, Eli Lilly, Novartis, Pfizer, Sanofi Genzyme, and Sermonix; and has received research support from Eli Lilly, Pfizer, and Sermonix. DJP and PVP are employees and stockholders of Sermonix. HCFM has received research funding (paid to institution) from Daiichi Sankyo, Roche, AstraZeneca, Seattle Genetics, and Sermonix, and consulting fees from Myovant. All other authors have declared no conflicts of interest.

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