Open-label, phase 2, multicenter study of lasofoxifene (LAS) combined with abemaciclib (Abema) for treating pre- and postmenopausal women with locally advanced or metastatic ER+/HER2-breast cancer and an ESR1 mutation after progression on prior therapies.

1022 Background: Resistance to endocrine therapy can develop when treating estrogen receptor positive (ER+), metastatic breast cancer (mBC). Treatment with aromatase inhibitors can lead to acquired mutations in the estrogen receptor 1 ( ESR1), which can constitutively activate the ER, leading to endocrine resistance and worse disease prognosis. Treatment options for mBC patients with an ESR1 mutation are limited. Further, data suggest that patients could derive clinical benefit from Abema after progression on prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). LAS, a third-generation selective estrogen receptor modulator, as monotherapy or combined with a CDK4/6i, was shown to have superior efficacy over fulvestrant (FVT) in preclinical breast cancer models expressing ESR1 mutations. Based on these results, a phase 2 clinical trial of LAS combined with Abema was initiated in mBC patients with ESR1 mutations. Methods: ELAINE 2 is an open-label, phase 2, multicenter trial evaluating the safety and efficacy of LAS combined with the CDK4/6i, Abema. Study participants were pre- and postmenopausal women with ER+/HER2- mBC with acquired ESR1 mutation (identified by ctDNA testing), whose disease had progressed on one or two lines of hormonal therapy for metastatic disease with or without a CDK4/6i (including Abema). Patients took oral LAS 5 mg/day and Abema 150 mg BID. Treatment continued until evidence of disease progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint was safety, and secondary endpoints were progression free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Results: 29 patients were enrolled at 16 US sites (Oct 2020 to June 2021). Mean age was 58.3 y (35-79 y); 86% were Caucasian. Most had progressed with at least 2 previous hormonal treatments (80%). All except 1 patient received a prior CDK4/6i and 72% had received prior FVT; 48% had chemotherapy in the metastatic setting. Four patients discontinued the trial due to adverse events (AEs, n = 2), consent withdrawal (n = 1), or investigator withdrawal (n = 1). No deaths occurred during the study and few Grade 3/4 AEs were observed. Most common AEs were diarrhea, nausea, and leukopenia. Five patients had an Abema dose reduction from 150 mg to 100 mg BID. To date, 11 patients have progressed and 14 continue treatment. The censored median PFS was 13.9 mos (95% CI, 8.0‒NE), the ORR 33.3% (95% CI, 16.3‒56.3) with 6 confirmed partial responses, and the CBR 62.1% (95% CI, 44.0‒77.3). Conclusions: LAS combined with Abema in the ELAINE 2 trial was well tolerated and demonstrated robust and meaningful efficacy in women with ER+/HER2- mBC and an ESR1 mutation who had progressed on previous CDK4/6i therapies. Clinical trial information: NCT04432454.