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Background <p>Hormone receptor-positive (HR+), human epithelial growth factor receptor 2 (HER2) overexpressed breast cancer (BC) represents the more aggressive subtype of HR + BC, typically associated with poor clinical outcomes. Despite significant advancements in the treatment of estrogen receptor-positive (ER+)/HER2 + BC, resistance to endocrine therapy (ET) poses a continued challenge. Imlunestrant is a next-generation, oral, brain-penetrant, pure antagonistic ER degrader designed to deliver continuous ER target inhibition. It has shown favorable clinical benefit, safety, and pharmacokinetics (PK) when used as monotherapy or with targeted therapy in patients with ER+/HER2- advanced BC (ABC). Here, we present the safety and efficacy of imlunestrant with HER2 targeted therapy in patients with ER+/HER2 + ABC of the EMBER trial.</p> Methods <p>Patients were randomized to imlunestrant (400&#xa0;mg RP2D) + trastuzumab (group A) versus imlunestrant + trastuzumab ± abemaciclib [(150&#xa0;mg twice daily) group B] or received maintenance treatment with imlunestrant + trastuzumab + pertuzumab until progression or discontinuation at standard doses (group C). In the randomized allocation, eligible patients with locally advanced or metastastic disease had received ≥ 2 prior HER2-directed regimens in the metastatic setting, and no prior treatment with CDK4/6 inhibitors or fulvestrant. The maintenance cohort (group C) was added later to include patients without disease progression after first-line induction taxane-based chemotherapy (any duration), trastuzumab, and pertuzumab. Endpoints included safety, PK, antitumor activity, and tumor biomarker assessments.</p> Results <p>In total, 45 patients with ER+/HER2 + ABC were treated (group A, <i>n</i> = 18; group B, <i>n</i> = 21; group C, <i>n</i> = 6). Adverse events were consistent with the known safety profiles of the partner drugs. Imlunestrant PK was consistent with previously reported data. For groups A, B, and C, the objective response rates (ORRs) were 7%, 25%, and 33%, respectively, while the clinical benefit rates (CBRs) were 44%, 48%, and 100%. In group C, the duration of response ranged between 5.13 and 9.46 months. In groups A and B, baseline plasma ctDNA sample sequencing identified prevalent alterations in <i>ERBB2</i> amplification (57%), <i>CCND1</i> amplification (22%), and mutations in <i>TP53</i> (49%), <i>PIK3CA</i> (30%), <i>ESR1</i> (24%), and <i>GATA3</i> (14%).</p> Conclusions <p>Imlunestrant in combination with trastuzumab ± abemaciclib or pertuzumab presented a safety profile that was consistent with those of the partnered drugs. No new safety findings were observed. Furthermore, imlunestrant in combination with the partnered drugs demonstrated preliminary antitumor activity in patients with ER+/HER2 + ABC.</p> Trial registration <p>ClinicalTrials.gov identifier NCT04188548 (Registered 18 November 2019).</p>

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Imlunestrant, an oral selective estrogen receptor degrader, in combination with HER2 directed therapy, with or without abemaciclib, in ER-positive, HER2-positive advanced breast cancer: results from the phase 1a/1b EMBER study

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  • 发表日期：

    2025年12月21日

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  • Manali Bhave,
  • Komal L. Jhaveri,
  • Peter A. Kaufman,
  • Philippe Aftimos,
  • Janine Lombard,
  • Karthik V. Giridhar,
  • Seock-Ah Im,
  • Cynthia X. Ma,
  • Kuo-Ting Lee,
  • Sung-Bae Kim,
  • Joohyuk Sohn,
  • Yujia Li,
  • Eunice Yuen,
  • Shawn T. Estrem,
  • Bastien Nguyen,
  • Monish Ram Makena,
  • Roohi Ismail-Khan,
  • Muralidhar Beeram

摘要

Background

Hormone receptor-positive (HR+), human epithelial growth factor receptor 2 (HER2) overexpressed breast cancer (BC) represents the more aggressive subtype of HR + BC, typically associated with poor clinical outcomes. Despite significant advancements in the treatment of estrogen receptor-positive (ER+)/HER2 + BC, resistance to endocrine therapy (ET) poses a continued challenge. Imlunestrant is a next-generation, oral, brain-penetrant, pure antagonistic ER degrader designed to deliver continuous ER target inhibition. It has shown favorable clinical benefit, safety, and pharmacokinetics (PK) when used as monotherapy or with targeted therapy in patients with ER+/HER2- advanced BC (ABC). Here, we present the safety and efficacy of imlunestrant with HER2 targeted therapy in patients with ER+/HER2 + ABC of the EMBER trial.

Methods

Patients were randomized to imlunestrant (400 mg RP2D) + trastuzumab (group A) versus imlunestrant + trastuzumab ± abemaciclib [(150 mg twice daily) group B] or received maintenance treatment with imlunestrant + trastuzumab + pertuzumab until progression or discontinuation at standard doses (group C). In the randomized allocation, eligible patients with locally advanced or metastastic disease had received ≥ 2 prior HER2-directed regimens in the metastatic setting, and no prior treatment with CDK4/6 inhibitors or fulvestrant. The maintenance cohort (group C) was added later to include patients without disease progression after first-line induction taxane-based chemotherapy (any duration), trastuzumab, and pertuzumab. Endpoints included safety, PK, antitumor activity, and tumor biomarker assessments.

Results

In total, 45 patients with ER+/HER2 + ABC were treated (group A, n = 18; group B, n = 21; group C, n = 6). Adverse events were consistent with the known safety profiles of the partner drugs. Imlunestrant PK was consistent with previously reported data. For groups A, B, and C, the objective response rates (ORRs) were 7%, 25%, and 33%, respectively, while the clinical benefit rates (CBRs) were 44%, 48%, and 100%. In group C, the duration of response ranged between 5.13 and 9.46 months. In groups A and B, baseline plasma ctDNA sample sequencing identified prevalent alterations in ERBB2 amplification (57%), CCND1 amplification (22%), and mutations in TP53 (49%), PIK3CA (30%), ESR1 (24%), and GATA3 (14%).

Conclusions

Imlunestrant in combination with trastuzumab ± abemaciclib or pertuzumab presented a safety profile that was consistent with those of the partnered drugs. No new safety findings were observed. Furthermore, imlunestrant in combination with the partnered drugs demonstrated preliminary antitumor activity in patients with ER+/HER2 + ABC.

Trial registration

ClinicalTrials.gov identifier NCT04188548 (Registered 18 November 2019).