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Avutometinib, Abemaciclib, and Fulvestrant in Patients with HR+/HER2- Metastatic Breast Cancer Previously Treated

Adrienne G Waks1, Elia Segui1, Tianyu Li2

  • 1Dana-Farber Cancer Institute Boston, MA United States.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 13, 2026
PubMed
Abstract

Insights

This Phase I trial combined a dual RAF/MEK inhibitor with abemaciclib and fulvestrant for advanced breast cancer. The regimen showed preliminary clinical activity and was well tolerated, supporting further investigation.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • Hormone receptor-positive/HER2-negative metastatic breast cancer (mBC) often develops resistance to CDK4/6 inhibitors.
  • Mitogen-activated protein kinase (MAPK) pathway activation is a key resistance mechanism.
  • Targeting RAF/MEK alongside CDK4/6 inhibition may overcome resistance.

Purpose of the Study:

  • To evaluate the safety and tolerability of avutometinib (a dual RAF/MEK inhibitor) combined with abemaciclib and fulvestrant in patients with HR+/HER2- mBC.
  • To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination regimen.
  • To assess preliminary efficacy, including overall response rate (ORR) and progression-free survival (PFS).

Main Methods:

  • A Phase I clinical trial enrolled patients with prior progression on CDK4/6 inhibitors.
  • Dose escalation of abemaciclib (50-150 mg BID) and avutometinib (2.4-4.0 mg BIW) was performed, with fulvestrant (500 mg IM q28d) as a constant dose.
  • Safety, MTD, RP2D, pharmacokinetics (PK), ORR, clinical benefit rate (CBR), and PFS were evaluated.

Main Results:

  • Sixteen patients were treated; the MTD and RP2D were established as abemaciclib 100 mg BID, avutometinib 3.2 mg BIW, and fulvestrant 500 mg IM q28d.
  • Common treatment-related adverse events included elevated creatine phosphokinase, neutropenia, diarrhea, and rash; no Grade 4-5 TRAEs occurred.
  • Preliminary efficacy showed an ORR of 13% and a 24-week CBR of 40% in patients with measurable disease; median PFS was 3.6 months.

Conclusions:

  • The combination of avutometinib, abemaciclib, and fulvestrant was well tolerated at the RP2D with no new safety signals.
  • The regimen demonstrated preliminary clinical activity in heavily pretreated HR+/HER2- mBC.
  • A Phase II trial is currently ongoing to further evaluate this combination therapy.

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