What is the second-line treatment for hormone receptor-positive, HER2 (Human Epidermal growth factor Receptor 2) low breast cancer after progressing on one line of endocrine therapy?

From the Guidelines

For hormone receptor-positive, HER2-low breast cancer that has progressed after one line of endocrine therapy, the recommended second-line treatment is typically a different endocrine therapy combined with a targeted agent, such as a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) in combination with fulvestrant or an aromatase inhibitor, as supported by the NCCN guidelines 1. The choice of second-line hormonal therapy should take into account prior treatment exposure and response to previous endocrine therapy, as outlined in the ASCO guideline update 1. Key considerations include:

• The use of fulvestrant with a CDK 4/6 inhibitor (palbociclib, ribociclib, abemaciclib) for postmenopausal women with HR-positive, HER2-low recurrent/stage IV breast cancer 1
• The potential benefit of alpelisib 300 mg daily plus fulvestrant for patients with PIK3CA mutations 1
• The importance of monitoring for side effects, including neutropenia with CDK4/6 inhibitors and hyperglycemia with alpelisib 1 Treatment should continue until disease progression or unacceptable toxicity, with regular assessment of response and adjustment of therapy as needed 1. In terms of specific dosing, palbociclib 125 mg daily for 21 days of a 28-day cycle plus fulvestrant 500 mg on days 1,15, and 29, then monthly thereafter, is a commonly used regimen 1. Ultimately, the goal of second-line treatment is to improve outcomes, including progression-free survival and overall survival, while minimizing toxicity and maintaining quality of life, as emphasized in the ASCO guideline update 1.

From the FDA Drug Label

1 INDICATIONS AND USAGE

1.2 Advanced or Metastatic Breast Cancer VERZENIO (abemaciclib) is indicated: in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy

The second-line treatment for hormone receptor-positive, HER2-low breast cancer after progressing on one line of endocrine therapy is:

• Combination therapy with fulvestrant and a CDK4/6 inhibitor such as abemaciclib 2 or palbociclib 3. Key points:
• The patient should have disease progression following initial endocrine therapy.
• The treatment should be in combination with fulvestrant.

From the Research

Second-Line Treatment for Hormone Receptor-Positive, HER2-Low Breast Cancer

• The second-line treatment for hormone receptor-positive, HER2-low breast cancer after progressing on one line of endocrine therapy may involve the use of targeted agents and combination strategies 4.
• Clinical trials have demonstrated that the mammalian target of rapamycin inhibitor, everolimus, enhances the efficacy of exemestane or fulvestrant after progression on an aromatase inhibitor 4.
• CDK4/6 inhibitors in combination with fulvestrant have demonstrated superior progression-free survival and overall survival versus fulvestrant alone 4.
• The combination of fulvestrant with alpelisib in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA) mutated HR+, HER2- MBC following progression on or after endocrine therapy has been approved, based on the SOLAR-1 study 4.
• For HER2-low breast cancer, trastuzumab deruxtecan (T-Dxd) has shown promising results in clinical trials and may be considered as a treatment option after progression on CDK4/6 inhibitors 5.
• Targeted approaches to HER2-low breast cancer, including directly targeting HER2 receptors on the cell surface, targeting HER2-related intracellular signaling pathways, and targeting the immune microenvironment, are being explored 6.

Treatment Strategies

• The optimal sequencing of treatments for hormone receptor-positive, HER2-low breast cancer is unknown, especially following disease progression on a CDK4/6 inhibitor 4.
• Strategies to delay or overcome endocrine resistance and thereby postpone chemotherapy have been explored, including the use of second-line endocrine agents with different mechanisms of action, adding targeted agents that inhibit specific resistance pathways, and adding agents that act in complementary or synergistic ways to inhibit tumor cell proliferation 7.
• The treatment of HER2-low breast cancer may involve a combination of chemotherapy, endocrine therapy, and HER2-targeted therapy, and efforts are being made to compare the sequencing and combination of these therapies to improve prognosis 6.