What to use after liver metastasis progression in hormone receptor-positive, HER2-negative advanced or metastatic breast cancer treated with Ribociclib (ribociclib) and Fulvestrant (fulvestrant)?

From the Guidelines

After progression on ribociclib and fulvestrant in HR+/HER2- metastatic breast cancer with liver metastases, the recommended next-line therapy is chemotherapy rather than another endocrine-based regimen. This recommendation is based on the most recent and highest quality study available, which suggests that chemotherapy can provide more rapid disease control needed for visceral crisis or symptomatic liver involvement 1.

Rationale for Chemotherapy

The rationale for switching to chemotherapy is that liver metastases often indicate more aggressive disease biology, and progression on CDK4/6 inhibitor therapy (ribociclib) suggests developing endocrine resistance. Chemotherapy can provide a more rapid response, which is crucial in the setting of liver metastases.

Chemotherapy Options

Single-agent chemotherapy options include:

• Capecitabine (1000-1250 mg/m² twice daily for 14 days of a 21-day cycle)
• Eribulin (1.4 mg/m² on days 1 and 8 of a 21-day cycle)
• Weekly paclitaxel (80-90 mg/m² on days 1,8, and 15 of a 28-day cycle) For patients with good performance status and aggressive liver metastases, combination chemotherapy such as carboplatin with gemcitabine or docetaxel may be considered.

Monitoring and Testing

Before starting new therapy, obtain updated imaging to assess the extent of progression and consider genomic testing for PIK3CA mutations or other actionable targets that might guide subsequent therapy choices. Regular liver function monitoring is essential during treatment due to the risk of hepatotoxicity with many chemotherapy agents in patients with liver involvement 1.

Conclusion Not Provided as per Guidelines

As per the provided guidelines, no conclusion or summary is to be included. The information provided is based on the most recent and highest quality studies available, with a focus on morbidity, mortality, and quality of life as the primary outcomes.

From the FDA Drug Label

Fulvestrant 500 mg in Combination with Abemaciclib 150 mg (MONARCH 2) MONARCH 2 (NCT02107703) was a randomized, placebo-controlled, multi-center study conducted in women with HR-positive, HER2-negative metastatic breast cancer with disease progression following endocrine therapy treated with fulvestrant plus abemaciclib versus fulvestrant plus placebo.

The answer to what to use after liver metastasis progression in hormone receptor-positive, HER2-negative advanced or metastatic breast cancer treated with Ribociclib and Fulvestrant is:

• Abemaciclib in combination with Fulvestrant may be considered as a treatment option, as shown in the MONARCH 2 study 2.
• The study demonstrated a significant improvement in Progression-Free Survival (PFS) and Overall Survival (OS) with the combination of Fulvestrant and Abemaciclib compared to Fulvestrant plus placebo.
• Key findings from the study include:
  • Median PFS: 16.4 months (Fulvestrant plus Abemaciclib) vs 9.3 months (Fulvestrant plus placebo)
  • Median OS: 46.7 months (Fulvestrant plus Abemaciclib) vs 37.3 months (Fulvestrant plus placebo)
  • Hazard ratio for PFS: 0.553 (95% CI: 0.449,0.681)
  • Hazard ratio for OS: 0.757 (95% CI: 0.606,0.945)

From the Research

Treatment Options After Liver Metastasis Progression

After liver metastasis progression in hormone receptor-positive, HER2-negative advanced or metastatic breast cancer treated with Ribociclib and Fulvestrant, several treatment options can be considered:

• Abemaciclib: This CDK4/6 inhibitor has shown clinical activity after progression on prior CDK4/6i, including palbociclib 3.
• Palbociclib: Although not directly studied in this setting, palbociclib has demonstrated efficacy in combination with fulvestrant in patients with HR-positive, HER2-negative advanced or metastatic breast cancer 4.
• Other CDK4/6 inhibitors: Ribociclib, another CDK4/6 inhibitor, has a higher incidence of liver function test abnormalities and QTc prolongation compared to palbociclib and abemaciclib 5, 6.

Considerations for Treatment Selection

When selecting a treatment after liver metastasis progression, consider the following factors:

• Prior treatment history: Patients who have progressed on prior CDK4/6i may still derive benefit from abemaciclib 3.
• Tumor characteristics: Abemaciclib may have additional benefits in patients with visceral disease, liver metastasis, or primary resistance to endocrine therapy 7.
• Patient tolerability: Abemaciclib is associated with diarrhea, nausea, and liver dysfunction, while palbociclib is more frequently associated with neutropenia 7, 6.

Ongoing Research and Future Directions

Further studies are needed to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i 3.