Ribociclib Plus ET Is More Effective Even in Advanced Breast Cancer with Aggressive Biology

Key Points:

• Ribociclib plus endocrine therapy (ET) represents a potential new first-line option for patients with hormone receptor (HR)-positive/HER2-negative advanced breast cancer.
• With ribociclib plus ET, median progression-free survival (PFS) was extended compared with standard combination chemotherapy by 9 months.
• The PFS benefit with ribociclib plus ET was less pronounced in patients with visceral crisis, whose median PFS was similar in the ribociclib/ET and combination chemotherapy arms.
• As first-line treatment, adding the CDK4 inhibitor ribociclib to ET prolonged PFS compared with standard combination chemotherapy in clinically aggressive HR-positive/HER2-negative advanced breast cancer. The ribociclib/ET regimen was also better tolerated.

The First Head-to-Head Comparison in Aggressive HR-Positive/HER2-Negative Advanced Breast Cancer

On May 21, 2024, JCO published the RIGHT Choice final analysis, directly comparing ribociclib plus ET with combination chemotherapy for clinically aggressive HR-positive/HER2-negative advanced breast cancer. It is the first head-to-head comparison of these approaches, making it particularly important.

Patients receiving ribociclib plus endocrine therapy (ET) had significantly longer median progression-free survival (PFS) than those receiving investigator-selected combination chemotherapy (21.8 versus 12.8 months). Median follow-up was 37.0 months, and these results represent a 39% improvement in median PFS in the ribociclib plus ET group (HR 0.61; P = 0.003).

Treatment Superior to Chemotherapy Even with Aggressive Cancer Biology

We consider ribociclib plus ET a new standard option for clinically aggressive breast cancer. It provides a similar overall response rate (ORR) and clinical benefit rate (CBR), with a significant PFS improvement of approximately 1 year over combination chemotherapy.

Median PFS benefit was consistent with the overall population across subgroups, although the benefit with ribociclib plus ET was smaller in patients with visceral crisis and recurrent disease.

Visceral crisis describes rapid, severe deterioration in the function of vital organs such as the liver or lungs because of cancer spread.

According to the exploratory RIGHT Choice analysis presented at the 2023 European Oncology Congress, PFS was similar with ribociclib plus ET and combination chemotherapy in patients with visceral crisis (12.9 versus 11.2 months). Without visceral crisis, however, PFS was markedly longer with ribociclib plus ET (24.0 versus 12.7 months).

ORR was 66.1% in the ribociclib arm and 61.8% in the chemotherapy arm; CBR was 81.3% versus 74.5%, respectively.

RIGHT Choice ends the reflex assumption that chemotherapy is better than ET plus a CDK4/6 inhibitor in HR-positive/HER2-negative advanced breast cancer. It reinforces the recommendation for ET plus a CDK inhibitor as first-line treatment in HR-positive/HER2-negative advanced breast cancer.

Greater Efficacy in Newly Diagnosed Patients and Those with Strong ER Positivity

The greatest benefit from ribociclib plus ET was seen in the approximately two thirds of RIGHT Choice participants with newly diagnosed cases of metastatic breast cancer . A robust PFS advantage was also present in patients whose tumors had more than 50% estrogen receptor (ER)-positive cells. (Patients with fewer than 10% ER-positive cells were excluded because of very low ER sensitivity and features resembling ER-negative tumors.)

Further studies are recommended for patients with recurrent disease or a short disease-free interval after adjuvant/neoadjuvant treatment.

Study Design

RIGHT Choice was an open-label randomized study comparing oral ribociclib (600 mg daily, 3 weeks on and 1 week off) plus a daily oral aromatase inhibitor or a subcutaneous goserelin analogue every 28 days against one of 3 investigator-selected intravenous and oral chemotherapy combinations: docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine.

The chemotherapy regimens used in RIGHT Choice are commonly used for advanced breast cancer.

The trial enrolled 222 premenopausal or perimenopausal patients (that is, younger patients) with hormone-positive, HER2-negative, locally/regionally recurrent or metastatic breast cancer. If an adverse event required one chemotherapy agent to be stopped, patients could continue chemotherapy as monotherapy.

A total of 143 patients (64.4%) had newly diagnosed advanced or metastatic disease, and 79 (35.6%) had recurrent disease. Most (55.9%) had 3 or more metastatic sites. Symptomatic visceral metastases were present in 150 (67.6%), rapid disease progression in 41 (18.5%) and symptomatic nonvisceral metastases in 31 (14.0%). Approximately half (47.7%) had investigator-assessed visceral crisis.

At 12 and 24 months, PFS rates were 68.9% and 46.5% in the ribociclib plus ET arm, compared with 54.5% and 23.6% in the chemotherapy arm, respectively.

Importantly, median PFS in patients receiving any of the three combination chemotherapy regimens was markedly lower than in those receiving ribociclib plus ET.

In subgroup analysis, the benefit of ribociclib plus ET over combination chemotherapy was observed only in patients with ER levels above 50% . Results for those with ER levels below 50% should be interpreted cautiously because of the small sample size.

Because RIGHT Choice involved premenopausal and perimenopausal women, generalization to other groups, such as postmenopausal women, may require further study. However, based on the primary RIGHT Choice results presented at the 2022 San Antonio Breast Cancer Symposium , a large majority of an international expert panel at the ABC7 International Consensus Conference in Lisbon, Portugal, in November 2023 believed the findings also applied to postmenopausal women and men with similar disease characteristics.

Notably, response time was slightly longer with ribociclib plus ET than combination chemotherapy (4.9 versus 3.2 months). This may support starting with a short course of combination chemotherapy before switching to ribociclib plus ET in some patients needing a faster response or with ER in fewer than 50% of tumor cells.

Overall survival (OS) data were immature at the final database lock and showed similar survival trends between arms (median OS was not reached in either). ORR and CBR support choosing ribociclib plus ET. The 3-month treatment failure rate was also lower with ribociclib plus ET than combination chemotherapy (11.6% versus 21.8%).

Adverse Events

Although all-grade and grade 3 or 4 toxicity frequencies were similar between arms, symptomatic adverse events differed. In particular, with ribociclib plus ET versus combination chemotherapy, all-grade nausea (14% versus 27%), alopecia (12% versus 20%), vomiting (8% versus 30%), diarrhea (3% versus 26%), fatigue (9% versus 25%) and palmar-plantar erythrodysesthesia (3% versus 27%) were much less frequent.

Conclusion