First-line ribociclib plus endocrine therapy potentially more effective than combination chemotherapy in premenopausal patients with HR+/HER2- aggressive breast cancer

Results from the phase II RIGHT Choice trial demonstrated that in patients with hormone receptor-positive, HER2-negative, advanced breast cancer, including patients with visceral crises, those treated with first line ribociclib plus endocrine therapy had a significantly longer progression-free survival and fewer adverse events compared to those treated with combination chemotherapy.

Patients whose breast tumours express the oestrogen receptor (ER) and/or the progesterone receptor and do not overexpress the growth factor receptor HER2 are most commonly treated in first line with a CDK4/6 inhibitor plus a form of endocrine therapy (ET). However, some tumours with clinically aggressive disease features that include rapidly progressing or highly symptomatic disease and life-threatening visceral crisis, are treated with chemotherapy instead. To date, no data have been published on a head-to-head comparison of a CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) vs. combination chemotherapy (CT) in this patient population. RIGHT Choice, a randomised, open-label, multi-national, phase II trial, investigated the efficacy and safety of first-line ribociclib (RIB) + ET vs. combination CT in pre/perimenopausal patients with HR+/HER2− advanced breast cancer (ABC) with aggressive disease where combination CT is clinically indicated by physician’s judgment.

Study design

Pre/perimenopausal patients with HR+/HER2− ABC (>10% ER+) and no prior systemic therapy for ABC were randomised 1:1 to receive either RIB (600 mg daily, 3 weeks on/1 week off) with letrozole or anastrozole + goserelin or investigator’s choice of combination CT (docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine). Randomisation was stratified by presence of liver metastases and whether the disease-free interval was less than two years. Patients included in the trial had ABC not amenable to curative therapy for which combination CT was clinically indicated by physician’s judgment (i.e., symptomatic visceral metastases, rapid disease progression or impending visceral compromise, or markedly symptomatic non-visceral disease). Median PFS (mPFS) and median time to treatment failure (mTTF) were evaluated by Kaplan-Meier methods.

Results

In total, 222 patients were randomised to RIB + ET (N= 112) or CT (N= 110). Patients with symptomatic visceral metastases (67.6%), rapid disease progression (18.5%), and markedly symptomatic non-visceral metastases (14.0%) were included. Overall, 116 patients (52.3%) had visceral crisis based on guideline definitions. A majority of patients (85.6%) had tumours that were ≥50% ER+. After a median follow-up of 24.1 months, treatment was still ongoing in 45.5% of patients in the RIB + ET arm (vs. 23.6% in the CT arm). Patients treated with RIB + ET had a PFS of 24.0 months, nearly one year longer than that of patients treated with chemotherapy (12.3 months, HR[95%CI]: 0.54[0.36-0.79], p= 0.0007). The PFS benefit with RIB + ET over combination CT was consistent across most subgroups of patients with aggressive HR+/HER2- ABC. The mTTF was also longer among patients treated with ribociclib plus ET vs. those treated with chemotherapy (18.6 vs. 8.5 months, HR[95%CI]: 0.45[0.32-0.63]). The three-month treatment failure rate in the RIB arm was approximately half (11.6%) that in the CT arm (21.8%). The overall response rate was similar between the two treatment arms (65.2% for RIB + ET and 60% for chemotherapy). Furthermore, also the time to onset of response for RIB + ET was similar to combination CT (4.9 vs. 3.2 months, respectively). The median duration of exposure to study treatment was 15.0 months in the RIB arm and 8.6 months in the CT arm.

No new safety signals were observed in patients on RIB. Serious, treatment-related adverse events (TRAEs) emerged in 1.8% of patients receiving ribociclib plus ET and in 8.0% of patients receiving combination chemotherapy. Similarly, 7.1% of patients treated with ribociclib plus ET and 23.0% of patients treated with chemotherapy discontinued at least one component of study treatment due to TRAEs.

Conclusion

RIGHT Choice is the first prospective study comparing a CDK4/6 inhibitor + ET with combination CT and demonstrated PFS superiority of RIB + ET over combination CT in patients with HR+/HER2- ABC with aggressive clinical features of rapidly progressing or highly symptomatic disease, including visceral crisis. Compared with RIB +ET, combination CT was associated with higher rates of TRAEs, many that impact quality of life. As such, first line RIB + ET offers an efficacious, clinically meaningful treatment option for patients with aggressive HR+/HER2− ABC, obviating the need for combination CT and related toxicities.

Reference

Lu Y, et al. Primary Results From the Randomized Phase II RIGHT Choice Trial of Premenopausal Patients With Aggressive HR+/HER2− Advanced Breast Cancer Treated With Ribociclib + Endocrine Therapy vs Physician’s Choice Combination Chemotherapy. Presented at SABCS 2022; Abstract GS1-10.