Primary results of the exploratory CORALLEEN phase 2 trial showed that neoadjuvant ribociclib and letrozole in high-risk Luminal B breast cancer achieved similar rates of risk of recurrence (ROR)-low disease at surgery as multi-agent chemotherapy. These findings suggest that a chemotherapy-free treatment strategy based on cyclin-dependent kinase (CDK)4/6 inhibition in these patients is worth exploring in future neo(adjuvant) trials.
Although different approaches for treatment de-escalation are being investigated, the current ongoing phase 3 adjuvant trials with CDK4/6 inhibitors are not addressing the question of whether these drugs can replace multi-agent chemotherapy in high-risk early breast cancer. In the CORALLEEN phase 2 trial, the efficacy of ribociclib plus endocrine therapy as neoadjuvant treatment in patients with high-risk Luminal B disease is being assessed . The study was designed as an open-label, parallel, multicentre, two-arm, randomised exploratory study in postmenopausal women with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative stage I-IIIA breast cancer, an operable tumour size of at least 2 cm measured by MRI, and high-risk Luminal B subtype disease as defined via the Prosigna genomic tumour profiling test (PAM50), on which they had a baseline median ROR score of 74 out of 100 and ECOG performance status 0-1. A total of 106 patients were randomised 1:1 to neoadjuvant therapy with either six 28-day cycles of oral ribociclib at 600 mg once daily for 3 weeks followed by 1 week off plus daily oral letrozole at 2.5 mg/day, or 4 cycles of intravenous doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 21 days, then weekly intravenous paclitaxel at 80 mg/m2 for 12 weeks. The primary endpoint of the study was the rate of PAM50 ROR-low disease at the time of surgery in each arm, which means a score <40 points if pathologically node-negative at surgery, and <15 with 1 to 3 positive nodes, which are the cut-offs for a <10% risk of distant recurrence at 10 years. Secondary endpoints included pathologic complete response in the breast and axilla (ypT0/isN0), residual cancer burden (RCB) and Preoperative Endocrine Prognostic Index (PEPI), changes in the PAM50 intrinsic subtype, ROR score and Ki67 across the 3 time points, safety, overall response rate (ORR) by MRI and physical examination, rate of breast conserving surgery, quality of life (QoL), and biomarkers of response. It was assumed that 20-25% of subjects in each arm would achieve PAM50 ROR-low disease, meaning that the study required a sample size of 47% evaluable patients for estimating the expected proportion with 12% absolute precision and 95% confidence. This assumption was based on prior PAM50 results derived from the SOLTI-1007 NeoEribulin trial .
From July 2017 to November 2018, 198 patients were screened across 21 sites in Spain. Of recruited patients, 54% (n=106) had Luminal B disease, and 90.6% of these completed treatment as planned. Main baseline patient characteristics were similar between both treatment arms; mean age was 64 years, mean tumour size was 3.8 cm, N+ 39%, mean Ki67 33.2%, and mean ROR score was 72.9 (86.8% were ROR-high). A total of 95.3% surgical samples were analysed.
The results showed that a low ROR score was achieved by 46.9% (95% CI 32.5-61.7) of patients in the ribociclib/letrozole group and by 46.1% (95% CI 32.0-61.5) of patients on standard multi-agent chemotherapy (see Table). The number of patients in both treatment arms who were ROR-intermediate at surgery was comparable at 30.6% and 30.8%, respectively. The reduction in ROR score at day 15 of the study was more pronounced in the ribociclib/letrozole group than in those patients receiving chemotherapy. With regard to the secondary outcomes, 6% of the ribociclib/letrozole group and 12% of the chemotherapy group had an RCB score of 0 or 1, which correlates with a pathologic complete response or minimal residual disease at time of surgery. A PEPI score of 0 was attained in 22% of patients who received the chemotherapy-free regimen versus 17% of patients receiving chemotherapy. Median levels of the tumour cell proliferation biomarker Ki67 improved from 32% at baseline to 3% in the ribociclib/letrozole group and 10% in the chemotherapy arm. Conversion from Luminal B to the less aggressive Luminal A intrinsic subtype occurred in 88% of patients receiving ribociclib/letrozole; the same was true for 83% of patients receiving neoadjuvant chemotherapy.
Table. Primary endpoint results of the SOLTI-1402/CORALLEEN study 
Serious adverse events occurred in 4% of patients who were treated with ribociclib/letrozole versus 15% of those receiving chemotherapy. The most common grade ≥3 adverse event was neutropenia in both study arms, followed by increased transaminase levels in the ribociclib/letrozole group and febrile neutropenia in the chemotherapy arm. The percentage of patients who had their dose reduced or had a temporary interruption of treatment as a result of an adverse event was 59% in the ribociclib/letrozole group and 83% in the chemotherapy group. Researchers added that future studies in high-risk early breast cancer evaluating the survival outcomes and QoL of this combination in the absence of cytotoxic therapy are justified .
1. Gavilá J, et al. GS2-06. SABCS 2019.
2. Prat A, et al. P5-20-19. SABCS 2017.
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Table of Contents: SABCS 2019
Screening, Detection, and Diagnosis
Phase 2 Trial Update
Phase 3 Trial Update
Long-Term Study Results
Triple-Negative Breast Cancer
HER2-Positive Breast Cancer
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