CORALLEEN Trial Induces Clinical Activity in HR-Positive, HER2-Negative Breast Cancer

The CDK4/6 inhibitor ribociclib (Kisquali) plus endocrine therapy with letrozole may induce molecular downstaging of disease in certain patients with high-risk, early-stage, hormone receptor (HR)—positive, HER2-negative breast cancer compared with multiagent chemotherapy, according to results from the randomized phase II CORALLEEN trial.

Patients were randomized 1:1 to receive either ribociclib plus letrozole or multiagent chemotherapy. The randomization was stratified by tumor size and nodal involvement. The primary end point was the proportion of patients with low-risk-of-relapse (ROR) disease after neoadjuvant treatment as determined by Prediction Analysis of Microarray 50. Overall, 106 patients were enrolled in the study; 52 patients were assigned to the combination and 54 received chemotherapy.

Investigators analyzed individual absolute changes in the ROR score between baseline and surgery in both arms. At surgery, the score was 25.0 in the combination arm (95% CI, 19.5-30.5) versus 29.4 in the chemotherapy arm (95% CI, 23.5-35.3). The mean ROR score at surgery for the combination arm was 14.0 (95% CI, 10.3-17.6) in patients with low-ROR, 28.9 (95% CI, 21.4-36.3) in patients with intermediate-ROR, and 42.8 in patients with high-ROR (95% CI, 24.7-60.9). For the chemotherapy arm, corresponding mean ROR scores at surgery were 14.0 (95% CI, 9.3-18.6), 35.0 (95% CI, 28.5-41.5), and 54.9 (95% CI, 42.1-67.7).

Overall, 2 patients did not have a decrease in their ROR score in the combination arm and had tumors that were luminal B and HER2-enriched at surgery. Two additional patients in the combination arm had a decrease in the ROR score by at least 60 points and were identified as high-ROR at surgery because of 4 or more positive residual nodes.

In the combination arm, 28 (57.1%) out of 49 patients achieved an objective response (95% CI, 42.2-71.2), and 41 (78.8%) out of 52 patients in the chemotherapy arm achieved an objective response (95% CI, 65.3-88.9). Seven patients (14.3%) had a complete response (CR) in the combination arm (95% CI, 6.6-30.1) versus 10 patients (19.2%) in the chemotherapy arm (95% CI, 10.4-34.9). Partial responses were seen in 21 patients (42.9%) in the combination arm (95% CI, 32.4-63.3) and 31 patients (59.6%) in the chemotherapy arm (95% CI, 49.5-77.9). Sixteen patients (32.6%) had stable disease in the combination arm (95% CI,22.4-52.3) versus 7 patients (13.5%) in the chemotherapy arm (95% CI, 6.1-27.8). These responses were assessed by MRI.

The proportion of patients at surgery with a pathologic CR in the breast and axillary lymph nodes in the combination arm was 0% versus 5.8% with chemotherapy. Residual cancer burden of 0 to 1 was seen in 6.1% of patients versus 11.8%, respectively. Additionally, 44 patients (85.7%) in the combination arm had breast-conserving surgery versus 39 patients (72.2%) in the chemotherapy arm.

Forty-three of 49 patients (87.8%) had intrinsic subtype conversion to luminal A in the combination arm versus 43 out of 52 (82.7%) in the chemotherapy arm. Both groups experienced lower Ki67 at surgery compared with baseline. By day 15, 47 patients (96%) switched to luminal A subtype versus 24 patients (37%) in the chemotherapy arm. A decrease in ROR score at day 15 was observed in patients in both arms.

In a subgroup of patients who had ROR scores at baseline, day 15, and surgery, the mean change in ROR score was -49.7 in the first 15 days versus 3.3 between day 15 and surgery; the mean change was -17.2 versus -27.0, respectively, for chemotherapy. In terms of the changes seen between day 15 and surgery in patients who received the combination, 21 patients (44%) had a decrease, 10 patients (21%) had an increase of 1 to 10 ROR points, and 14 patients (29%) had an increase of more than 10 points (range, 17-60).

The most common grade 1/2 adverse events (AEs) were neutropenia (47%), increased alanine aminotransferase (26%), and asthenia (26%) in the combination arm versus alopecia (100%), neutropenia (69%), and asthenia (54%) in the chemotherapy arm. Almost all of these AEs were determined to be potentially related to study treatment.

Overall, 57% of patients in the combination arm and 69% in the chemotherapy arm experienced grade 3/4 toxicities. The most common grade 3/4 AEs in the combination arm included neutropenia (43%) and increased alanine aminotransferase concentrations (20%), and 16% of patients discontinued treatment due to grade 3/4 increased alanine and aspartate aminotransferases. Four patients (8%) required a dose reduction of ribociclib. Two patients reported serious events, the most reported being lung abscess and increased aminotransferase concentrations.

In the chemotherapy arm, the most common grade 3/4 AEs included neutropenia (60%), and febrile neutropenia (13%), and 19% of patients discontinued treatment due to grade 3/4 peripheral neuropathy and colitis during paclitaxel treatment. Eight patients reported serious events, of which febrile neutropenia was the most common in 4 patients. No deaths occurred in either study arm on this study.

CORALLEEN is a multicenter, open-label, parallel-arm study in which patients were enrolled across 21 hospitals in Spain. To be included in the study, patients had to have postmenopausal disease and operable stage I to IIIa breast cancer with a primary tumor of at least 2 cm in diameter. Patients also had to have an ECOG performance status of 0 or 1. Patients with stage IV disease or those who had other malignancies were excluded from the study.

“The results from the CORALLEEN study suggest that a high proportion of patients achieve a molecular downstaging in clinically high-risk luminal B breast cancer treated with neoadjuvant ribociclib plus letrozole,” study authors wrote. “Our results provide evidence for further studies in high-risk disease that aim to evaluate the long-term survival outcomes of a chemotherapy-free strategy after selecting patients based on variables such as the patient’s baseline risk of relapse and the pathological and biological response of the tumor to treatment.”

Reference:

Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-ppositive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicenter, randomized, phase 2 trial [Published Online: December 11, 2019].Lancet Oncol. doi.org/10.1016/S1470-2045(19)30786-7.