Joaquin Gavilá, MD
Almost half of patients with high-risk luminal-B breast cancer converted to a low risk of recurrence following chemotherapy-free neoadjuvant therapy, matching the performance of standard chemotherapy in small randomized trial according to data presented at the 2019 San Antonio Breast Cancer Symposium.
The combination of ribociclib (Kisqali) and letrozole led to risk conversion in 46.9% of patients compared with 46.1% with chemotherapy. Additionally, 87.8% of patients converted from luminal B to lower-risk luminal A subtype with the combination regimen versus 82.7% in the chemotherapy arm.1
The ribociclib-letrozole regimen led to lower median risk of recurrence (ROR) score, and more patients treated with ribociclib-letrozole achieved a preoperative endocrine prognostic index score of 0.
“Neoadjuvant ribociclib and letrozole in high-risk luminal B breast cancer achieves high rates of ROR-low disease at surgery,” said Joaquin Gavilá, MD, of Instituto Valenciano de Oncologia in Valencia, Spain. “Multi-agent chemotherapy also achieves high rates of ROR-low disease at surgery but with higher toxicity.
“This suggests that, in clinically high-risk luminal B disease, a chemo-free treatment strategy based on CDK4/6 inhibition is worth exploring in future neoadjuvant and adjuvant trials.”
Hormone receptor (HR)-positive/HER2-negative breast cancer is clinically and biologically heterogeneous. The PAM50 luminal B intrinsic subtype accounts for 30-40% of all HR-positive/HER2-negative breast tumors and is associated with 10-year risk of distant recurrence >10%. Most patients with luminal B disease receive neoadjuvant and/or adjuvant chemotherapy, Gavilá noted.
Ongoing phase III trials are evaluating adjuvant CDK4/6 inhibition in early HR-positive/HER2-negative breast cancer, but none of these are evaluating combined treatment as a replacement for chemotherapy. The phase II NeoPAL trial (NCT02400567) compared neoadjuvant palbociclib (Ibrance) plus endocrine therapy versus chemotherapy in high-risk HR-positive/HER2-negative disease, but the trial ended early because of a low rate of residual cancer burden (RCB) 0/1 in the palbociclib arm.2
“The potential value of CDK4/6 inhibitors to help de-escalate chemotherapy remains unanswered,” said Gavilá. “We hypothesized that CDK4/6 inhibition with ribociclib in combination with letrozole offers high biological and clinical efficacy in PAM50 luminal B early breast cancer.”
The CORALLEEN trial (NCT03248427) recruited postmenopausal women with HR-positive/HER2-negative, stage I-IIIa, luminal B breast cancer associated with tumor size ≥2 cm. Patients were randomized to 6 months of neoadjuvant treatment with doxorubicin/cyclophosphamide chemotherapy and paclitaxel or to ribociclib and letrozole.
The primary objective was the proportion of PAM50 ROR-low disease at surgery. Secondary endpoints included pathologic complete response (pCR) in the breast and axilla (ypT0/isN0), residual cancer burden (RCB) and PEPI score, changes in PAM50 intrinsic subtype, ROR score, Ki67 score, and safety.
Investigators randomized 106 patients, and data analysis included 100. The patients had a median age of 63-64, approximately 80% had T2 tumors, and 57-59% had negative lymph nodes. The median ROR score was 77 in the chemotherapy arm and 70 in the ribociclib-letrozole arm. Gavilá reported that 11.1% of the chemotherapy arm and 15.4% of the ribociclib/letrozole arm had intermediate ROR risk; the rest had ROR-high disease.
The primary-endpoint analysis showed similar rates of ROR-low (46.1% vs 46.9%), ROR-intermediate (30.8% vs 30.6%), and ROR-high disease (21.2% vs 22.5%) following completion of neoadjuvant chemotherapy and chemo-free therapy.
Median ROR score decreased from 75 in all 100 patients to 25 in the chemotherapy arm and 18 in the ribociclib-letrozole group. The median Ki67 expression score decreased from 35 to 10 in the chemotherapy arm and from 30 to 3 in the ribociclib-letrozole group. Few patients achieved pCR (3 total, all in the chemotherapy arm), and more patients in the chemo-free had a PEPI score of 0 (22.4% vs 17.3%).
At surgery, 82.7% patients randomized to neoadjuvant chemotherapy had luminal A breast cancer, and 15.4% still had luminal B. Among patients who received neoadjuvant ribociclib and letrozole, 87.8% had been downstaged to luminal A, and 8.2% remained with luminal B breast cancer.
Gavilá reported that 69.2% of the chemotherapy group had grade ≥3 adverse events (AEs) as compared with 56.9% of the experimental arm. The most common grade ≥3 were neutropenia and febrile neutropenia in the chemotherapy group and neutropenia and increased liver enzymes in the ribociclib-letrozole group. AEs leading to discontinuation occurred in 19.2% and 15.7% of the 2 groups, and AEs leading to dose reduction or interruption occurred in 82.7% and 58.8% of patients. Serious AEs occurred almost 4 times more often with chemotherapy (15.4% vs 3.9%).
- Gavila J, Saura C, Pascual T, et al. SOLTI-1402 CORALLEEN phase II trial of neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: an open-label multicenter, two-arm, randomized study. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS2-06.
- Cottu P, D’Hondt, Dureau S, et al. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol. 2018;29(12):2334-2340. doi: 10.1093/annonc/mdy448.