Promising New Neoadjuvant Strategy in Luminal B Breast Cancer

Bruce Jancin

December 16, 2019

SAN ANTONIO ― The combination of ribociclib and letrozole proved to be an attractive alternative to standard multidrug neoadjuvant chemotherapy for women with high-risk luminal B breast cancer in the exploratory phase 2 SOLTI-1402/CORALLEEN trial.

Neoadjuvant therapy with ribociclib (Kisqali), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), in combination with the aromatase inhibitor letrozole (Femara) proved as effective for presurgical molecular disease downstaging as standard multiagent chemotherapy, but with considerably less toxicity, Joaquín Gavilá, MD, reported at the San Antonio Breast Cancer Symposium.

'We believe that these results suggest that in clinically high-risk luminal B disease, a chemotherapy-free treatment strategy based upon CDK4/6 inhibition is worth exploring in future neoadjuvant trials," declared Dr. Gavilá, a medical oncologist at the Valencia (Spain) Institute of Oncology.

SOLTI-1402/CORALLEEN was an open-label, multicenter trial involving 106 postmenopausal women with hormone receptor–positive and HER2-negative stage I-IIIA breast cancer, an operable tumor size of at least 2 cm measured by MRI, and high-risk luminal B subtype disease as defined via the Prosigna genomic tumor profiling test, also known as PAM50, on which they had a baseline median Risk of Recurrence (ROR) score of 74 out of a possible 100 points. The luminal B subtype accounts for 30%-40% of all hormone receptor–positive/HER2-negative breast cancer and carries a greater than 10% risk of distant recurrence at 10 years.

The women were randomized to 6 months of neoadjuvant therapy involving one of two regimens: 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 four 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 study endpoint was achievement of a low ROR score at the time of surgery: that is, a score below 40 points if pathologically node-negative at surgery, and below 15 with one to three positive nodes, which are the cutoffs for a less than 10% risk of distant recurrence at 10 years. A low ROR score was accomplished in 47% of the ribociclib/letrozole group and 46% of patients on standard multiagent chemotherapy. The median ROR score improved from 74 points at baseline to 18 in the investigational treatment arm and 25 in the standard chemotherapy arm.

'In other words, we observed that nearly half of the patients were downstaged from high risk to low risk in both treatment arms," Dr. Gavilá noted.

Another 31% of patients in both treatment arms were ROR-intermediate at surgery.

The reduction in ROR score at day 15 of the study was more pronounced in the ribociclib/letrozole group than in the chemotherapy arm.

Turning to secondary outcomes, Dr. Gavilá noted that a Residual Cancer Burden score of 0 or 1, correlating with a pathologic complete response or minimal residual disease at time of surgery, was documented in 6% of the ribociclib/letrozole group and 12% of the chemotherapy group. A Preoperative Endocrine Prognostic Index (PEPI) score of 0 was attained in 22% of the novel treatment group and similarly in 17% of those on chemotherapy. Median levels of the tumor cell proliferation biomarker Ki 67 improved from 32% at baseline to 3% in the ribociclib/letrozole group and 10% in the chemotherapy arm. Eighty-eight percent of the ribociclib/letrozole group converted from luminal B to the less aggressive luminal A intrinsic subtype, as did 83% of patients following neoadjuvant chemotherapy.

The rate of serious adverse events was 4% in the ribociclib/letrozole group and 15% in the chemotherapy arm. The most common grade 3 or higher 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. Fifty-nine percent of the ribociclib/letrozole group experienced an adverse event leading to dose reduction or temporary interruption of treatment, as did 83% of the chemotherapy group.

The SOLTI-1402/CORALLEEN trial was sponsored by Novartis, the Breast Cancer Research Foundation, The American Association for Cancer Research, and the Breast Cancer Now Career Catalyst. Dr. Gavilá reported serving as a consultant to Novartis, Roche, and MSD.

Simultaneously with Dr. Gavilá’s presentation in San Antonio, the study results were published online in The Lancet Oncology.

In an accompanying editorial, Massimo Cristofanilli, MD, opined that while the novel neoadjuvant treatment strategy tested in SOLTI-1402/CORALLEEN is promising, the most important concept introduced in the study is that a molecular subtyping tool such the Prosigna test can be used to assess the success of neoadjuvant therapy.

'The increasing availability of molecular testing in both the primary and metastatic setting is contributing to a change in the ability to stratify, select, and monitor disease biology and molecular evolution. This is resulting in the introduction of new frameworks in breast cancer treatments with potentially profound effects on patient outcomes and quality of life," according to Dr. Cristofanilli, professor of medicine at Northwestern University, Chicago.

San Antonio Breast Cancer Symposium (SABCS) 2019: Abstract GS2-06. Presented December 11, 2019.

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