The addition of ribociclib to endocrine therapy as adjuvant therapy significantly improves invasive disease-free survival (iDFS) for patients with hormone receptor (HR)-positive, HER2-negative early-stage breast cancer. In the large Phase III NATALEE trial, at a prespecified interim analysis of 426 iDFS events, 189 patients (7.4%) in the ribociclib group experienced a recurrence versus 237 patients (9.2%) in the hormonal therapy alone group. Adding ribociclib to hormonal therapy led to a significant improvement in iDFS, with 3-year iDFS rates of 90.4 percent in the ribociclib group compared with 87.1 percent in the hormonal therapy alone group.
"We saw a difference of 25 percent in the relative reduction in risk of invasive breast cancer when ribociclib was added to endocrine therapy. The benefit was seen across all subgroups, regardless of disease state, menopausal status, or even nodal status," said lead author Dennis J. Slamon, MD, PhD, Director of Clinical/Translational Research and Director of the Revlon/UCLA Women's Cancer Research Program at the UCLA Jonsson Comprehensive Cancer Center in Los Angeles. He presented the research results at the 2023 ASCO Annual Meeting (Abstract LBA500).
Slamon noted that "with current standard therapy, one-third of patients with Stage II and more than one-half of patients with Stage III HR-positive, HER2-negative breast cancer will still recur up to 2 decades post-diagnosis. There is a significant unmet need for both reducing the risk of recurrence and providing a tolerable treatment option that keeps patients cancer-free without disrupting their daily lives. The NATALEE study investigated the addition of ribociclib to standard-of-care adjuvant endocrine therapy and was specifically designed to address these unmet needs."
Ribociclib, a small molecule inhibitor that targets CDK4/CDK6 proteins, is currently approved by the FDA to treat HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor for premenopausal people or in combination with fulvestrant for postmenopausal people. The NATALEE study showed that ribociclib may also improve outcomes in earlier-stage disease, including those with cancer that has not yet spread to the lymph nodes.
The current recommended starting dose of ribociclib for metastatic breast cancer is 600 mg. However, an extended duration of treatment can help stop cells from duplicating and dividing and destroy any remaining cancer cells. For this study, the researchers chose a 3-year treatment duration of ribociclib at a dose of 400 mg to reduce side effects while maintaining efficacy, Slamon noted.
The clinical trial included 5,101 men and premenopausal or postmenopausal women from 20 different countries with Stage IIA, IIB, or III HR-positive, HER2-negative breast cancer at risk for recurrence. Patients were randomized ribociclib 400 mg/day, 3 weeks on/1 week off for 3 years plus endocrine therapy with letrozole 2.5 mg/day or anastrozole 1 mg/day for 5 or more years (2,549 patients) or endocrine therapy alone (2,552 patients). Men and premenopausal women also received goserelin.
Eligible patients had an ECOG PS of 0-1 and breast cancer anatomic Stage IIA (either no nodal involvement with additional risk factors or 1-3 axillary lymph nodes, Stage IIB, or Stage III per AJCC; prior (neo)adjuvant endocrine therapy was allowed if initiated before 12 months of randomization.
At a median follow-up of 34 months, 20.2 percent of participants in the ribociclib group had completed 3 years of treatment and 56.8 percent had completed 2 years of treatment. Overall, 74.7 percent of participants remained on the study treatment at data cutoff, with 1,984 patients on ribociclib and 1,826 patients on hormonal therapy alone.
"We met the primary endpoint, demonstrating a statistically significant, clinically meaningful improvement in iDFS," said Slamon. He emphasized the benefit was also seen in patients with node-negative disease. Ribociclib also showed more favorable outcomes in overall survival, recurrence-free survival, and distant disease-free survival.
The 3-year regimen was well-tolerated, and the 400 mg dose improved the safety signal, he said. For patients receiving ribociclib, the most common adverse effects were neutropenia and joint pain. Rates of gastrointestinal adverse effects and fatigue were low in patients receiving ribociclib. For patients receiving hormonal therapy alone, the most common adverse effects were joint pain and hot flashes.
The major side effect of the combination was neutropenia, seen in 62.1 percent of patients, with Grade 3 or higher neutropenia in 43.8 percent of patients. QT interval prolongation was seen in 5.2 percent of patients.
In summary, Slamon said: "The NATALEE results support ribociclib plus endocrine therapy as a new treatment of choice for patients with Stage II or Stage III HR-positive, HER-negative breast cancer at risk of recurrence."
Rita Nanda, MD, Director of the Breast Oncology Program at the University of Chicago Medicine, commented: "This very important trial shows early, but impressive data. Ribociclib was effective and well-tolerated and I expect the trial results will change practice. To have another option for patients with HR-positive, HER-negative breast cancer with node-negative disease is an important contribution."
Mark L. Fuerst is a contributing writer.