The addition of ribociclib (Kisqali) to a nonsteroidal aromatase inhibitor (NSAI) shows promise for patients with high-risk, node-negative, early-stage breast cancer. An analysis of the phase 3 NATALEE trial (NCT03701334) indicates a significant improvement in invasive disease-free survival with this combination.
The NATALEE trial enrolled patients with estrogen receptor (ER)-positive, HER2-negative breast cancer, specifically those with stage II and III disease. Participants were randomized to receive either ribociclib plus an NSAI or an NSAI alone. The subgroup of interest in this analysis comprised patients with no lymph node involvement (N0 disease) but with tumor sizes and features indicative of high risk.
Efficacy of Ribociclib in Node-Negative Breast Cancer
Data from the trial demonstrated that the addition of ribociclib to NSAI therapy led to a significant improvement in invasive disease-free survival in the high-risk, node-negative group. Specifically, there was a 27.7% reduction in the risk of invasive disease. This suggests that patients with high-risk node-negative disease can benefit from the combination therapy, expanding the potential group of patients who could benefit from ribociclib.
According to Dr. Denise Yardley, director of breast cancer research at Sarah Cannon Research Institute, the focus is now on identifying patients who would benefit most from ribociclib and other therapies, potentially avoiding the need for chemotherapy. "We are hoping that as this moves forward and the FDA looks at ribociclib in early-stage breast cancer patients, that these high-risk, node-negative patients also stand to benefit from that combination therapy," Yardley stated in an interview with Targeted Oncology™.
Trial Design and Patient Characteristics
The NATALEE trial enrolled 5100 patients with stage II and III breast cancer. The analysis of the node-negative population included 613 patients with T2, T3, or T4 node-negative disease. Patients with T2 and 0 disease were required to have an additional high-risk feature, such as grade 3 histology, high risk by genomic stratification assay, or a high Ki-67 level (greater than 20%).
The data set of 613 patients was well-balanced between the two arms, comparing ribociclib plus NSAI versus NSAI alone. The results showed a similar benefit in terms of invasive disease-free survival in the intent-to-treat population. This indicates that even in a select high-risk group of node-negative patients, the addition of ribociclib to anastrozole or letrozole therapy resulted in a 27.7% risk reduction in the development of invasive disease.
Safety Profile and Tolerability
The safety profile observed in the lymph node-negative population was consistent with what was seen in the overall intent-to-treat population and aligns with the known safety profile of CDK4/6 inhibitors. Notably, there was no incidence of febrile neutropenia. Interestingly, arthralgias were reported more frequently in the NSAI-only group, a phenomenon observed in other studies involving ribociclib. The rate of arthralgias actually decreased in the ribociclib arm, suggesting a potential added benefit of reducing musculoskeletal aches associated with NSAI therapy.
Clinical Implications and Future Directions
The key takeaway for clinicians is the demonstrated benefit of adding ribociclib to an NSAI in stage II and III breast cancer patients with ER-positive, HER2-negative disease. The data now support extending this benefit to high-risk, lymph node-negative patients who also face a risk of recurrence with the current standard of care. These patients benefited from the addition of ribociclib to their standard NSAI therapy.
Future steps involve refining risk stratification to identify patients who will benefit most from additional therapies and those who can be spared chemotherapy. The goal is to extend the observed benefits from lymph node-positive patients in previous trials and the NATALEE trial to a high-risk, lymph node-negative population as part of their adjuvant endocrine treatment strategy. The hope is that regulatory agencies will consider these findings and approve ribociclib for use in high-risk, node-negative patients with early-stage breast cancer.
