Improving Outcomes Using Ribociclib in High-Risk Node-Negative Breast Cancer

Denise Yardley, MD

The combination of ribociclib (Kisqali) and a nonsteroidal aromatase inhibitor (NSAI) offers significant benefits for patients with high-risk, node-negative, early-stage breast cancer, according to an analysis of the phase 3 NATALEE trial (NCT03701334).¹

NATALEE enrolled patients with estrogen receptor (ER)-positive, HER2-negative breast cancer, targeting those with stage II and III disease. Patients were randomized to receive either ribociclib with an NSAI or an NSAI alone. The subgroup of patients with no lymph node involvement (N0 disease) included those with specific tumor sizes and features indicating high-risk.

Findings showed that the addition of ribociclib to NSAI therapy led to a significant improvement in invasive disease-free survival in this high-risk group, with a 27.7% reduction in the risk of invasive disease. These data suggest that patients with high-risk node-negative disease also benefit from the combination, broadening the potential group of patients who could benefit from ribociclib.

According to Denise Yardley, MD, with more data supporting this combination, the next steps involve identifying patients who could benefit from ribociclib and other therapies while sparing 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, director of breast cancer research at Sarah Cannon Research Institute in Nashville, Tennessee, told Targeted Oncology^TM, in an interview.

In the interview, Yardley discussed the implications of findings from an analysis of the phase 3 NATALEE trial which included patients with early-stage breast cancer with no lymph node involvement.

3D rendered medically accurate illustration of breast cancer: © SciePro - stock.adobe.com

Targeted Oncology: What are the unmet needs in the patient population that the NATALEE trial is investigating?

Yardley: The unmet need in the patient population from the NATALEE trial looked at the node-negative group of patients. We have had trials with node-positive patients in CDK4/6 inhibitors, but the NATALEE trial incorporated a high-risk node-negative population, in addition to the node-positive population in their trial.

Can you discuss your evaluation of the subset data in the node-negative population of patients?

I was looking at the subset data in the node-negative population of the [patients with] hormone receptor-positive HER2-negative early-stage breast cancer. These were patients treated on the NATALEE trial, which enrolled 5100 patients that had stage II and III breast cancer. It has reported data in terms of statistically significant invasive disease-free survival, with the addition of ribociclib to NSAI.

Looking within that group to try to carve out data on the highly selected high-risk node-negative population, there were 613 patients treated on that trial that met qualifications in terms of having either T2, T3, or T4 node-negative disease. The T2 and 0 patients had to have an additional high-risk feature that was either grade 3 histology or high risk by a genomic stratification assay,or have a high Ki-67 of greater than 20%. So, trying to look at high-risk node-negative patients to see if they could also benefit from the addition of ribociclib to their nonsteroidal aromatase inhibitor.

Can you summarize your findings?

Looking at that data set of the 613 patients, they were well-balanced between the 2 arms that received ribociclib in addition to the NSAI vs the NSAI alone. It showed a strikingly similar benefit in terms of invasive disease-free survival, and that was seen in the intent-to-treat population. Looking at a select high-risk group of node-negative patients and being able to demonstrate that they also benefited with a 27.7% risk reduction in the development of invasive disease with the addition of ribociclib to their anastrozole or letrozole therapy, I think, just broadens the group of patients in early-stage breast cancer that stand to benefit from an agent like ribociclib added to their standard endocrine therapy. The trial did show those that received only the current standard of care, which is endocrine therapy by itself, fared poorly on that trial as compared with the group that had the NSAI and ribociclib combination.

Please discuss the safety profile of the combination.

Looking at the safety profile in the lymph node-negative population, it mirrored what was seen in the intent-to-treat [population and] reflects what we know with CDK4/6 inhibitors. There was no febrile neutropenia. Interestingly, arthralgias were higher in the NSAI group, as has been seen and reported by other studies in combination with ribociclib. Actually, the rate of arthralgias goes down [in the ribociclib arm]. I think it is an interesting safety profile and an additional little bonus perk of decreasing the musculoskeletal aches that some of these patients get with their NSAI therapy.

Based on these findings, what would your key takeaways be for clinicians?

I think the key takeaway would be that we have seen the benefit in the final interim analysis of the addition of ribociclib to an NSAI in stage II and III [patients with] breast cancer with ER-positive, HER2-negative disease. I think now we have more data to support. The majority of the patients on the trial were lymph node-positive and now looking at that same data set in the lymph node-negative patients that were enrolled on the trial with high-risk features—so the T1 and 0s were excluded, grade 1 patients were excluded—and showing that node-negative, early-stage breast cancer also has risk of recurrence with current standard of care and benefited from the addition of ribociclib to their standard NSAI therapy.

What are the next steps?

We are continuing to try to risk stratify patients and identify patients who are going to benefit from additional therapies and try to identify those who can be spared chemotherapy and then an additional combination of endocrine therapy. I think the takeaway will be now we have seen the data for lymph node-positive and we have seen that benefit from another trial and the NATALEE trial and now being able to extend that benefit to a high-risk, lymph node-negative population as part of their adjuvant endocrine treatment strategy. We are hoping that as this moves forward and the FDA looks at ribociclib in [patients with] early-stage breast cancer, that these high-risk, node-negative patients also stand to benefit from that combination therapy.

REFERENCE:

Yardley DA, Untch M, Barrios Sr CH, et al. Baseline (BL) characteristics and efficacy endpoints for patients (pts) with node-negative (N0) HR+/HER2− early breast cancer (EBC): NATALEE trial. J Clin Oncol. 2024;42(suppl 16): abstr 512. doi:10.1200/JCO.2024.42.16_suppl.512