Denise A. Yardley, MD, on Early Breast Cancer: Findings From the NATALEE Trial on Patients With Node-Negative Disease

Patients diagnosed with early-stage breast cancer, unfortunately, are at risk of recurrence, despite undergoing curative surgery, chemotherapy, and/or endocrine therapy. And so based on the data of ribociclib in the advanced breast cancer population, showing a phenomenal progression-free survival and overall survival with the addition of ribociclib to endocrine therapy, the NATALLEE trial sought to evaluate ribociclib in combination with nonsteroidal aromatase inhibitors anastrozole and letrozole in stage II and III early breast cancer patients. And the reason was designed to try to see if we could further improve the outcomes of these patients to see if we could increase the cure rate for early stage breast cancer patients. The NATALEE trial randomized just over 5,100 patients to receive ribociclib at a dose of 400 milligrams given three weeks on one week off for 36 months with the NSAI of anastrozole-letrozole as compared to those agents alone. The primary endpoint of the trial was invasive disease-free survival, and the trial has presented data at prior meetings and showed the invasive disease-free survival. That interim and final analysis did demonstrate a benefit in favor of the arm having the ribociclib, and it was statistically significant and meaningful. I think one of the questions arises that the trial nicely included high-risk select node-negative patients in addition to the node-positive patients. And those node negative patients also demonstrated benefit. The trial did exclude low-risk node-negative patients. Those were the T1N0s, but did include the T2N0, T3 and T4N0 patients. The T2N0 or our anatomic stage IIA patients had to have additional high-risk features, either grade III histology or grade II histology with a high risk from a genomic stratifying assay. And what we were able to demonstrate is that in the node negative high risk population that received ribociclib, in addition to their NSI, they also demonstrated and benefit in the invasive disease-free survival. And for the endpoints that are important in terms of distant disease-free survival, those benefits were consistent in both the DDFS and the DRFS groups as well. And so I think the NATALEE trial stands to benefit a large population of early-stage breast cancer patients who are at risk of recurrence, namely those that are node-positive and the high-risk node-negative patients. The safety profile is very tolerable and demonstrates just neutropenia, elevated liver function tests. Interestingly, arthralgias, which are common to the NSAI group, were reduced in the group that received ribociclib in combination. And so when we see a safety profile such as demonstrated with the NATALEE trial matched with improvement in invasive disease-free survival for the intent-to-treat population as well as the node-negative population, I think we can see now where this has implications for general practice. What we can see is that we have at least one CDK4/6 in the setting in node-positive patients only. Ribociclib, through the NATALEE trial, encompassed both node-positive and select high-risk node-negative patients. So I think we can see that there's a large group of patients that are at risk of recurrence that have every reason to expect a risk reduction with the addition of ribociclib without any untoward safety signals other than what we know for those agents alone. And that just further improves and hopefully translates into improve survival for those patients. We only have the invasive disease-free survival at this point. But I think now looking at adjuvant endocrine strategies for this population, we do see ribociclib added to adjuvant endocrine therapy of nonsteroidal aromatase inhibitors, improving the invasive disease-free survival and further increasing the magnitude of benefit for both populations at risk, the high-risk node-negative and the hormone receptor-positive.