Dr Gabriel Hortobagyi on NATALEE Trial Outcomes and Future Research Directions

Gabriel Hortobagyi, MD, FACP, shares insights from the NATALEE trial (NCT03701334), which analyzed final invasive disease-free survival in patients with HR+/HER2- early breast cancer who received a combination of ribociclib and a nonsteroidal aromatase inhibitor in the adjuvant setting. As the trial concluded, lingering questions remained that will direct further research in this area.

This transcript has been lightly edited.

Transcript

What were the main takeaways from the NATALEE trial?

The NATALEE trial is a phase 3 randomized trial that evaluates the addition of ribociclib, a CDK4/6 inhibitor, to standard adjuvant endocrine therapy for patients with stages II and III breast cancer. With a median follow up of about 33 months, we have now not only replicated, but exceeded, the positive results that were presented earlier in the year showing the superiority of the ribociclib plus endocrine therapy, in terms of invasive disease-free survival—and demonstrating that at 3 years, we find a an absolute difference or an absolute benefit of 3.3%, which corresponds to a relative reduction of 24% in terms of invasive disease-free survival. With these additional 6 months of follow up, there have been no new adverse events identified, and the compliance with treatment has remained about the same. And now, almost 80% of patients have either completed or stopped taking ribociclib. One of the important points is that, despite having stopped taking ribociclib, the benefit persists, which is reassuring and suggests that the difference between the control and the investigational arms of the trial will continue.

What might be the next steps for building off of the results from the NATALEE trial?

The results of the NATALEE trial led us to consider a number of new questions. First and foremost is the development of biomarkers that would allow us to identify patient groups that will benefit more or benefit less from the addition of ribociclib—something to personalize treatment more. Another aspect is to identify mechanisms of resistance to determine whether we can prevent or reverse the development of resistance. Along those lines, there are other CDK inhibitors in development, including CDK2 and CDK7 inhibitors, but other CDK and cyclin-directed therapies. And the question will be whether those will be best utilized in combination with the currently available CDK4/6 inhibitors, or in subsequence, or whether paired with some other targeted therapeutics. So, there's much more work to be done in this area.

Furthermore, there are important developments in the area of immune-oncology, both in the metastatic and adjuvant setting for HR-positive/HER2-negative breast cancer. And then there are other targeted therapeutics that are being developed in the metastatic setting and eventually will be tested in the adjuvant setting if they are well enough tolerated. And all of that hopefully will continue to improve the outcome of our treatments.

Now this has become a little bit challenging because the clinical course of HR-positive/HER2-negative primary breast cancer is relatively indolent. So, there are relatively few recurrences during the first 3 to 5 years, and more than half of the recurrences occur after the first 5 years of follow-up. So, it is becoming increasingly difficult and challenging to demonstrate further improvement because it requires a lot of time. And it requires large numbers of patients and large numbers of resources invested to reach the end points desired. But I'm very optimistic that the changes that are occurring, those that have already taken place, and the ones that are developing will continue to improve the outcome of these patients.