Final Data From NATALEE Trial Show Benefit of Ribociclib Across Subgroups

In an interview with Pharmacy Times, Gabriel N. Hortobagyi, MD, MACP, FASCO, a professor at the University of Texas MD Anderson Cancer Center, discussed the final data on invasive disease-free survival from the NATALEE trial of ribociclib in combination with a nonsteroid aromatase inhibitor (NSAI).

Q: The NATALEE trial has demonstrated significant benefits in both pre- and post-menopausal patients with breast cancer. Can you discuss why this is important?

A: The hormone receptor (HR)-positive, HER2-negative population of patients with breast cancer is the largest segment of patients with breast cancer. And while we have made very significant progress in the curative approach to their management, there is still a significant probability of recurrence and therefore death for these patients. Furthermore, while the prognosis of these patients is very favorable during the first 5 years, the reality is that more than half of the recurrences occur beyond the first 5 years, whether that is due to lack of senescence, whether that is due to tumor dormancy, or a variety of other mechanisms is uncertain. But there is an unmet need for more effective and long-term treatments for these patients. The CDK 4/6 inhibitors in the metastatic setting have shown significant improvement in progression free survival—and, in the case of ribociclib, overall survival—in several large trials. And on the basis of that observation, we designed the NATALEE trial, which was a phase 3 prospective, placebo-controlled, randomized clinical trial in which patients after completing local regional therapy as per the standard of care were started on endocrine therapy and randomized to receive either ribociclib or not. And ribociclib was given at a 400 mg-per-day dose, 3 weeks on [and] 1 week off, for a total duration planned for 3 years. In June, we reported the first significant results in terms of invasive disease-free survival (iDFS). And the next analysis, which I will present at this meeting, has 6 more months of follow-up and about 100 more iDFS events and continues to show a very highly significant iDFS benefit for the addition of ribociclib to endocrine therapy. This is true for pre-menopausal and postmenopausal patients, and it is true for all prognostic subsets we have examined to date.

Q: What have new data shown with regard to improved tolerability as well as efficacy?

A: Looking at the Kaplan Meier curves of iDFS I presented at the ASCO meeting in June and those I will present at this meeting, there is a continued separation of the control and investigational groups with an ever-expanding difference between the 2 groups. So, at 3 years now, we have observed a 3.3 absolute difference in iDFS, which represents approximately 25% reduction in iDFS.

In relative terms, the dose we used—400 milligrams per day—is 1/3 lower than the dose used for metastatic breast cancer, which was 600 milligrams per day. And we chose that dose for 2 reasons: One, because we were hoping that it would allow us to produce less and less severe adverse events, and therefore would enhance not only tolerability, but more importantly, compliance with treatments. Because, by definition, a drug you don't take cannot possibly help you. The second reason we chose that was because we wanted to extend the duration of adjuvant CDK 4/6 inhibitor therapy to 3 years on the basis of preclinical observations and the hypothesis that longer administration would produce greater suppression of proliferation and induce senescence for the tumor cells. Now, of course, this trial does not compare the different doses of ribociclib, so we cannot be absolutely certain of that comparison, but comparing the adverse event profile or safety profile of the NATALEE trial with the safety profile of the MONALEESA trial, for instance, in the metastatic setting, there are fewer and less severe toxicities with the 400 mg dose. That is true for neutropenia, leukopenia; it is true for fatigue, it is true for nausea. It is also true for the electrocardiographic abnormalities that were observed in both studies. In the NATALEE trial, the QT prolongation was observed in only about 3% of patients and grade 3 or 4 in less than one-half percent. So, overall, we think that the lower dose produces fewer and less severe side effects by indirect comparison of the adjuvant and the metastatic trials, and that should lead to better compliance and adoption of treatment.

Q: How could these improvements be potentially paradigm-shifting for the treatment of HR+/HER2- breast cancer?

A: Now, the NATALEE trial and similar trials with other CDK 4/6 inhibitors are at an early stage of maturity. As I mentioned earlier, the HR-positive/HER2-negative group of patients tends to have a more indolent course, so maturity will come after 5 or 10 or even 15 years. So, we need to be patient before determining exactly how much impact these treatments will have on the field. From what we have seen to-date, and specifically what we have seen in the NATALEE trial, we are very optimistic that not only will we continue to see the benefit for the addition of ribociclib in future years, but possibly this will have repercussions and influence on other endpoints in the trial. Now I failed to mention that by now, almost 80% of patients on the NATALEE trial have stopped taking ribociclib, and the benefit persists beyond the stopping of the drug. And that, of course, is a very important point because sometimes we see transient improvement during the administration of a specific drug. In this case, with almost 80% of the patients having stopped ribociclib, the benefit persist and in fact, it's greater than it was 6 months ago.

Q: What is the role of the pharmacist in managing this regimen?

A: The pharmacist is a critical member of the health care team in oncology, and my group at MD Anderson has formed therapeutic teams that include, of course, the oncologist, the nurse, the pharmacist, the research nurse, and other health care professionals. The role of the pharmacist is multi-pronged. Number one, the pharmacist is intimately familiar with the safety profile of these drugs, [and] not only these but all other oncology drugs in our community. [The pharmacist] also helps us with the identification of potential drug-drug interactions and prevent or minimize such drug interactions. And [they] also help with patient education and help control or prevent the development or minimize the severity of adverse events. So, the pharmacist has a very important role in our therapeutic team. And for drugs that are administered chronically, such as ribociclib, that is even more important because continued reinforcement of compliance with treatment, continued education, and continued encouragement to patients with potential solutions to their side effects and adverse events is very important, and the pharmacists do that better than most other members of the team.