Weighing the Options: Considerations for Adjuvant CDK4/6 Inhibitor Selection in HR+ Breast Cancer

Caution is needed when extrapolating the results of the phase 3 NATALEE trial (NCT03701334) with adjuvant ribociclib (Kisqali) in hormone receptor (HR)–positive breast cancer in the absence of data definitively demonstrating the agent’s long-term efficacy and safety, according to Jason A. Mouabbi, MD.

Currently, abemaciclib (Verzenio) is the only FDA approved CDK4/6 inhibitor for adjuvant treatment of patients with HR-positive breast cancer, based on data from the phase 3 monarchE trial (NCT03155997). Although abemaciclib appears to be the therapy of choice for patients with higher-risk disease, ribociclib could provide an effective alternative for patients in this population pending its approval. With this expansion of potential treatment options in the adjuvant setting, Mouabbi added that is imperative for further research to clarify which patients would benefit most from each agent.

“We need to have a mindset of abundancy,” Mouabbi, chair of a recent State of the Science Summit™ on breast cancer, explained in an interview with OncLive^®. “Both drugs have a role in early-stage HR-positive breast cancer; we just need to pick the right patient for the right drug.”

In the interview, Mouabbi outlined the current armamentarium of FDA approved adjuvant CDK4/6 inhibitors in HR-positive breast cancer; discussed the need for a more comprehensive understanding of ribociclib’s long-term benefits in light of its anticipated FDA approval; and explained the importance of considering differences in trial populations, treatment protocol, and patient preferences when selecting between these 2 agents.

Mouabbi is an assistant professor in the departments of breast medical oncology and general oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: Could the present landscape of available adjuvant CDK4/6 inhibitors soon shift in HR-positive breast cancer?

Mouabbi:Currently there is only 1 FDA approved CDK4/6 inhibitor for the adjuvant setting, and that’s abemaciclib. [The approval is] based on data from the monarchE trial, although the NATALEE study, which is evaluating ribociclib, did meet its primary end point of improved invasive disease-free survival in patients who are at higher risk for recurrence. It’s yet to be FDA approved, but we are highly anticipating its FDA approval.

How do the differences in patient populations and treatment protocols between the monarchE and NATALEE trials influence the selection of adjuvant CDK4/6 inhibitors?

The way we define high risk varies from 1 study to another. In monarchE, investigators exclusively enrolled patients with lymph node–positive disease, whereas the NATALEE trial included those also with lymph node–negative disease, which is a big distinction between the 2 trials. Basically, NATALEE [enrolled patients with] all the high-risk features that monarchE [required for enrollment], plus patients [regardless of] node status. [Accordingly], a broader range of patients can qualify for ribociclib than abemaciclib. It’s hard and not advisable to do cross-trial analysis, but because there is nothing else to do and we’re not going to compare those drugs head-to-head, we can just look at the type of patients who were being studied [in each trial to determine the optimal roles of these agents.] monarchE had more patients with extensive lymph node involvement, whereas NATALEE did not have a big proportion of these patients in the study population. [Therefore,] some key opinion leaders in the field are currently stating that abemaciclib may be [considered] for the highest-risk patients. For the patients who are node negative or not as high risk as the patients with significant lymph node involvement, [they feel] ribociclib may be more appropriate.

I don’t know if that’s how I would cherry pick between them. I’m waiting for the FDA approval to then cross that bridge, but I strongly believe that there is a role for each of those drugs. Even the way those drugs are taken [could influence selection], as [abemaciclib] is taken twice a day continuously, and [ribociclib] is taken once a day for 3 weeks with a week off every month. Also, the adverse effect profiles and [treatment] duration of these drugs are different. Very importantly, ribociclib in the NATALEE trial was administered for 3 years, whereas abemaciclib was administered for 2 years in monarchE.

I always like to involve my patients in the decision-making. Some patients will want to go with 1 drug over the other, and some will not have the option to choose, as they only qualify for one drug based on the eligibility criteria of the initial study. Patients need to be involved in the decision-making at the end of the day.

What research still needs to be conducted to better inform the use of these 2 agents?

There is a cautionary tale that happened before those 2 studies with palbociclib [Ibrance], the first CDK4/6 inhibitor developed in the adjuvant setting. There were 2 big [phase 3] studies evaluating it: PALLAS [NCT02513394] and PENELOPE-B [NCT01864746]. Both did not demonstrate improved outcomes [with palbociclib]. The PENELOPE-B study focused on high-risk patients. In that study, at the 2- to 3-year mark, [initial data] showed that there was an improvement in outcomes for patients who received the drug. However, [we later saw that] this gap closed, and those curves have [since] crossed, meaning that there is no significant improvement of outcomes.

But we have over 4 years [worth of] data from the monarchE trial and it’s still going strong. It looks like there is a [continued] effect, because at this point in time, all the patients who receive abemaciclib on the study already finished the 2-year course of treatment. Those patients are still going strong, and we’re not observing as many recurrences [with abemaciclib] as [we are in] the control arm. I would say it’s out of the woods.

For NATALEE, we only have 3-year data. This matters, as it is very important to have long-term follow-up of the primary end point. [We want to see if] this difference [in outcomes continues to favor ribociclib and] gets better with time, like we’re seeing with the monarchE study, or if the [gap] is going to start closing like we observed in the PENELOPE-B study. I don’t want to take the excitement away from these data, and having more options at any stage of any cancer is always encouraged and highly recommended. However, we always need to wait for long-term data.

Given the rapid expansion of therapeutic options in breast cancer, how can oncologists best guide patients through the complex treatment decision-making process?

We are in an era in breast cancer that we’ve never experienced before, and there has been a big expansion of [available] therapeutics. Just a few years ago, we used to get maybe 1 novel drug every couple of years. Nowadays, we’re getting a new drug almost every month. The [armamentarium is] expanding, so it’s important to keep up-to-date and come to events that dive deep into [these] various drugs.

A lot of times the study [evaluating a given agent] itself will not give you the answer. [Instead, you need to] meet with other key opinion leaders, with people who have tried those drugs either on or off study, and dive into those minute differences between studies to know which patient is better for [a given] drug vs the other. We have so many options, which is great for our patients, but it is important to know which drug [should be used] for which patients. Our patients cannot just pick and choose the drugs––they rely on their doctor to know exactly what’s happening in each study, to know the numbers, and what they mean. [They expect us] to give them the best recommendation. Of course, we need to let them be a part of treatment decision-making. Offer them all the options, offer them the numbers, [discuss] how outcomes compare with what’s currently being done, and let them be a part of the decision-making process.

Reference

US FDA broadens indication for Verzenio (abemaciclib) in HR+, HER2-, node-positive, high risk early breast cancer. News release. Eli Lilly and Company. March 3, 2023. Accessed August 21, 2024. https://investor.lilly.com/news-releases/news-release-details/us-fda-broadens-indication-verzenior-abemaciclib-hr-her2-node