AE Profiles and Dosing Schedules Define the Role of CDK4/6 Inhibitors in HR+ Metastatic Breast Cancer

Ribociclib (Kisqali) and abemaciclib (Verzenio) are top frontline and adjuvant treatment choices for patients with hormone receptor–positive metastatic breast cancer, although, in the absence of predictive biomarkers, decisions between CDK4/6 inhibitors in these settings often ultimately hinge on patient characteristics and ability to tolerate each agent, according to Kari Wisinski, MD.

“There’s high-level evidence that ribociclib and likely abemaciclib improve overall survival [OS] for first-line metastatic hormone receptor–positive breast cancer,” Wisinski said in an interview with OncLive^® following a State of the Science Summit™ on breast cancer, which she chaired.

In the interview, Wisinski discussed factors that influence her decision between available CDK4/6 inhibitors for patients with previously untreated, hormone receptor–positive metastatic breast cancer, questions regarding the potential role of these agents in the adjuvant setting, and what the future may look like regarding the sequential use of these agents.

Wisinski noted that data from trials such as the phase 3 NATALEE trial (NCT03701334) are helping to inform the adjuvant use of CDK4/6 inhibitors, although questions about optimal patient selection remain. In NATALEE, at a median follow-up of 44.2 months, ribociclib plus a nonsteroidal aromatase inhibitor (AI) generated an invasive disease-free survival (IDFS) benefit vs a nonsteroidal AI alone in patients with hormone receptor–positive, HER2-negative early breast cancer (HR, 0.715; 95% CI, 0.609-0.840; nominal 1-sided P < .0001).¹ Furthermore, at a median follow-up of 44.3 months, investigators observed a positive trend for overall survival (OS) favoring the ribociclib arm (HR, 0.827; 95% CI, 0.636-1.074; nominal P = .0766).

She also pointed out that gaps in currently available trial data indicate the need for improved patient selection tools when considering using one CDK4/6 inhibitor after another. For instance, although the phase 3 postMONARCH trial (NCT05169567) showed that treatment with abemaciclib plus fulvestrant (Faslodex) following disease recurrence on a prior CDK4/6 inhibitor in the advanced setting led to a 27% reduction in the risk of developing a progression-free survival (PFS) event vs fulvestrant alone (HR, 0.73; 95% CI, 0.57-0.95; nominal P = .02), it is not yet known which subgroups of patients may benefit the most from this treatment approach.²

Wisinski is the Endowed Professor of Hematology and Oncology and chief of the Division of Hematology, Medical Oncology and Palliative Care in the Department of Medicine at the University of Wisconsin (UW) School of Medicine and Public Health in Madison. She is also the associate director of Clinical Research and co-lead of the Breast Cancer Disease Oriented Team at the UW Carbone Cancer Center.

OncLive: How is your selection between the currently available CDK4/6 inhibitors for patients with previously untreated HR-positive metastatic breast cancer influenced by the safety profiles of these agents and patient characteristics?

Wisinski: I tend to pick [either ribociclib or abemaciclib] to start, often ribociclib because it is the only agent that has shown a clear survival [benefit compared with chemotherapy]. There are times, though, that either the [ribociclib dosing] schedule of 3 weeks on and 1 week off vs the daily [abemaciclib dosing schedule] or safety can encourage you to pick a different medication, and that’s often [decided] in discussion with the patient.

For example, if a patient is a little more frail and I’m a bit more worried about the adverse effects [AEs] of diarrhea or neutropenia or just general tolerance, I have picked palbociclib [Ibrance] at times. Although the neutropenia rates can be similar [between all these agents], I find [palbociclib] to be a bit more tolerable from an AE standpoint than both the other agents. Sometimes, because of cardiac risk factors, I’ll pick palbociclib as well. Occasionally, there’s [a patient for whom the] 3 weeks on 1 week off schedule [of ribociclib] will be harder for them to follow, so abemaciclib is a good choice too. I continue to keep all 3 [agents] on my radar and use all 3. The PFS outcomes were similar between all the first-line studies [of these agents], but the OS data have sent me to use ribociclib or abemaciclib more often.

What new information do we still need to learn about CDK4/6 inhibitors to optimize their use in the adjuvant setting?

In the adjuvant setting with the CDK4/6 inhibitors, there remain some key questions. First and foremost: Does an improvement in IDFS lead to an OS benefit? That may be difficult for us to ever prove, as patients go on to receive subsequent lines of therapy, but it remains a big question.

The second big question is the selection of patients. The [phase 3] adjuvant CDK4/6 inhibitor studies that demonstrated [IDFS] benefit [vs standard of care], monarchE [NCT03155997] and NATALEE, showed that the absolute number of [patients who] benefit is still relatively small, and therefore the number [of patients] needed to treat [to see that benefit] is relatively high. That just means it would be ideal if we could develop an improved biomarker to help select which patients get the benefit from this therapy, or maybe flip it the other way [to determine] which patients don’t need that therapy because they’re going to continue to do well because that is what we see in most of these patients.

The third big question I have is: How long is the optimal duration [of treatment]? Is it 2 years, which [is the length of] abemaciclib [treatment]? Is it 3 years [like the length of treatment with] ribociclib? Could it be shorter? It is a big commitment for patients to continue that therapy, [including] additional visits for them in the clinic. Even if we can think about creative strategies like telemedicine, [treatment with these agents] still ends up [taking] more time and more potential AEs for a long duration of time.

Is the sequential use of CDK4/6 inhibitors feasible and effective?

In the metastatic setting, switching from a first-line CDK4/6 inhibitor to a subsequent-line CDK4/6 inhibitor plus endocrine therapy is reasonable and feasible. Overall, it’s a well-tolerated approach and can be a way to delay the onset of systemic therapies, either antibody-drug conjugates or chemotherapy, for at least a period. The challenges we have now are identifying whether we should use a sequential CDK4/6 inhibitor vs a different genomically targeted agent, such as an AKT inhibitor, in this setting if a patient has a known PI3K pathway alteration. We don’t know the answer to that, and that remains one of our challenges.

In addition, the PFS benefits seen [with CDK4/6 inhibitor switch] in both the [phase 3] MAINTAIN [NCT02632045] and postMONARCH studies were relatively modest. I think that tells us we still need to have better tools to select which patients are going to benefit the most from this type of approach and [which patients] should maybe move on to a different therapy.

References

1. Fasching PA, StroyakovskiyD, Yardley D, et al. Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial. Ann Oncol. 2024;35(suppl_2):1-72. doi:10.1016/annonc/annonc1623
2. Kalinsky K, Bianchini G, Hamilton EP, et al. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: primary outcome of the phase 3 postMONARCH trial. J Clin Oncol. 2024;42(suppl 17):abstr LBA1001. doi:10.1200/JCO.2024.42.17_suppl.LBA1001