Selection of Frontline CDK4/6 Inhibitors Hinges on Patient Health Status in HR+/HER2– Metastatic Breast Cancer

Tanya Gupta, MD

In the hormone receptor (HR)–positive, HER2-negative metastatic breast cancer setting, frontline treatment with CDK4/6 inhibitor–based regimens are standard of care, and selecting between the approved CDK4/6 inhibitors should rely on patient-specific factors, according to Tanya Gupta, MD.

She added that dose adjustments with these agents could help improve tolerability and allow patients to continue receiving treatment.

“We now have data from both the [phase 3] monarchE (NCT03155997) and NATALEE (NCT03701334) studies that demonstrate that efficacy is retained across relative dose intensities [of CDK4/6 inhibitors,” said Gupta, of the Palo Alto Medical Foundation in Mountain View, California. “In other words, we have data from both studies that as you lower the dosage of the medication, you do still retain efficacy, and I found that in my practice, that can really be a source of comfort for patients when they're on the cusp of considering a dose reduction due to adverse effects (AEs).”

Although a CDK4/6 inhibitor plus endocrine therapy is a common selection in the frontline setting for HR-positive metastatic breast cancer, other considerations should be made for certain populations, Gupta explains. For example, in patients with endocrine-resistant disease, treatment of inavolisib (Itovebi) may be optimal, she noted. In October 2024, the FDA approved inavolisib plus palbociclib (Ibrance) and fulvestrant (Faslodex) for the treatment of adult patients with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)–positive, HER2-negative, locally advanced or metastatic breast cancer, which was detected by an FDA-approved test after recurrence on or after completing adjuvant endocrine therapy.1

In an interview with OncLive® following the State of the Science Summit on breast cancer, Gupta detailed the role of CDK4/6 inhibitors in HR-positive, HER2-negative metastatic breast cancer, considerations when selecting optimal treatment, and the safety implications of lowering doses of CDK4/6 inhibitors.

OncLive: What role do CDK4/6 inhibitors have in treating HR-positive, HER2-negative metastatic breast cancer?

Gupta: In the frontline HR-positive, HER2-negative metastatic breast cancer setting, we currently have 3 CDK4/6 inhibitors that are FDA-approved: ribociclib [(Kisqali), abemaciclib [Verzenio], and palbociclib [Ibrance]. Of these 3, ribociclib [plus letrozole] showed a statistically significant improvement in OS [vs placebo plus letrozole], based on data from the phase 3 MONALEESA-2 trial [NCT01958021].2

Abemaciclib [plus an aromatase inhibitor] just narrowly missed the statistical significance for OS benefit [vs placebo plus an aromatase inhibitor in the phase 3 MONARCH 3 trial (NCT02246621)]. Because of that, many oncologists in the United States tend to favor using ribociclib for patients who are being treated for frontline, metastatic HR-positive, HER2-negative [breast cancer].

That being said, there are still appropriate times to use abemaciclib and palbociclib in patients as well. Often, the appropriate choice of CDK4/6 inhibitor is made for each individual patient, and usually, we will take into account the patient's health status, their other comorbidities, and how patients feel about the various AEs associated with each of the individual CDK4/6 inhibitors.

Based on these treatment options for patients with metastatic disease, what are your considerations when selecting optimal treatment?

When I'm selecting optimal treatment in the frontline setting for [patients with] metastatic HR-positive, HER2-negative breast cancer, there are a few different factors that I think about. The first is whether this is relapsed disease or de novo metastatic disease. In particular, if this is relapsed disease, I think about whether the patient was on adjuvant endocrine therapy at the time of relapse, or whether there had been a sizable interval since the patient completed adjuvant endocrine therapy and then had this relapse. If a patient has de novo metastatic disease, then I would typically select, outside of a clinical trial, a CDK4/6 inhibitor, with an aromatase inhibitor. If they are premenopausal, I would also add ovarian suppression. If a patient had a relapse while they were on adjuvant endocrine therapy, they had been on adjuvant endocrine therapy for a period, and they appear to still have endocrine-sensitive disease, then in that case, I would use a CDK4/6 inhibitor with fulvestrant.

Now, there are a few different exceptions here. If a patient had an early relapse after being treated for early-stage breast cancer and I'm concerned that they have endocrine-resistant disease, then I would use the more recently approved therapy inavolisib, which is an oral therapy given in conjunction with palbociclib and fulvestrant. This is based on the phase 3 INAVO120 trial [NCT04191499] that ultimately led to the approval of inavolisib.

Finally, this situation doesn't happen very often, but if a patient is in a visceral crisis, where there is a very high burden of disease, and they're starting to be organ failure due to this high burden of disease, then in those cases, I would generally pick a chemotherapy-based regimen to have a very brisk response.

In general, when treating HR-positive, HER2-negative breast cancer, what evidence has been shown that lowering the dose of CDK4/6 inhibitors is safe?

That’s a common question [I get] from patients who are taking adjuvant CDK4/6 inhibitors and whether it's safe for them to receive a lower dose. Sometimes patients have AEs, and they're trying to push through them. [However,] they could potentially benefit when it comes to quality of life by lowering the dosage of the CDK4/6 inhibitor. It can be helpful for patients to know that efficacy is still retained at lower dosages of the drugs.

References

1. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. FDA. October 10, 2024. Accessed March 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive
2. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med. 2022;386(10):942-950. doi:10.1056/NEJMoa2114663