CDK4/6 inhibitor therapy has become a mainstay for the frontline treatment of patients with HR+/HER2- advanced breast cancer. Researchers at the 2024 ASCO Annual Meeting presented data from studies highlighting important considerations in the use of these agents.

Following these proceedings, featured expert Sara M. Tolaney, MD, MPH, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Dr Tolaney’s clinical perspectives on these findings are presented here.

In patients with HR+/HER2- advanced breast cancer, we traditionally would start with an endocrine treatment and 1 of the CDK4/6 inhibitors (ie, palbociclib, ribociclib, or abemaciclib). We have seen a significant overall survival benefit with ribociclib and a trend toward an overall survival benefit with abemaciclib but, unfortunately, no overall survival benefit with palbociclib. So, I think that most physicians are choosing an endocrine drug with either ribociclib or, occasionally, abemaciclib in the upfront setting.

Over the last 6 months, new data have come out suggesting a novel approach in the upfront setting for some patients who have a cancer that is more endocrine refractory (eg, someone whose disease has recurred after or within 1 year of receiving endocrine therapy and has a PIK3CA mutation). The phase 3 INAVO120 trial added the alpha-specific PI3K inhibitor inavolisib to endocrine therapy and a CDK4/6 inhibitor in patients with PIK3CA-mutated HR+/HER2- advanced/metastatic breast cancer. The primary analysis of this study found that median progression-free survival nearly doubled, from 7.3 months to 15 months. At ASCO 2024, additional data from the INAVO120 trial were presented (abstract 1003). I am excited about the priority review by the US Food and Drug Administration (FDA), and I think it is likely that we will see an FDA approval of this triplet strategy.

An FDA approval would change our approach to first-line treatment because it would mean that we would need to know up front whether patients have a PI3K mutation. We often do not have that data right away, and many of us are not rushing to get that information because genomic testing has not impacted treatment decision making in the first-line setting. I think that we will have to shift toward obtaining genomic data. In select patients who have a PIK3CA mutation and are endocrine refractory, we would think about the triplet treatment strategy of fulvestrant, palbociclib, and inavolisib.

One important question that we have been asking is whether there are any benefits to switching the endocrine backbone and continuing a CDK4/6 inhibitor beyond progression in patients who become endocrine resistant and progress on first-line treatment. Will that be useful to maintain cell cycle arrest with the CDK4/6 inhibitor with subsequent lines of therapy?

Data from the phase 3 postMONARCH trial addressing this question were presented at ASCO 2024 in abstract LBA1001. The study looked at whether abemaciclib could be used in patients who had progressed on upfront CDK4/6 inhibitor therapy (ie, palbociclib, ribociclib, or abemaciclib) plus endocrine therapy. Patients who progressed were randomized to fulvestrant plus placebo or fulvestrant plus abemaciclib. We saw that patients in the fulvestrant-plus-abemaciclib arm showed significant improvement in progression-free survival compared with those in the fulvestrant-alone group, suggesting that continuing a first-line CDK4/6 inhibitor beyond progression can be considered. It should be noted that, in the first line, 59% of patients in the study received palbociclib, 33% received ribociclib, and 8% received abemaciclib. It is not clear if it matters which CDK4/6 inhibitor the patient got first and if that influences whether giving abemaciclib will work, since most people had received palbociclib. The problem moving forward is that we are going to see palbociclib being used less in the first-line setting because many of us have switched to using ribociclib, given the survival benefit. There are still some nuanced questions to address regarding who should continue to receive CDK4/6 inhibition beyond progression.

I think that the first-line space is evolving and that it is going to evolve even further because we are even using CDK4/6 inhibitors in the adjuvant space. One could imagine that, over the next several years, we will start seeing some patients who relapse after an adjuvant CDK4/6 inhibitor. How to treat that patient in the first-line metastatic setting is really unknown because we do not have data on treating patients after relapse on an adjuvant CDK4/6 inhibitor. That is something that we will have to address very soon.