CDK4/6 Inhibitors Exhibit Similarities in Progression-Free Survival for Metastatic ER-Positive/HER2-Negative Breast Cancer

At the 2022 GDU Women’s Oncology virtual meeting, David Cescon, MD, PhD, Princess Margaret Cancer Centre, Toronto, Ontario, Canada, shared important insights evaluating the similarities and differences in CDK4/6 inhibitors for patients with metastatic ER-positive (ER+)/HER2-negative (HER2-) breast cancer.

Dr Cescon discussed the current CDK4/6 inhibitors available for patients with metastatic ER+/HER2- breast cancer: palbociclib, ribociclib, abemaciclib, as well as the novel dalpiciclib. He highlighted the similarities in progression-free survival among these agents and addressed the question of acquired resistance.

Transcript:

Hi, I'm David Cescon, a medical oncologist and clinician scientist from the Princess Margaret Cancer Center in Toronto. I had the recent opportunity to debate one of my colleagues, Dr Dejan Juric [MD] from the Massachusetts General Hospital [Boston, Massachusetts], on the topic, "Are all CDK4/6 inhibitors created equal?" I think that we all recognize this is an important question framed in the context that CDK4/6 inhibitors, in combination with endocrine treatment, have become the standard first-line therapy for metastatic ER-positive, HER2-negative breast cancer.

The interesting difference between CDK4/6 inhibitors, which has of course existed for a while, has really been crystallized following the release of overall survival results from the PALOMA-2 study of palbociclib in combination with an aromatase inhibitor I presented earlier this year, where we saw that the addition of palbociclib was not associated with an improvement in overall survival, when prior results from ribociclib studies have shown statistically significant and clinically important improvement in overall survival. Also, we've seen data from adjuvant studies where abemaciclib has improved outcomes when used for high-risk early breast cancer, where similar studies for palbociclib have not.

So, are CDK4/6 inhibitors equal? My role in the debate was to take the “yes” side, that all CDK4/6 inhibitors are equal. We of course, do recognize that there are different toxicities and schedules with the different agents and that there are biochemical differences in the target profiles of abemaciclib, ribociclib, and palbociclib when they're assessed in detail in vitro. However, a critical similarity between these agents is the progression-free survival data that has been observed in these first-line studies when the different CDK4/6 inhibitors are added to standard endocrine treatment. In each of those, we've observed a hazard ratio, almost identical, around 0.55.

And indeed, a fourth agent, dalpiciclib, evaluated in the DAWNA trial outside of North America, the results which were reported at the 2022 ESMO Congress, demonstrated almost that identical hazard ratio of around 0.5 for progression-free survival when evaluated in the first-line setting. Here we see not 1, not 2, not 3, but indeed, 4 CDK4/6 inhibitors that improve disease control during the time period when they are administered in the metastatic setting in a very similar, if not identical way. If that's the case, why do we see differences in overall survival?

Certainly, there are differences in the trial design which might influence the overall survival end point and its association with the progression-free survival end point. Perhaps there are other post-trial interventions that differ between the agents, or differences in the patient populations who are enrolled. One difference that could explain such a result, if indeed there is a difference in post-progression biology or clinical outcomes between the CDK4/6 inhibitors, might be the mechanisms of acquired resistance that occur with these agents.

We are beginning to understand acquired resistance, the CDK4/6 inhibitors, and the impact that that has on subsequent lines of therapy, but we haven't truly characterized acquired resistance across the full spectrum of CDK4/6 inhibitor response in pivotal studies or in clinical practice. I think that this is an area certainly deserving of future investigation, which might help us understand differences between the CDK4/6 inhibitors. This will certainly inform the way that we better develop subsequent strategies for metastatic ER-positive breast cancer following resistance to CDK4/6 inhibitors.

Source:

Cescon D. Debate: Are All CDK4/6 Inhibitors Created Equal? - YES. Presented at: Great Debates & Updates in Women’s Oncology; September 21-23, 2022; Virtual.