Pivotal Studies for CDK4/6 Inhibitors

William J. Gradishar, MD provides a summary of the pivotal trials for CDK4/6 inhibitors.


William J. Gradishar, MD: The data from the use of CDK4/6 inhibitors in metastatic breast cancer have been remarkably consistent across all the different trials and settings. That’s a very broad statement, but we know that when the CDK4/6 inhibitors were introduced initially, they had a profound effect on progression-free survival that was consistent both in the first- and second-line settings.

Now, we’re starting to see overall survival data emerge from the pivotal trials looking at each of the different drugs that are currently available—palbociclib, ribociclib, and abemaciclib. If we look at the individual trials that have been most informative, we have the MONARCH-2 trial that looked at the combination of abemaciclib and fulvestrant versus fulvestrant alone. That trial clearly demonstrated that there was an impact on overall survival that was clinically significant.

The same can be when looking at the other drugs when they were evaluated in a similar fashion, including the PALOMA-3 trial, which was a palbociclib trial in which palbociclib was combined with fulvestrant versus fulvestrant alone. A similar survival benefit was found in these patients who had previously received endocrine therapy. Finally, the data with ribociclib were demonstrated in the MONALEESA-7 trial, which was conducted in pre- and perimenopausal women rendered postmenopausal by getting goserelin. They either received tamoxifen or an aromatase inhibitor [AI] alone or with a CDK4/6 inhibitor. In this case, it was ribociclib.

This trial also demonstrated that there was an impact on survival favoring the inclusion of a CDK4/6 inhibitor, which in this case, was ribociclib. The interesting thing is that it demonstrated for the first time that in premenopausal women rendered postmenopausal, the impact of a CDK4/6 inhibitor was the same as we see in postmenopausal women. Finally, the MONALEESA-3 trial that Dennis Linehan, MD, published in the New England Journal of Medicine showed a similar finding to all the other trials that I’ve mentioned. That is, when you combine CDK4/6 inhibitors, in this case ribociclib with fulvestrant compared with fulvestrant alone, you see the same impact on survival.

There has been a consistency across the trials demonstrating that using this class of drugs in combination with endocrine therapy in the setting where you’re using fulvestrant has impacted overall survival in a positive way. In the MONALEESA-7 trial, you can demonstrate a similar impact on overall survival when combining ribociclib with goserelin to render patients postmenopausal, either with an AI or tamoxifen, and see the same impact. It’s been a remarkable demonstration of consistency with a class of drugs that we widely use today.

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