Options With CDK4/6 in HR+ Metastatic Breast Cancer

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Aditya Bardia, MD, MPH: The introduction of CDK4/6 inhibitors has changed the landscape of ER-positive metastatic breast cancer. Before the approval of CDK4/6 inhibitors for first-line management of metastatic breast cancer, it was only endocrine therapy. But with the introduction of CDK4/6 inhibitors, we’ve seen a major and significant improvement in progression-free survival in patients with metastatic ER-positive breast cancer. The PALOMA-1 trial, which was a trial of patients with postmenopausal ER-positive metastatic breast cancer, demonstrated that with the addition of a CDK4/6 inhibitor—palbociclib—to letrozole, you had more than a doubling of progression-free survival. And this led to the accelerated approval of palbociclib in metastatic ER-positive breast cancer.

The PALOMA-2 trial was the confirmatory trial that validated the concept of CDK4/6 inhibitors in metastatic ER-positive breast cancer, and essentially had similar results as PALOMA-1. The patients who received letrozole along with palbociclib had a progression-free survival of almost 25 months as compared to 14 months with the letrozole arm. So, it was more than a 2-year median progression-free survival—something that was never seen in ER-positive metastatic breast cancer before—and led to the full approval of palbociclib as a first-line therapy for metastatic ER-positive breast cancer.

Besides palbociclib, we now have another choice as far as CDK4/6 inhibitor is concerned, and that is ribociclib. The MONALESSA-2 trial demonstrated that the addition of ribociclib to letrozole resulted in an improvement in median progression-free survival in patients with metastatic ER-positive breast cancer. And similar to PALOMA-1 and PALOMA-2, this was also a clinical trial in the first-line setting. The letrozole/ribociclib arm had a median progression-free survival of 25.3 months as opposed to approximately 14 months in the letrozole arm. So, again, it demonstrated a major and a significant improvement in progression-free survival.

Ribociclib is similar to palbociclib in that it’s a CDK4/6 inhibitor. It affects both CDK4 and 6, does not have much impact on CDK2, CDK9. That’s why it is a selective CDK4/6 inhibitor and does not have the toxicity that was seen with the pan-CDK inhibitors. The major toxicity that is observed with ribociclib is neutropenia. Anemia and thrombocytopenia can also be seen.

Now ribociclib is different from palbociclib as far as mechanism of action, but I would say they’re quite similar. Ribociclib might be slightly more selective towards the CDK 4 and 6 if you look at the IC50, but in the clinic, I would say it’s pretty much similar to palbociclib.

If you look at the subset analysis of MONALEESA-2, if you look at patients who had visceral disease—in patients who had visceral disease—you could see a benefit with letrozole/ribociclib as opposed to letrozole alone. And on the opposite spectrum, patients who had bone metastases, you could also see a benefit with ribociclib/letrozole as opposed to letrozole alone. The authors also did a subset analysis looking at elderly patients more than 65 years of age, and even in that subset, you could see an improvement in progression-free survival with letrozole/ribociclib. So, essentially in most patient populations, you could see a benefit with the combination of letrozole/ribociclib and it is the first-line recommended therapy for metastatic ER-positive breast cancer. If you have someone who’s elderly, if you have someone with bone metastases, if you have someone with visceral metastases, for all these indications, letrozole/ribociclib was superior to letrozole alone.

Essentially an aromatase inhibitor, usually letrozole but any aromatase inhibitor with ribociclib or palbociclib, is now the recommended first-line therapy for metastatic ER-positive breast cancer. What happens when a patient progresses on the CDK4/6 regimen, what therapy to choose next? I think that’s an open question at this time. There are a couple of options one could consider. One could consider fulvestrant alone, one could consider fulvestrant with a CDK4/6 inhibitor, one could consider exemestane/everolimus. Whether one option is better than the other, we don’t know at this time. There are ongoing clinical trials comparing these various options, but at this time, the recommended second-line regimen for ER-positive breast cancer is not established.

In terms of my own practice, it’s in part dictated by the amount of disease. In someone who has a lot of bone metastases along with visceral metastases that I’m concerned about, I would feel a bit uncomfortable using fulvestrant as a single agent. Might consider doublets or consider chemotherapy. On the other hand, if I have a patient who had progression in the bone, no evidence of visceral disease, fulvestrant as a single agent would be a very reasonable therapeutic option.

Transcript Edited for Clarity