Richard Finn, MD
Earlier this month, the FDA granted an accelerated approval to the CDK 4/6 inhibitor palbociclib (Ibrance) as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer.
The drug was approved based on results from the phase II PALOMA-1 trial, which showed a remarkable increase in progression-free survival (PFS) with palbociclib and letrozole compared to letrozole alone. Palbociclib, which previously received the FDA’s breakthrough therapy designation, is the first CDK4/6 inhibitor made available for any indication.
For further insight on the significance of palbociclib’s approval, OncLive
sat down with the lead investigator of PALOMA-1, Richard Finn, MD, from the Jonsson Comprehensive Cancer Center at UCLA.OncLive: What makes palbociclib such a groundbreaking treatment for advanced breast cancer and what was the basis for the FDA’s approval?Dr Richard Finn:
Palbociclib is the first cyclin-dependent kinase 4/ 6 (CDK4/6) inhibitor approved by the FDA for any indication. The current indication is for first-line treatment of advanced postmenopausal, ER+/HER2- breast cancer. This approval is based on a strong preclinical and clinical data set that suggests that CDK4/6 inhibition is important in this subtype of breast cancer. It is based on laboratory data initially done by Dr Dennis Slamon and myself and the team here at UCLA in collaboration with Pfizer, which identified that ER+/HER2- models seem sensitive to CDK 4/6 inhibition. In addition, we demonstrated preclinically that there was synergistic inhibition of growth when combined with antiestrogen.
With this in mind, we designed a global, open-label randomized phase II study comparing palbociclib and letrozole with letrozole alone. And it is the result of this phase II study that really demonstrated a significant improvement in PFS. In the study, about 165 women were randomized between the two arms and those who received letrozole alone had a PFS of about 10 months, and those who received palbociclib had a PFS of about 20 months. So that’s a hazard ratio of 1.49 or a 51% decrease in the risk of progression. So it’s really this striking improvement in PFS that garnered palbociclib a breakthrough therapy designation and then expedited approval for this indication.Were you expecting those results or were you surprised by the drug’s success?
I think we were all pleasantly surprised by the magnitude of benefit that we saw with palbociclib and letrozole. The preclinical data were very striking to us, but as we all know, preclinical data don’t always lead to improvements in patients in the clinic. But this significant improvement of over 10 months, essentially doubling the PFS, I cannot say was expected. We are all very happy and pleased that the FDA made this agent available to patients as soon as possible, and we are really struck that this was such a positive study. What do you think will be the biggest impact of palbociclib being approved so quickly for this patient population?
Palbociclib and letrozole are now a good option for women with advanced post-menopausal, ER+/HER2- breast cancer. This is a large indication; ER+ breast cancer makes up about 60% of breast cancer, and antiestrogens have been a standard first-line approach for these women. Now with the addition of palbociclib, given the magnitude of benefit and the safety profile, I think this is a very good option with this indication.
There are ongoing studies of palbociclib with other antiestrogens specifically the PALOMA-3 study with fulvestrant and palbociclib or fulvestrant alone for women with aromatase inhibitor (AI)–refractory disease. But right now, as it stands, with the expedited approval, this is a very good frontline option for women with ER+ breast cancer.Do you anticipate other similar drugs coming down the pipeline or other indications being approved for palbociclib?
This is the first approved CDK4/6 inhibitor. I think given that CDK biology has been known for several decades, now this is an important step forward because it has validated the target as a valid therapeutic target in cancer medicine. CDK inhibitors have been around in the past, but they never really advanced very far in the clinic because of toxicity and lack of activity. What has been delivered now is proof of concept that a CDK4/6 inhibitor can play a role in treating human cancer. I think this first indication is just that, a first indication. I have a lot of confidence that in other areas of breast cancer and other lines of therapy that drugs like palbociclib will play a role. Hopefully, now that CDK4/6 inhibition has found a first step, there will be a role in other malignancies.