Today, we are discussing a class of oncology drugs, the CDK 4/6 inhibitors with Dr. Richard Finn, an associate professor of medicine at the Geffen School of Medicine and a medical oncologist at the University of California Los Angeles Jonsson Comprehensive Cancer Center. Dr. Finn has taken part in clinical trials with CDK 4/6 inhibitors for breast cancer.
—Interviewed by Anna Azvolinsky, PhD
OncoTherapy Network: Dr. Finn, can we start with the functions of CDK 4 and 6 are in the cell, and why might they be important to target in breast and other tumor types?
Dr. Finn: Cyclin-dependent kinases are a large family of intracellular serine, threonine kinases that play a very important role in regulating cell cycle progression and ultimately cell division. They have an important role in both normal and increasingly, [we are finding] in malignant conditions. They do not function independently, but are activated by copartnering with the cyclin proteins, and hence their name of cyclin-dependent kinases. CDK 4/6 specifically have been selected for drug development more recently. There have been older drugs in development that have not succeeded in moving beyond phase 1, 2 studies largely because of toxicity issues. These first generation CDK inhibitors tended to be less specific, targeting other CDKs in a broad fashion and were associated with chemotherapy-like toxicities. More recently we have seen the development of a new generation of very specific CDK 4/6 inhibitors and these drugs may play a role in treatment of various cancer types. The CDK 4/6 inhibitors play a key role in regulating the transition from G1 to the S-phase of the cell cycle. Normally, this is all tightly regulated, but in malignancy, this transition point can become less closely regulated allowing for less controlled proliferation. CDK 4/6 cyclin D complex are responsible for adding phosphates or phosphorylating the retinoblastoma protein (Rb). When the retinoblastoma protein becomes hyperphosphorylated, it releases its break on the G1-S transition allowing for cell cycle progression. The idea is that by blocking CDK 4/6 kinase activity, we can block phosphorylation of Rb and induce G1 arrest, preventing cell cycle progression.
OncoTherapy Network: Can you briefly discuss some of the data thus far that has been seen of these oral agents in breast cancer?
Dr. Finn: The idea of targeting CDK 4/6 in cancer is a relatively old idea. The discovery of CDKs goes back several decades and the Nobel Prize was awarded for this discovery in the early 2000s. But the clinical translation of this biology has been slow in coming partly because of not having good compounds. What’s aided their use in breast cancer is work done at UCLA by myself and my colleague Dr. Dennis Slamon, and a collaboration with Pfizer where we evaluated a very specific CDK 4/6 inhibitor, PD-0332991. Currently that compound has the name palbociclib. Pre-clinical work identified the role of CDK 4/6 inhibition specifically in ER-positive breast cancer. This was not necessarily intuitive, but in an unbiased approach we evaluated the compound in various subtypes of breast cancer, and the models predicted that the specific activity of this compound in the ER-positive subtype. There was also data to suggest that it might have activity in the HER2-amplified group as well. When we looked at some of the biological reasons for the specificity to this type of breast cancer, it was related to the fact that the ER-positive breast cancers were dependent on the cyclin D1 CDK 4/6 pathway. That is to say, they have an intact Rb function that is amenable to being manipulated by CDK 4/6 inhibition.
We went on to show preclinically that in the ER-positive subtype, that there was a synergistic effect of blocking proliferation with palbociclib and antiestrogens. With this information, we developed a phase 1/2 study to evaluate these preclinical observations. The PALOMA-1 study which we presented at the AACR meeting this year, 2014, was designed to evaluate the safety and efficacy in an open-label format of palbociclib plus letrozole versus letrozole alone. Results from this study were quite significant. The study was relatively small, but we saw a dramatic improvement in progression-free survival with the addition of palbociclib to letrozole in a frontline ER-positive, postmenopausal population. We saw that progression-free survival with letrozole alone was a little over 10 months, and with the addition of palbociclib this increased to over 20 months. This is a very significant finding and has now been used to drive a phase 3 program with palbociclib in the same type of patient population in the same combination. What was also striking about the data is that the addition of palbociclib to letrozole had a very predictable and manageable safety profile. The common side effects we saw were neutropenia, leucopenia, and fatigue. While there was frequent grade 3 neutropenia, and specifically that is absolute neutrophil count between 500 and 1,000, this typically recovered with time or dose modification. Importantly, we did not see any neutropenia fever or infection secondary to the neutropenia.
OncoTherapy Network: So far, the clinical trials with these agents have focused on hormone-receptor positive metastatic breast cancer patients who have not yet received prior therapies. Can you talk a little bit about the rationale for targeting this patient population?
Dr. Finn: The preclinical data generated, demonstrated unique synergy between palbociclib and antiestrogens in vitro. The rationale for that, biologically, seems to be that estrogen receptor-driven proliferation ties into the cyclin D1 CDK4/6 Rb pathway. In addition, we are now targeting that pathway now, not only with antiestrogens, but with a CDK inhibitor. That is one hypothesis as to why we are seeing synergy in the lab and now, likely in the clinic. That being said, there is reason to think that this combination will work in patients beyond the first-line setting. The first-line setting was selected because letrozole and other aromatase inhibitors are a standard therapy in this space, and it provided for a clean clinical read out in this population of patients. But as I said, there is no reason to think that this combination might not work in later lines of therapy. Certainly, there have been phase I data in heavily pretreated patients with palbociclib as well as the Eli Lilly compound that shows that these [CDK 4/6] inhibitors have single-agent activity even in patients who have received prior therapies. There are phase 3 studies ongoing with palbociclib and fulvestrant in patients who have had prior hormonal manipulations. And there are other studies with the other CDK 4/6 inhibitors in similar populations.
OncoTherapy Network: Are there studies that suggest these drugs may be synergistic with other targeted agents?
Dr. Finn: There is now a lot of activity around combining CDK 4/6 inhibitors with other standard of care, as well as other novel agents. As I mentioned, there is interest in combining CDK 4/6 inhibition with other antiestrogens. There are ongoing studies with Novartis’s CDK 4/6 inhibitor, LEE001, in combination with everolimus and exemestane, in a space where everolimus and exemestane are already being used in hormone-refractory patients. There has been data that suggests that inhibition of CDK 4/6 with PI3K inhibition may be a benefit in the ER-positive space as well. We had done work initially when we published the data with palbociclib and antiestrogens, we also demonstrated that palbociclib in combination with trastuzumab looks to be synergistic in vitro, and likely will be evaluated in the near future—or with another CDK 4/6 inhibitor that is in development. There is now interest outside of breast cancer looking at CDK 4/6 inhibition with other agents in other diseases such as in lung cancer and also others.
OncoTherapy Network: Thank you so much for joining us today, Dr. Finn.
Dr. Finn: Thank you for having me.