Richard S. Finn, MD
Associate Professor of Medicine
Division of Hematology/Oncology
Co-director, Signal Transduction and Therapeutics Program
Jonsson Comprehensive Cancer Center
Geffen School of Medicine at UCLA
Los Angeles, California
Transcript and References
Hi, I'm Dr. Richard Finn from the Division of Hematology/Oncology at the Geffen
School of Medicine at UCLA. Thank you for joining me today for this educational
activity reviewing the role of cyclin-dependent kinase (CDK) 4 and 6 inhibitors in the
management of breast cancer.
When we're talking about CDKs, we're focusing on a target that plays a critical role in
controlling cell division. If we step back and just think about the cell cycle, which we all
learn about in our training, we remember that the cell cycle under normal conditions is
very tightly controlled and is divided into several distinct phases, and the role and goal of
each phase is to prepare for the next phase and ultimately mitosis and cell division.
During each transition point from each phase to the next, there are key regulatory
components and proteins and genes involved that regulate cell division so that daughter
cells do not contain genetic errors. We know the four phases are G1, S, G2, and then
CDKs are a large family of serine/threonine kinases that play a role in regulating these
transitions from one phase of a cell cycle to the next. As their name implies, they do not
function by themselves but interact with regulatory subunits called the cyclin proteins.
Together, cyclins and their corresponding CDK function to regulate cell division.
There are several known CDKs and cyclins. In general, they play specific roles during
specific parts of the cell cycle. In addition, specific CDKs interact with specific cyclin
For example, CDKs 4 and 6, which play a key role in regulating their transition from G1
to S, typically associate with D-type cyclins; CDK2 proteins interact with the E- and Atype
and again regulate cell cycle progression at various stages. There are also some
CDKs that function as transcription factors and not as catalytic enzymes.
In breast cancer, alterations in the cyclin D/CDK 4/6 pathway have been described.
Throughout the years of basic science, we've understood that amplification of cyclin D1
occurs in a subset of breast cancers. Overexpression also occurs. There can be alterations
in CDK 4, both amplification and overexpression. Ultimately, retinoblastoma (Rb) loss—
the loss of the RB gene product that is critical in regulating G1 to S and is the target for
CDK 4/6—is lost in a subset of breast cancers.
There can also be loss of negative regulators of the pathway, such as p16 and p27, which
when lost cause this pathway to become hyperactive. When correlating all these genetic
alterations with various clinical findings, such as response to antiestrogens and prognosis,
we see that in some studies, the alterations appear to be favorable, and in others they are
negative prognostic factors.
But ultimately in breast cancer, when we think of the various molecular subtypes of this
disease, we know that breast cancer can be driven by growth factor signaling, which in
some cases involves peptide growth factors such as the human epidermal growth factor
receptor 2 (HER2) and epidermal growth factor receptor pathways, among others, or
steroid growth factors such as estrogen. Regardless of whether these breast cancers are
driven by peptide growth factors or steroid growth factors, the common denominator is
that these pathways feed into the cyclin D1/CDK 4/6 pathway.
On this slide, we see a diagram of how CDK 4/6, cyclin D, and Rb play a role in cell
cycle progression. As you can see on the outside of the cell, there are various mitogenic
factors, such as estrogen binding to the estrogen receptor, and other peptide growth
factors such as the HER family driving increased expression of cyclin D1, which then
interacts with CDK 4/6.
Together, cyclin D1 and CDK 4/6 are responsible for adding phosphates, or
hyperphosphorylating, the Rb protein in the nucleus. Once Rb is hyperphosphorylated, it
releases the E2F transcription factor to allow preparation and transition into S phase, and
this hyperphosphorylation of Rb is a critical point in this G1 to S progression.
There are various CDK 4/6 inhibitors in development—palbociclib, ribociclib (previously
known as LEE011), and abemaciclib—the LY compound on the diagram. All are
designed to block the CDK 4/6 kinase and therefore block hyperphosphorylation of Rb,
and therefore induce a G1 arrest and prevent cell cycle progression.
One of the first selective CDK 4/6 inhibitors to go to clinical development is this
compound, palbociclib. As you can see from its kinase profile, it is very selective for
CDK 4 and 6 with the low IC50 (50% inhibitory concentration). This is different from
early generation CDK inhibitors, which were very nonselective and had activity against a
broad spectrum of CDKs, and as a result did not function very well in the clinic.
Critical to the development of any new drug in cancer medicine is to identify a patient
population that we think is most likely to benefit. This slide demonstrates some of the
pivotal preclinical data that identified a role for CDK 4/6 inhibitors in estrogen receptor
(ER)–positive breast cancer. As you can see along the x axis, there's a large panel of
breast cancer cell lines color-coded according to their molecular subtype. Their
sensitivity to palbociclib is on the y axis—the lower number meaning the cell lines that
are more sensitive.
As you can see, the cell lines that were most sensitive to palbociclib represented the
luminal ER-positive breast cancer subtypes as well as some of the HER2 amplified cell
lines, whereas those that were most resistant tended to be the non-luminal or ER-negative
lines. This led to a hypothesis that perhaps if we were to move a drug like palbociclib or
other CDK 4/6 inhibitors into the clinic, we would focus on the ER-positive subgroup.
As a pathway to clinical development, I, Dr. Slamon, and other colleagues at UCLA
looked preclinically at the role of palbociclib in combination with tamoxifen in vitro in
several ER-positive cell lines. As you can see, there was a synergistic interaction between
antiestrogens and CDK 4/6 inhibition in increasing the amount of cell cycle arrest and
This led to an open-label, randomized, phase 2 study, the PALOMA-1 study, to test the
idea of whether this laboratory observation would hold up in the clinic. This study was
designed in two parts. Both parts of the study enrolled women that were ERpositive/
HER2-negative, postmenopausal, with advanced breast cancer and were not
treated for metastatic disease. They could have treatment for adjuvant disease, but had
not received therapy yet for their advanced disease and were randomized between the
combination of palbociclib and letrozole versus letrozole alone.
Palbociclib was given 125 mg daily, 3 weeks on/1 week off, and these cohorts were
accrued sequentially, initially just based on ER-positive/HER2-negative, then another
cohort, ER-positive/HER2-negative, but also evaluating patients who have molecular
alterations in the cyclin D1 pathway, such as cyclin D1 amplification or loss of p16, the
negative regulator, the idea being to try to select a finer group of patients other than ERpositive
The patients were well balanced for various prognostic factors. There were some slight
imbalances, perhaps a little more visceral disease in the letrozole-alone arm. However, I
would like to point out that about half the patients in each arm had a new diagnosis or had
never had prior systemic treatment in the adjuvant setting, but approximately one-third of
patients had prior anti-hormonal treatment such as tamoxifen or even aromatase
This was a positive study. This was an open-label study, but there was a significant
improvement in progression-free survival (PFS)—the primary endpoint—with the
addition of palbociclib to letrozole. Here you see the hazard ratio is 0.488 for PFS, or
approximately a 51% decrease in the risk for progression with the addition of palbociclib.
Median PFS was improved by about 10 months, from about 10.2 months with letrozole
alone to just over 20 months with the addition of palbociclib.
Here on this forest plot, you can see that across many clinically important subgroups,
there was a consistent benefit with the addition of palbociclib to the letrozole. That
includes cohorts 1 or 2, whether you considered just ER-positive or had the additional
markers of cyclin D1 and p16 loss. Both groups had a significant improvement in PFS.
There was also a significant improvement whether they had visceral disease or bone-only
disease, prior chemotherapy, prior antiestrogen therapy, or prior systemic therapy. There
was significant improvement for patients who had de novo disease or those who had prior
adjuvant chemotherapy or any adjuvant therapy.
Secondary endpoints include response rate; there was a significant improvement in
response rate. If we look at all randomized patients, not just those with measurable
disease, the improvement in response was from 33% to 43%. If we look at patients who
just had measurable disease, the improvement was from 39% to 55%, so there was a
consistent benefit in improving response.
Arguably, response rates of 55% with the combination of CDK 4/6 inhibition and
letrozole rival any combination chemotherapy regimen. If you include the stable disease
rate for more than 6 months of 32% in all patients, we're approaching a disease control
rate of 80% or higher.
Certainly, we need to consider side effects when evaluating a new agent in cancer
medicine. As we see on this slide of the side-effect profile of the combination of
palbociclib and letrozole, the most common adverse events that were observed were
leukopenia and neutropenia. This was an expected finding—given the mechanism of
action of a CDK 4/6 inhibitor—that it would affect the bone marrow, which is
proliferating. In the dosing regimen, palbociclib was dosed 3 weeks on/1 week off to
allow for bone marrow recovery. Remarkably, even though we had neutropenia, no cases
of febrile neutropenia were seen.
When we talk about grade 3 neutropenia, we mean an absolute neutrophil count of 500 to
1,000. Even though that happened with a high frequency, it was not complicated by
serious infections and typically resolved on its own; growth factors in general were not
required for managing patients. Importantly, other significant side effects of
chemotherapy were uncommon, such as complete alopecia, diarrhea, nausea, and
vomiting. Taken together, the combination had a very manageable side-effect profile that
balanced out the impressive results in improving PFS.
Based on these data, palbociclib was granted accelerated approval by the US Food and
Drug Administration (FDA) on February 3, 2015, for the indications studied in the
PALOMA-1 clinical trial—that is, in combination with letrozole for the treatment of
advanced postmenopausal breast cancer that is ER positive/HER2 negative.
Given that it was an accelerated approval, a confirmatory study was required. The
PALOMA-2 study enrolled 666 women in a 2:1 fashion. It was double-blind, placebocontrolled
to letrozole plus palbociclib 125 mg daily, 3 weeks on/1 week off, versus
letrozole and placebo, again selecting patients only for ER-positive/HER2-negative status,
given the cyclin D1 p16 evaluation in PALOMA-1 did not add any benefit over ER
positive alone. The results of this study will be presented at the American Society of
Clinical Oncology (ASCO) 2016 meeting. [Editor’s note: The clinical benefit and safety
of palbociclib and letrozole in postmenopausal women with ER-positive, HER2-negative
advanced breast cancer were confirmed in the randomized phase 3 PALOMA-2 study.]
Last year at the ASCO 2015 meeting, results of PALOMA-3 were presented. This study
evaluated palbociclib with fulvestrant versus placebo and fulvestrant and, unlike
PALOMA-1 and PALOMA-2, it enrolled patients who had endocrine resistance that had
progressed either on a prior endocrine regimen or within 12 months of completing
adjuvant therapy, and these patients had to have had an aromatase inhibitor. Also, this
study included patients who were premenopausal as long as they were on ovarian
These are the baseline characteristics for the study. About 20% of patients in each arm
were premenopausal or perimenopausal.
What was reassuring from the PALOMA-3 study is that the side effect profile of
palbociclib mimicked the smaller PALOMA-1 study; that is, the most common side
effects were neutropenia and leukopenia. But, again, there was no increase in the
incidence of neutropenic fever compared with fulvestrant alone. Again, these side effects
were managed with dose delays or dose reductions.
The primary endpoint of this study was PFS. Again, there was significant improvement in
PFS with the addition of palbociclib to fulvestrant, improving PFS from 3.8 months to
9.2 months. This correlated to a hazard ratio of 0.422 and was very statistically
If we look across patient subgroups, as seen in PALOMA-1, a consistent benefit with the
addition of palbociclib to fulvestrant based on several important clinical criteria,
essentially all of them showing a benefit with the addition of palbociclib.
There was a quality-of-life assessment included in PALOMA-1, and importantly despite
having some increased side effects compared with fulvestrant alone, there was an
improvement in quality of life with the addition of palbociclib.
There are several ongoing studies with palbociclib in breast cancer. Perhaps most
important is the movement of palbociclib to the adjuvant setting. This study, the
PALLAS study, is currently being conducted through the US cooperative groups and will
be evaluating palbociclib for 2 years plus standard endocrine therapy versus endocrine
therapy alone to see if this improvement in PFS that we've seen in PALOMA-1 translates
into a decrease in recurrence for early breast cancer.
There are other CDK 4/6 inhibitors in development. This compound abemaciclib is a very
potent inhibitor of CDK 4/6, as you can see on this kinase profile.
It's been evaluated in several single-arm studies. This study looked at a dose-expansion
cohort in patients with advanced breast cancer. Unlike palbociclib, abemaciclib is dosed
daily without a break on a 28-day cycle.
Abemaciclib showed impressive single-agent activity. Here on this waterfall plot, you
can see a number of patients have had significant decreases in their tumor burden, as well
as a number having prolonged stabilized disease. And as we saw from the preclinical data,
the patients who are achieving this are those that are hormone receptor-positive.
As mentioned before, many of these responses were maintained for a long time, and
again this was in a cohort of patients who had several prior treatments.
This slide shows the response data between the hormone receptor-positive and hormone
receptor-negative patients. This study accrued all patients with metastatic breast cancer,
but it was observed that it was the patients who were hormone receptor-positive who had
responses and prolonged stabilization of disease, supporting the idea that abemaciclib
could play a role in ER-positive breast cancer.
The side effect profile with abemaciclib is similar to palbociclib and other CDK 4/6
inhibitors. There might be a suggestion that the incidence of leukopenia might be a little
lower, whereas the incidence of gastrointestinal toxicity might be a little higher. This will
have to be further evaluated in larger studies.
However, based on this impressive single-agent activity in patients with advanced breast
cancer that has been heavily pretreated, abemaciclib was granted a Breakthrough Therapy
Designation by the FDA, and further action on that is awaited.
Meanwhile, abemaciclib has moved into several phase 3 studies. The MONARCH 2
study is evaluating abemaciclib with fulvestrant versus fulvestrant alone in patients with
advanced breast cancer that had prior treatment with antiestrogens.
The MONARCH 3 study is looking at abemaciclib with a nonsteroidal aromatase
inhibitor versus placebo and a nonsteroidal aromatase inhibitor. This study is very similar
to the PALOMA-1 and PALOMA-2 studies.
Ribociclib is the other CDK 4/6 inhibitor that is in advanced development. Like the prior
two compounds, it is very selective for CDK 4/6 versus other CDKs or other kinases.
Like the other compounds, this drug has demonstrated single-agent activity. Like
palbociclib, it is dosed 3 weeks on/1 week off to help manage the bone marrow
suppression that is seen. It's being evaluated as a single agent as well as in combination
with other novel agents.
The MONALEESA program is evaluating ribociclib in various indications.
MONALEESA-1 is a presurgical biomarker-driven study, whereas MONALEESA-2 and
MONALEESA-3 are phase 3 randomized studies in combination letrozole or fulvestrant,
respectively, very similar to the path taken by palbociclib and abemaciclib. Finally,
MONALEESA-7 is a phase 3 study in combination with antiestrogens. This appears to be
the only study that is exclusively enrolling only premenopausal women.
This is the schematic for MONALEESA-2, a 1:1 randomization of ribociclib 3 weeks
on/1 week off and letrozole, versus letrozole and placebo, the primary endpoint being
PFS. Enrollment to this study is completed and results are awaited. [Editor’s note: The
phase 3 MONALEESA-2 trial of ribociclib and letrozole in advanced HR-positive, HER2-
negative breast cancer was stopped due to positive efficacy results at the interim
MONALEESA-3, like the PALOMA-3 study, is evaluating ribociclib and fulvestrant
versus fulvestrant and placebo. The primary endpoint for this study is PFS.
And, finally, MONALEESA-7 is looking at the premenopausal cohort with ribociclib
either with tamoxifen or an aromatase inhibitor with ovarian suppression, or those agents
with placebo. Again, PFS is the primary endpoint.
At the San Antonio Breast Cancer Symposium in 2015, data were reported on ribociclib
in combination with the phosphoinositide-3 kinase inhibitor alpelisib and letrozole. There
are data to suggest that there could be synergic interaction between blocking both the
CDK 4/6 pathway and the phosphoinositide-3 kinase pathway.
This was a phase 1 study that evaluated a dose and supported the idea that perhaps a
triplet combination could further delay and control ER-positive breast cancer, rather than
letrozole alone or letrozole and CDK inhibition. It's a very exciting idea and we await
In addition, there was a study looking at ribociclib with everolimus and exemestane. As
we know, everolimus and exemestane is an FDA-approved regimen for hormonerefractory
ER-positive breast cancer. They evaluated the triplet combination and are
evaluating various doses of everolimus in this phase 1 study to help manage side effects.
Further data regarding efficacy are awaited as well.
Now we will talk about some cases that represent potential indications for CDK 4/6
inhibition in ER-positive breast cancer.
The first case involves a 60-year-old woman who is postmenopausal, initially diagnosed
with a stage II ER-positive/HER2-negative breast cancer 3 years ago. This was found
during routine healthcare maintenance. She underwent an evaluation and was found to
have a well-differentiated tumor. She is treated with breast-conserving surgery, radiation,
and then adjuvant letrozole. She is otherwise a healthy and active lady.
She's been tolerating her letrozole without significant side effects; however, on routine
follow-up she's noted to have some abnormalities in her liver enzyme levels. This refers
her to a computed tomography evaluation, and she's found to have a 3-cm mass on the
liver. Biopsy confirms recurrence of her ER-positive/HER2-negative breast cancer.
At this time, we'll consider various treatment options. They include chemotherapy,
exemestane, everolimus and exemestane, fulvestrant alone, or fulvestrant and palbociclib.
Certainly, there are data to support all of these options. However, based on the
PALOMA-3 data, fulvestrant and palbociclib provide a significant improvement in PFS
versus fulvestrant alone. This is disease that is progressing with letrozole, a nonsteroidal
aromatase inhibitor, and therefore drugs like letrozole or anastrozole are less likely to be
active. The patient does have visceral disease, but does not appear to be at risk for
immediate death from her tumor, and therefore an endocrine-based approach is
reasonable. Certainly, chemotherapy has activity here. However, in an effort to delay the
toxicity of chemotherapy, an endocrine-based approach is very appropriate, and we know
that fulvestrant plus palbociclib provides a significant improvement in PFS.
Case 2 is a 54-year-old woman who presents to her doctor complaining of bone pain.
During her evaluation, she is noted to have a right-sided breast mass and elevated
alkaline phosphatase. Biopsy is performed and pathology is consistent with an ERpositive/
HER2-negative breast cancer. Staging studies reveal bone-only disease but no
She is started on a bisphosphonate as well as palbociclib 125 mg daily, 3 weeks on/1
week off, and letrozole. Certainly, other options would include letrozole alone or
chemotherapy. However, she has newly diagnosed metastatic breast cancer, and we saw
that the addition of palbociclib to letrozole provided a 10-month improvement in PFS
over letrozole alone. And, in fact, for patients with bone-only disease, this was even
She comes in on cycle 1 day 14, as recommended in the FDA label for the first 2 cycles,
to have her white blood cell count closely monitored. Her laboratory results are generally
normal except for a white blood cell count of 2,000 and her absolute neutrophil count
(ANC) is 1,200. While her ANC has fallen, it is still grade 2, and no further adjustments
in dose are required.
She returns 2 weeks later for cycle 2 day 1. At this time, she finished her 1 week off of
palbociclib, and today her white blood cell count is 1,800 with an ANC of 800. Her ANC
is less than 1,000. Per the guidelines in the label for palbociclib and as was performed in
the clinical studies, patients did not start their next cycle of palbociclib until their ANC
was at least 1,000.
She continues on letrozole but palbociclib is withheld. She returns a few days later and
her white blood cell count is now 1,800 and her ANC is 1,100. She resumes palbociclib
because her ANC is greater than 1,000 on a 3 week on/1 week off schedule. She
continues to have her complete blood cell count checked on day 1 of each cycle. After 3
months on treatment, staging studies show that she has stable disease on imaging and her
breast mass is smaller on exam, and she continues on treatment.
Should her white blood cell count and ANC specifically be less than 1,000 on any day 1,
then it is recommended that her dose be withheld until her white blood cell count
recovers. Dose reductions should be withheld only for patients who have febrile
neutropenic or other serious non-hematologic toxicity or prolonged delays in recovering
her white blood cell count.
We are just scratching the surface with the role of CDK inhibitors in breast cancer. There
are a lot of unanswered questions. There are ongoing randomized studies evaluating CDK
4/6 inhibitors in the various indications of advanced breast cancer, as well as with various
antiestrogen combinations. Ultimately, we're excited to see if the introduction of CDK
inhibitors in early breast cancers increases the cure rate for this disease.
Preclinical data suggest there's a role for CDK inhibition in HER2-amplified breast
cancer, and studies of CDK inhibitors in combination with HER2-directed therapy are
The mechanisms of acquired resistance to CDK 4/6 inhibition are still largely unknown.
These will have to be elucidated so we have a better understanding of how to manage
patients once disease progresses on a CDK 4/6 inhibitor. In addition, while the first
approval for these drugs is in breast cancer, I think there's a lot of excitement to see how
CDK 4/6 inhibitors will play a role in other malignancies, as well as other types of breast
Thank you very much for your attention, I hope you found this program useful in
understanding the preclinical and clinical development of CDK 4/6 inhibitors in breast
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