CDK4&6 inhibitors have recently moved to the forefront of the treatment landscape when it comes to hormone-positive breast cancer, experts say.

&ldquo;The CDK4&6 inhibitors have been exciting for the last 3 years, and 2015 welcomed the PALOMA-1 data that really took the clinical science of the CDK4&6 dysregulation in cancers and [worked to inhibit] that with the CDK4&6 inhibitor,&rdquo; said Denise A. Yardley, MD.

In an interview with Targeted Oncology, Yardley, a senior investigator of breast cancer research at Sarah Cannon Research Institute, discussed the promise of CDK4&6 inhibitors in estrogen receptor (ER)-positive breast cancer, as well as the potential with immunotherapy agents.

Can you give an overview of the current state of ER-positive breast cancer?

: There are some changes in the management of hormone receptor [HR]-positive, HER2-negative breast cancer. There are all phases of treatment, such as going to early adjuvant breast cancer treatment recommendations and some of the recommendations with regard to extended adjuvant therapy.

Then, there is a changing standard now for the first-line HR-positive, HER2-negative patients with metastatic breast cancer; that really focused on the changing algorithm to incorporate CDK4&6 inhibitors in the first-line setting. Then, we looked at some data of later-line therapy with some of the recent [FDA] approvals of palbociclib [Ibrance] and abemaciclib [Verzenio]in combination with fulvestrant [Faslodex]. Then, from that, the next topic that was natural was looking at hormone resistance, so we really covered and focused a little bit more on different spectrums of hormone resistance.

What are the current recommendations for adjuvant endocrine therapy?

: The current recommendations for adjuvant endocrine therapy are still evolving. It takes a look at the premenopausal patients and the utilization of tamoxifen in that setting. If we look at the trials that are out there with axillary dissection with access min-imized [ADAM] and adjuvant tamoxifen longer against shorter [ATLAS], and then looking at extending the therapy from tamox-ifen from 5 to 10 years, the data are quite consistent. We have had the data there resonate very well throughout many of the trials. The problem is, is it a one-size-fits-all approach?

What we are learning is we&rsquo;re still tailoring it to the patient and their risks, so we are trying to look at modifiers or even incorporate some of the genomic assays that help distinguish that. When we look at the aromatase inhibitors [AIs], the story is a little more muddy than challenging. We have some trials that are positive, like the MA17R study that looked at 10 years of letrozole after a 5-year backbone of tamoxifen. This showed that there was a disease-free survival [DFS] advantage, but again, it encompassed that patients did well in both groups of that trial, with outcomes of 90% disease-free overall survival.&nbsp;

Now, the NSABP B-42 trial did not echo the same results of MA17R, but the design and the statistics were a little different; however, even though DFS was not overall statistically significant, [it showed that] breast cancer-free interval distance recurrence was a significant finding.

In some of the other trials, looking at the DATA trial and the IDEAL trial, in the subsets of the patients who had tumors that were ER-positive, those subsets who had prior chemotherapy for adjuvant therapy or had high-risk disease were groups who do seem to benefit when we look at subgroup analysis. For the AI, the challenge is to discuss that higher[-risk] patient toleranceto ask, what is their risk of disease recurrence&mdash;to tailor that and pair that with the recommendation of extended adjuvant AI therapy.

What else are we seeing with CDK4&6 inhibitors?

: The initial [approval] was palbociclib; you could affect outcomes and show the doubling of the disease control rate or DFS. In February 2015, that opened the door for accelerated approval of palbociclib in that setting.

The confirmatory trial, PALOMA-2, resonated that the signal was real and reproducible; that went on to lead to an approval this year in March 2017. PALOMA-3 took on a different lookstill wanting to test the role of CDK4&6 inhibitors in the patients with HR-positive metastatic breast cancer but [looking] at patients who have been on prior endocrine therapy, failed that, and then went on to receive fulvestrant with the CDK4&6 inhibitor. It showed that, while advantage wasn&rsquo;t as statistically significant as what we saw in the first-line setting, the signal was clearly there and was statistically significant at 5 months. The margin of benefit was a little bit smaller, but there was a later-line therapy group of patients.

The MONALEESA-2 trial resulted with ribociclib [Kisqali]in combination with letrozole, again in that first-line setting. What&rsquo;s so exciting there is that we saw a great benefit in show-ing that doubling of the progression-free survivals has essentially 1 year before patients are experiencing disease progres-sion with the addition of the ribociclib as the CDK4&6 inhibitor.

Abemaciclib is a little bit different as a CDK4&6 inhibitor in that it looked at a different patient population. [It was in] heavily pretreated patients who had prior chemotherapy and endocrine therapies, and those patients received abemaciclib, a CDK4&6 inhibitor as a single agent. Abemaciclib is a little bit different. It&rsquo;s dosed continuously and not on a 3 weeks on/off schedule, such as palbociclib and ribociclib.

It&rsquo;s continuous dosing and twice-daily dosing. As a single agent, we saw a nice signal in a later-line therapy group of patients. Of course, these patients were all CDK4&6-na&iuml;ve patients. They also embarked on a trial with fulvestrant, as well. It showed benefit in a patient who had a prior line of endocrine therapy.

In September 2017, it received FDA approval in endocrine- and chemotherapy-pretreated patients as a single agent and then endocrine-pretreated patients with fulvestrant. The challenge now is looking at the market of CDK4&6 inhibitors. We have 3 that are FDA approved. Are they all a class of drugs or are there nuances that make each unique? That&rsquo;s what we&rsquo;re trying really sort through at this point. If you look at ribociclib, we see that it has a total 100% inhibition of CDK4 and CDK6, which makes it a little dfferent from palbociclib as well as abemaciclib.

The toxicity profile is what you would expectlargely neutropenia. The other interesting part [from preclinical studies] is that ribociclib does cross into the bloodbrain barrier. Now, we&rsquo;ll see how that evolved. We are waiting for other data, too, with ribociclib. It has also been looked at in the first-line setting in combination with tamoxifen. To this point, all of the other trials have only used the AIs or fulvestrant, so now we&rsquo;re actu-ally going to see tamoxifen roll out. A lot of the patients aren&rsquo;t eligible for the AI or can&rsquo;t tolerate it, so we&rsquo;ll get some exciting data as we move forward with that.

They also had a great quality of life that showed that pain control was apparent as a benefit reported by the patients at an 8-week first assessment. As we start learning how these roll out, how patients tolerate them, and what the administration schedule is, we&rsquo;ll figure out abemaciclib, with those continu-ous dosing in different levels of CDK4&6 and some off-target effects with more gastrointestinal [GI] toxicity. It distinguishes itself with a little less neutropenia, but a little bit more GI toxic-ity. All of that will be a way of moving forwardof us exploring the patient populations a little bit more.

Can you talk about hormone resistance and how pathways are being looked at?

: Hormone resistance is an exploding arena in the HR-positive patients. We&rsquo;ve welcomed the data for BOLERO-2 that put everolimus in combination with exemestane as a standard for patients who are failing endocrine therapy or a nonsteroidal AI. That was our first signal that doublet therapy with an endocrine agent backbone in combination with the targeted agent was effcacious and did improve the outcomes and DFS for patients.

The CDK4&6 inhibitors now have rolled out in advanced patients in the second-line setting. Now, what we&rsquo;re learning is what the other patterns in pathways of resistance are. One of the most exciting [aspects] is ESR1 mutations and our ability to recognize them from even circulating tumor DNA. Some [analyses] that have looked at BOLERO-2 looked at the ESR1 prevalence as anywhere from 25% to 40% in AI-pretreated patients.

If you select a patient who failed on an AI, has an ESR1 mutation, and you have a choice of another steroidal, nonsteroidal AI, or fulvestrant, fulvestrant as a selective estrogen receptor degrade [SERD] has resulted in better outcomes from those patients. Understanding ESR1 mutations and being able to test for them is now helping us make better choices for those patients as the next line of endocrine therapy. It&rsquo;s also opened the door now for a variety of oral SERDs, so while fulvestrant is sometimes a little bit more labor intensive because of the injections, now looking at the potential of having an oral SERD in the market for that population of patients is quite interesting.

As we look at adjuvant patients and recommendations of extended AI therapy, we&rsquo;ll have to see the downstream effect of these patients if they relapse. Test them immediately for the consideration of an ESR1 mutation, and perhaps fulvestrant [combined with] a CDK4&6 inhibitor may be the ideal setting for that, so that&rsquo;s what we&rsquo;re looking for. PI3K has been great in terms of the science behind it.

Everolimus has led us to know that you can interrupt the mTOR/PI3/AKT pathway and improve outcomes in patients with HR-positive metastatic breast cancer. However, in the nearly 20 PI3K trials, none of them have really shown a benefit; there is clearly something different about the PI3K.

Then, there&rsquo;s a class of [drugs] looking at the IGFR pathway, and some of those have been hit-or-miss. None have come to the market, but there&rsquo;s a strong signal there if we can find the right way to interrupt that pathway[it could be] that a ligand binder seems to be attacking the receptors associated with a lot of hyperglycemia. That just doesn&rsquo;t seem to be a way to move forward.

Entinostat, which received a breakthrough designation from the FDA, has been a really exciting drug that we&rsquo;ve also worked with and is currently out in a big phase III trial, hopefully for registration. It also seems to have a great signal with immunotherapy; there&rsquo;s a lot of trials that are looking for that in patients, as well. We are partnering with our pharmaceutical industry to find drugs to attack those pathways, and it likely may be triplet drugs. I know we&rsquo;re looking at ribociclib in combination with exemestane and everolimus, an actually very tolerable combination, and early signals seem to be promising.

What potential is there with immunotherapy in this population?

: The immunotherapy potential is something that we still struggle in the HR-positive arena. There have been a lot of trials looking at it, but none that have had a strong resonating signal as with some of the other so allenge for the HR-positive patients; however, we don&rsquo;t know what these tumors are going to look like after CDK4&6 inhibition and failures, as well.

It&rsquo;s something that&rsquo;s continually being looked at. The signal is there. It&rsquo;s been lowa 10% response rate as a single agent in a heavily pretreated group. HR-positive breast cancer is also very heterogenic. Some of the trials now are taking an approach of partnering the immunotherapy with another biologic target. Whether it would be a CDK4&6 or it&rsquo;s going to be an AKT pathway, a MEK inhibitor, or PI3K, all of that are trials that are just now getting their foothold and then we&rsquo;ll have to look for those results.

What else is important to highlight about this evolving field?

: One of the real excitements that has come from looking at the data and now 3 FDA-approved CDK4&6 inhibitors in the metastatic setting is now rolling these into the adjuvant setting. In that setting, we can potentially improve outcomes for more patients. Many of the trials have rolled out in the adjuvant setting looking at different features. We are still trying to identify the high-risk ER-positive adjuvant or early breast cancer patient. One of the trials that is rolling out, EarLEE-1, is looking at patients who either had neoadjuvant therapy or adjuvant therapy and embracing the new prognostic categories that are emerging now through the eighth edition of the American Joint Committee on Cancer [AJCC]. That will roll out for clinicians in January 2018. That&rsquo;s a very interesting way of selecting patients for a trial and being able to select or predict outcomes.

The change in the AJCC is adding to the anatomic pathology that is the tumor, the nodes, or metastasis. Now, the ER or progesterone positivity, the grade of the tumor, and even incorporating some of the multigene assays in coming into a risk category. For the early EarLEE-1 adjuvant trial with ribociclib, which will be given for 2 years in HR-positive preEarLEE1 or postmenopausal patients. They&rsquo;ll be randomized with an endocrine therapy and ribociclib versus endocrine therapy [alone]. Ribociclib is given for 2 years, so we&rsquo;re going to see in a different patient population how that may improve the outcomes.

Abemaciclib is rolled out in the MONARCH 3 trial, and that&rsquo;s looking at abemaciclib in early-stage breast cancer using a different definition and categories of inclusion criteria to select a high-risk patient population. However, we will also roll out with the 2-year plan of abemaciclib versus just standard endocrine therapy in patients who are given an adjuvant endocrine therapy.

Moving forward, seeing how that may totally alter how we treat early-stage breast cancer HR-positive patients, it&rsquo;s going to be exciting, too. Now, we&rsquo;ll still have to wait some time for those signals; however, at least by selecting the higher-risk population and then subsequent trials, we&rsquo;ll get an intermediate group. Hopefully, we&rsquo;ll get a signal or readout quite early from those trials. What we see now is a new standard in first-line HR-positive, HER2-negative metastatic breast cancerperhaps an evolving standard for certain patients with early-stage HR-positive, HER2-negative breast cancer.

It is becoming so challenging in the management of HR-positive breast cancer because, up until a couple of years ago, we really didn&rsquo;t have a host of trials or new data with regard to science or understanding resistance in those patients. All of it was monotherapy single-agent endocrine therapy. Now, the challenge is that the new standard seems to be combination endocrine therapy, so an endocrine therapy agent with a biologic targeted agent.

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Clinical Articles

Denise A. Yardley, MD,&nbsp;discusses the promise of CDK4&amp;6 inhibitors in estrogen receptor (ER)-positive breast cancer, as well as the potential with immunotherapy agents.&nbsp;

CDK4&6 Inhibitors Revolutionize Hormone-Positive Breast Cancer Care

A trio of cyclin-dependent kinase (CDK) 4&6 inhibitors have continued to revolutionize the field of breast cancer, explains Richard S. Finn, MD, adding that at some point in a patient&rsquo;s course of treatment, a CDK4&6 inhibitorwhether palbociclib (Ibrance), ribociclib (Kisqali), or abemaciclib (Verzenio)&mdash;should be administered.

Palbociclib was approved by the FDA in February 2016 for use in combination with fulvestrant (Faslodex) in pretreated patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, based on results of the phase III PALOMA-3 trial. Palbociclib was initially granted approval by the FDA for use in combination with letrozole as a frontline treatment for postmenopausal women with estrogen receptor (ER)&minus;positive, HER2-negative metastatic breast cancer.Second, the FDA approved ribociclib for use in combination with an aromatase inhibitor (AI) for the frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced breast cancer. This decision was based on findings from the phase III MONALEESA-2 trial.

Finally, in September 2017, the FDA approved abemaciclib for use in combination with fulvestrant in women with HR-positive/HER2-negative advanced breast cancer with disease progression following endocrine therapy; the basis for the approval came from the MONARCH 2 trial. Abemaciclib was also approved as a single agent for patients with HR-positive/HER2-negative disease with metastatic disease who have previously received endocrine therapy and chemotherapy. The single-agent indication was considered based on the MONARCH 1 trial.

All 3 of the CDK4&6 inhibitors have demonstrated comparable levels of efficacy, but there are subtle mechanistic and toxicity differences, Finn added.

In an interview with Targeted Oncology, Finn, an associate professor of medicine at the Geffen School of Medicine at the University of California, Los Angeles, covers the evolution of CDK4&6 inhibition in the field of breast cancer and appropriately selecting patients for this type of therapy.

Can you share the history of CDK4&6 inhibitor development in breast cancer?

The field has changed very quickly in a short period of time after decades of, really, no real novel approaches in first-line estrogen receptorpositive breast cancerlet alone hormone-resistant breast cancer. We now have 3 CDK4&6 inhibitors approved. Several years ago, [we were] talking about CDK4&6 inhibitors at a time where we had only very early data with palbociclib, which came out of preclinical work done by Dennis Slamon and myself in collaboration with Pfizer. That led to the PALOMA-1 trial and, eventually, the accelerated approval of palbociclib and letrozole.

Now we have a phase III study with ribociclib and letrozole in a similar population and phase III data with palbociclib with letrozole. Recently, at the 2017 ESMO Congress, we saw the data with abemaciclib and nonsteroidal aromatase inhibitors. All these results, reassuringly, are very similar as far as efficacy. While there is some overlap with the toxicities, each molecule has a few unique aspects.

Now, with fulvestrant in patients who are felt to be resistant to nonsteroidal AIs, we have data with palbociclib and fulvestrant from PALOMA-3as well as data with abemaciclib and fulvestrant from their phase III study, the MONARCH studies. There are now 6 randomized studies&mdash;many of them reading out only in the past year or year and a half&mdash;with CDK4&6 inhibitors and endocrine therapy. The landscape has changed very dramatically.

With these 3 CDK4&6 inhibitors available, how is a patient chosen to receive one regimen over the others?

As far as efficacy [goes], these combinations all seem very similar. The frontline regimens have similar efficacy, the second-line regimens have similar efficacy, and only recently, we now have abemaciclib approved as a single agent in patients who have never had a CDK4&6 inhibitor in heavily pretreated patients from the single-agent MONARCH 1 study.

Therefore, we have not been able to identify a biomarker or a patient population that does not benefit from the addition of a CDK4&6 inhibitor to endocrine therapywhether that&rsquo;s a nonsteroidal AI or fulvestrant. Somewhere, during the course of treatment, I would argue that a patient needs to get a CDK4&6 inhibitor. My bias is that perhaps this 10-month improvement we see in the frontline setting [with a CDK4&6 inhibitor] is the place to get the greatest benefit.

Then, as far as distinguishing them on toxicities, there are probably some unique places where you would go to one versus the other. Ribociclib requires some monitoring of QT interval of patients who are on drugs known to create QT, or have some arrhythmia that is related to prolonged QT. It might not be your first choice.

There is deep vein thrombosis [DVT]-association that came out with abemaciclib. There was an increased risk of DVT in their phase III study with a nonsteroidal AI. All [the CDK4&6 inhibitors] cause neutropenia to some degreeless so with abemaciclib&mdash;but abemaciclib has more gastrointestinal toxicities. Therefore, there are subtle things. As far as efficacy, they are all fairly similar, as far as we can tell. There are some subtle toxicity differences that a clinician may take into account. Access might be an issue for some people. We would all like to see that if we have 3 drugs competing in the same space, then the price should come down. But that is yet to be seen.&nbsp;

Are there next-generation CDK4&6 inhibitors emerging in the pipeline?

We have seen, very rapidly, 3 molecules go into the same space. You can make the argument: Do you need 3 molecules that do similar things and give similar efficacy? But that is the case. The big question now is, &ldquo;How will these work in early breast cancer?&rdquo; The adjuvant studies with these molecules are ongoing, and maybe that will be a place where we will see an even bigger impact and cure.

There is a big interest in understanding acquired resistance to these drugs. What do you do after you progress on a CDK4&6 inhibitor? All the data we have with single-agent fulvestrant, exemestane, and exemestane with everolimus [Afinitor] were all generated in the pre-CDK4&6 era. Therefore, we need some sense of how these patients do, and that will probably come [more] from the phase III studies. We had some data from that on PALOMA-1the phase II study. There is interest now in maybe targeting other CDK4&6 inhibitors to overcome resistance. It&rsquo;s an area that has been looked at for a while. It has been limited a little bit by medicinal chemistry, but there is a lot still in play.

Could any of the CDK4&6 inhibitors have potential in combination with immunotherapy?

Richard S. Finn, MD,&nbsp;covers the evolution of CDK4&amp;6 inhibition in the field of breast cancer and appropriately selecting patients for this type of therapy.

Expert Shares How CDK4&6 Inhibitors Break the Mold on Breast Cancer Paradigm

Charles J. Sherr, MD, PhD, of St. Jude Children&rsquo;s Research Hospital, Memphis, Tennessee, and colleagues noted in a review article published in Cancer Discovery, &ldquo;In the next few years, we are likely to see combinations of targeted therapiessome obvious combinations being RAF/MEK/ERK and PI3K inhibitors used in conjunction with those targeting CDK4&6&mdash;for which trials are now underway.&rdquo;

Ongoing Research in Breast Cancer Subtypes

Brain metastases are a common incidence in patients with breast cancer, specifically those with human epidermal growth factor receptor 2 (HER2)-positive disease. A phase II trial has been designed to evaluate potential antitumor activity of the CDK4&6 inhibitor palbociclib in patients with metastatic HER2-positive breast cancer with brain metastasis (NCT02774681).

The primary endpoint is the radiographic response rate in the central nervous system (CNS) as measured by the modified Response Assessment in Neuro-Oncology Brain Metastasis. Additional outcomes include the incidence of adverse events (AEs), overall survival (OS), progression-free survival (PFS), objective response rate (ORR), time to CNS progression, change in cognitive function, change in genomic landscape of CNS and non-CNS tumors, change in quality of life, and cyclin D1 aberrations. This study is currently recruiting, with an estimated enrollment of 33 patients and a primary completion date of November 2019.

Additionally, a phase II trial has been created to determine the safety and efficacy of abemaciclib in approximately 247 patients with hormone receptor (HR)positive breast cancer, non&ndash;small cell lung cancer, or melanoma that has spread to the brain (NCT02308020).

Investigators are focusing on the percentage of patients who achieve a complete or partial response as the primary endpoint. Moreover, secondary outcome measures will include best overall intracranial response, duration of intracranial response, intracranial disease control rate, intracranial clinical benefit rate, OS, ORR, disease control rate, PFS, and change from baseline in neurologic symptoms on the MD Anderson Symptom InventoryBrain Tumor Scale. The ongoing trial is set to be completed in October 2018.

An ongoing phase I/II trial was designed to evaluate the combination of ribociclib and bicalutamide in advanced androgen receptorpositive triple-negative breast cancer (NCT03090165).

Here, researchers will determine the maximum-tolerated dose (MTD) and the clinical benefit rate of the combination. Additional outcome measures include duration of response (DOR), safety and tolerability, pharmacokinetics, PFS, OS, and ORR. Approximately 58 patients will be enrolled in the trial, which is estimated to be completed in September 2018.

Ongoing clinical trials are also investigating the efficacy of palbociclib in women of different ethnicities who have breast cancer. For example, the PALINA trial, a phase II open-label study, is evaluating the hematological safety of palbociclib combined with letrozole and fulvestrant (Faslodex) in African-American women with HR-positive, HER2-negative advanced breast cancer (NCT02692755).

The primary outcome is the proportion of patients who complete therapy without developing a hematological event. Investigators will also be looking at the number of patients who require dose delays or reductions attributed to neutropenia, as well as the clinical benefit rate. An estimated 35 patients will enroll on this study, which has an approximate primary completion date of December 2018.

Moreover, PALOMA-4 is a multicenter, double-blind, randomized phase III study that is evaluating the clinical benefit rate and PFS following treatment with palbociclib and letrozole versus placebo and letrozole in approximately 330 Asian postmenopausal women with estrogen receptor (ER)positive, HER2-negative advanced breast cancer who have not received prior systemic therapy (FIGURE 1; NCT02297438).

Additional endpoints include OS, ORR, DOR, Euro Quality of Life Health State Profile Utility Score, change from baseline in Functional Assessment of Cancer TherapyBreast, tumor tissue biomarkers, and probability of participant survival. The trial has an estimated primary completion date of March 29, 2019.

HR-Positive Breast Cancer: Combinations in Early Disease&nbsp;

To improve outcomes for patients with early stage breast cancer, combinations with CDK4&6 inhibitors are being considered. The phase II neoMONARCH clinical trial is looking at a combination of neoadjuvant abemaciclib with anastrozole in patients with HR-positive, HER2-negative early stage breast cancer (NCT02441946). Findings from the study were presented during the 2017 San Antonio Breast Cancer Symposium.

The ORR at 16 weeks, by caliper measurement, was 53.6% overall (95% CI, 46.8%-60.2%), and 7.6% of patients experienced a complete response. The combination induced complete cell cycle arrest, as measured by Ki-67 level, for 67.8% of patients.

HR-Positive Breast Cancer: Combinations in Advanced or Metastatic Disease

Combination regimens with CDK4&6 inhibitors are also being explored in patients with advanced and metastatic disease, specifically those who express HR positivity. For example, the ongoing phase II nextMONARCH 1 study is evaluating the safety and efficacy of the combination of abemaciclib plus tamoxifen or abemaciclib alone in approximately 225 women with previously treated HR-positive, HER2-negative metastatic breast cancer (NCT02747004).7 Researchers are using PFS as a primary endpoint. Additional outcomes of the study, which is expected to be completed in February 2018, include ORR, DOR, OS, mean steady state exposure of abemaciclib and its metabolites, mean steady state exposure of tamoxifen and endoxifen, change from baseline in symptom burden, and change from baseline in pain and symptom burden assessment.

The phase I/II open-label TRINITI-1 trial is exploring the efficacy of a triplet regimen composed of ribociclib, everolimus (Afinitor), and exemestane as a potential treatment for patients with locally advanced or metastatic breast cancer following treatment with a CDK4&6 inhibitor (FIGURE 2; NCT02732119).

Investigators will determine the MTD and/or the recommended phase II dose for the 3-drug combination as well as the clinical benefit rate. Additional endpoints include PFS, OS, ORR, duration of overall response, and time to definitive deterioration of ECOG performance status in 1 category of the score. This study is currently recruiting, with an estimated enrollment of 51 patients and an estimated primary completion date of May 25, 2018.

The combination of palbociclib, fulvestrant, and erdafitinib is being investigated in an open-label, multi-institution, phase Ib trial to evaluate the safety, tolerability, and preliminary antitumor activity in approximately 32 patients with ER-positive/HER2-negative/FGFR-amplified metastatic breast cancer (NCT03238196).

The primary endpoint is the incidence of treatment-emergent AEs, but investigators are also determining PFS, ORR, and clinical benefit rate, and assessming AEs, and pharmacokinetics. This trial has an estimated primary completion date of September 2020.

The future clinical development of ribociclib, alpelisib (a PI3K inhibitor), and letrozole is being explored in patients with ER-positive breast cancer (NCT01872260).

Investigators are looking at primary endpoints of incidence of dose-limiting toxicities, safety, and pharmacokinetic profiles of ribociclib and letrozole. This study, estimated to enroll 253 patients, has an estimated primary completion date of April 30, 2019.

Moreover, the phase II LEADER trial is evaluating the combination of ribociclib with adjuvant endocrine therapy in patients with ER-positive breast cancer (NCT03285412).11 Researchers are using as a primary endpoint the number of patients who complete 12 months of treatment. Should more than 66% of participants complete 12 months of treatment with ribociclibat least 75% of intended doses&mdash;the treatment will be considered safe and reasonably well tolerated.

Ribociclib is also being investigated in combination with standard endocrine therapy in the phase III MONALEESA-7 trial in patients with pre- and perimenopausal advanced HR-positive, HER2-negative breast cancer (NCT02278120). Findings from the ongoing study were presented at the 2017 San Antonio Breast Cancer Symposium, showing a median PFS of 23.8 months with the combination of ribociclib with tamoxifen or a non-steroidal aromatase inhibitor and goserelin, a luteinizing hormone-releasing hormone analog.

The open-label, randomized phase II monarcHER study is investigating the efficacy of abemaciclib plus trastuzumab (Herceptin) with or without fulvestrant or chemotherapy in patients with HR-positive, HER2-positive locally advanced or metastatic breast cancer following prior treatment with at least 2 HER2-directed therapies (NCT02675231).

The primary endpoint of the trial, with an estimated primary completion date of August 2018, is PFS with additional endpoints being OS, ORR, DOR, disease control rate, clinical benefit rate, pharmacokinetics, and changes from baseline in pain and symptom burden assessment on the Modified Brief Pain InventoryShort Form, in symptom burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire&ndash;C30, and in health status on the EuroQol 5-Dimension, 5-Level Questionnaire. This study is enrolling approximately 225 patients.&nbsp;

HR-Positive Breast Cancer: Adjuvant Therapy Trials

CDK4&6 inhibitors are also being tested in the adjuvant space for patients with HR-positive breast cancer. For example, the randomized, open-label, phase III monarchE study is exploring the safety and efficacy of the most recently approved CDK4&6 inhibitor, abemaciclib, in patients with high-risk, node-positive, early-stage, HR-positive, HER2-negative breast cancer (FIGURE 3; NCT03155997).

Investigators are evaluating invasive diseasefree survival (DFS) as the primary endpoint. Additional outcomes include invasive DFS in patients with Ki-67 index &ge;20%, distant relapse-free survival, OS, pharmacokinetics, and changes from baseline on the Functional Assessment of Cancer Therapy&ndash;Breast, Functional Assessment of Cancer Therapy&ndash;Endocrine Symptoms, Functional Assessment of Chronic Illness Therapy&ndash; Fatigue, and the EuroQol 5-Dimension, 5-Level Questionnaire.

PALLAS, an ongoing international, multicenter, open-label, randomized phase III study, is testing whether adding palbociclib to adjuvant endocrine therapy will improve invasive DFS in patients with HR-positive, HER2-negative early breast cancer (NCT02513394).

The secondary endpoint is safety at 2 years of palbociclib with adjuvant endocrine therapy versus adjuvant endocrine therapy alone. Expected to complete in September 2020, the trial is enrolling approximately 4600 patients.

Checkpoint inhibitors in combination with CDK4&6 inhibitors is a treatment strategy researchers have also been exploring to ramp up benefit for larger populations of patients with breast cancer.

For example, the ongoing phase Ib JPCE clinical trial is looking at the combination of abemaciclib with the PD-1 inhibitor pembrolizumab (Keytruda) (NCT02779751). Preliminary findings from the third cohort, which included 28 patients with HR-positive, HER2-negative metastatic breast cancer, were presented at the 2017 San Antonio Breast Cancer Symposium.

The combination demonstrated a tolerable safety profile in this patient population with no grade 4/5 AEs seen. Serious AEs were seen in 21.4% of patients and AEs led to discontinuations in 14.3%. At 16 weeks, the combination demonstrated an ORR of 14.3%; 60.7% of patients demonstrated stable disease.

Additionally, a phase I, open-label study has been designed to evaluate the combination of ribociclib and PDR001, an antiPD-1 monoclonal antibody, for the treatment of patients with metastatic HR-positive, HER2-negative breast cancer in combination with fulvestrant (NCT03294694).

It is also being looked at for the treatment of patients with metastatic epithelial ovarian cancer. Investigators will determine the MTD and the recommended phase II dose of the combination of ribociclib plus PDR001 as well as the combination of ribociclib plus PDR001 with fulvestrant. Additional outcome measures are AEs and ORR. This study is currently recruiting, with an estimated enrollment of 60 patients and a primary completion date of June 1, 2018.

&ldquo;It is obvious that this class of agents with their efficacy, low and easily manageable toxicity, and oral dosage is a very important treatment option for breast cancer,&rdquo; noted Dorota Kwapisz, MD, MSc, of Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland, in a review article.

In conclusion, Sherr and colleagues stated, &ldquo;Despite the decades required for drug discovery and clinical applications, much remains to be learned. Future work will indicate whether the promise of CDK4&6 inhibitors, most advanced for breast cancer, can be validated and extended to other cancers.&rdquo;

Sherr CJ, Beach D, Shapiro GI. Targeting CDK4 and CDK6: from discovery to therapy.

2016;6(4):353-367. doi: 10.1158/2159-8290.CD-15-0894.

Martin M, Hurvitz SA, Chan D, et al. Final results of NeoMONARCH: A phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive (HR+), HER2 negative breast cancer (BC). Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract PD5-01. abstracts2view.com/sabcs/view.php?nu=SABCS17L_791&terms=.

Tripathy D, Sohn J, Im SA, et al. . GS2-05. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the randomized phase III MONALEESA-7 trial. Presented at: the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS2-05. abstracts2view.com/sabcs/view.php?nu=SABCS17L_828&terms=.

Rugo HR, Kabos P, Dickler MN, et al. A phase 1b study of abemaciclib plus pembrolizumab for patients with hormone receptor positive, human epidermal growth factor receptor 2 negative metastatic breast cancer. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract P1-09-01. abstracts2view.com/sabcs/view.php?nu=SABCS17L_908&terms.

Prospects for patients with breast cancer have improved with the use of CDK4&amp;6 inhibitors, including palbociclib, ribociclib, and abemaciclib; however, the effects of these inhibitors in many subsets of patients have not been investigated.

Ongoing Trials in Other Settings for CDK4&6 Inhibitors in Breast Cancer

&ldquo;This encouraging efficacy signal is combined with a lack of emerging worrying toxicities at this point in clinical development.&rdquo;

Palbociclib is a reversible, highly selective inhibitor of CDK4&6. In March 2017, palbociclib was approved by the FDA for the treatment of hormone receptor (HR)positive, human epidermal growth factor receptor 2 (HER2)&ndash;negative, advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women.

This approval was based on the PALOMA-2 trial that included 666 postmenopausal women who were randomized 2:1 to receive palbociclib plus letrozole or placebo plus letrozole until disease progression or unacceptable toxicity.3 Patients who received palbociclib plus letrozole had a significantly longer median progression-free survival (PFS; 24.8 months) compared with patients who received placebo plus letrozole (14.5 months; HR, 0.58; 95% CI, 0.46-0.72; P <.001). Evaluation of safety data in 444 patients receiving palbociclib plus letrozole revealed neutropenia in 80% of patients. Other commonly reported adverse events (AEs) occurring in &ge;10% of patients include infections, leukopenia, fatigue, nausea, stomatitis, alopecia, diarrhea, rash, anemia, asthenia, thrombocytopenia, vomiting, decreased appetite, dry skin, dysgeusia, and pyrexia. Commonly reported grade &ge;3 AEs include neutropenia, leukopenia, infections, and anemia.

Abemaciclib was approved by the FDA in September 2017 for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer that has progressed following endocrine therapy.

Abemaciclib is approved in combination with fulvestrant following progression on endocrine therapy or as monotherapy in patients previously treated with endocrine therapy and chemotherapy after metastasis. This approval was based on a trial of 669 patients with HR-positive, HER2-negative breast cancer, demonstrating an improved median PFS in patients receiving abemaciclib plus fulvestrant compared with patients receiving placebo plus fulvestrant (16.4 vs 9.3 months). A single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer was designed to evaluate abemaciclib as a monotherapy. Of the patients treated with abemaciclib alone, 19.7% experienced complete or partial tumor shrinkage for a median of 8.6 months.

Frequently reported AEs include diarrhea, nausea, abdominal pain, vomiting, headache, infections, fatigue, decreased appetite, neutropenia, leukopenia, and anemia. Serious AEs include diarrhea, neutropenia, elevated liver function tests, and deep venous thrombosis/pulmonary embolism.

In March 2017, ribociclib, a reversible, highly selective inhibitor of CDK4 and CDK6, was approved by the FDA in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

This approval was based on results from the MONALEESA-2 trial that included 668 postmenopausal women who received no prior therapy for advanced disease. These women were randomized to receive ribociclib plus letrozole or placebo plus letrozole until disease progression or unacceptable toxicity. A pre-planned interim efficacy analysis revealed a significantly improved median PFS in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole (not reached vs 14.7 months). An improved objective response rate (ORR) was also reported in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole (52.7% vs 37.1%). Commonly reported AEs in &ge;20% of patients receiving ribociclib include neutropenia, nausea, diarrhea, fatigue, leukopenia, vomiting, alopecia, headache, constipation, and back pain. Frequent grade 3/4 AEs include vomiting, lymphopenia, neutropenia, leukopenia, and abnormal liver function tests.

In the preclinical setting, estrogen receptor (ER)-positive and HER2-amplified breast cancer cell lines were reported to be the most sensitive to treatment with palbociclib, whereas ER-negative and HER2-negative cell lines were the most resistant to treatment with palbociclib. A synergistic inhibitory effect was also observed when tamoxifen was added to palbociclib.

The PALOMA-1/TRIO-18 trial was designed to evaluate the safety and efficacy of the combination of palbociclib and letrozole as first-line treatment for patients with ER-positive, HER2-negative breast cancer.

The phase Ib study determined the recommended phase II dose of palbociclib of 125 mg once daily for 3 weeks followed by 1 week without treatment, combined with letrozole 2.5 mg once daily in a 28-day cycle. Patients were randomized to receive the combination or letrozole only. The median PFS was significantly longer in patients receiving the combination (20.2 vs 10.2 months). Both the ORR and clinical benefit rate (CBR; complete response, partial response [PR], and stable disease) were higher in the combination arm compared with the letrozole arm (43% vs 33% and 81% vs 58%, respectively). No difference in overall survival was reported.

In the double-blind PALOMA-3 trial, 521 pre- and post-menopausal women with HR-positive, HER2-negative breast cancer who relapsed or progressed during prior endocrine therapy were enrolled to assess the efficacy of palbociclib plus fulvestrant compared with placebo plus fulvestrant. The median PFS was significantly longer in patients receiving palbociclib plus fulvestrant compared with placebo plus fulvestrant (9.5 vs 4.6 months; hazard ratio, 0.46; 95% CI, 0.36-0.59;

A dose-escalation study reported that a dosage break is not necessary with abemaciclib, which is administered at 200 mg every 12 hours.10 Results from a phase I trial that included 47 patients with advanced breast cancer with a median of 7 prior systemic therapies reported a 70% disease control rate for all patients with breast cancer, and 81% for the 36 patients with HR-positive breast cancer. The median PFS was 5.8 months and 8.8 months for all patients with breast cancer and for HR-positive patients, respectively.

This study was expanded to determine the efficacy of abemaciclib plus fulvestrant in patients with HR-positive metastatic breast cancer. A total of 13 patients with a median of 4 prior systemic therapies were enrolled, resulting in 62% confirmed PRs and 23% unconfirmed PRs. No patients discontinued treatment due to toxicity.

The phase II MONARCH-1 trial included 132 patients with previously treated HR-positive, HER2-negative breast cancer, reporting an ORR of 19.7% and a CBR of 42.4% with a median PFS of 6 months from treatment with abemaciclib monotherapy. Due to toxicity, 7.6% of patients discontinued treatment (TABLE 1).

The phase II monarcHER trial (NCT02675231) was designed to evaluate the effectiveness of abemaciclib plus trastuzumab (Herceptin) with or without fulvestrant or chemotherapy. A total of 225 women with HR-positive, HER2-positive locally advanced or metastatic breast cancer who had received at least 2 HER2-directed therapies were enrolled to assess PFS, and the trial is still ongoing.

The phase III MONARCH-2 trial was designed to evaluate PFS in postmenopausal patients with HR-positive, HER2-negative breast cancer treated with abemaciclib plus fulvestrant or fulvestrant alone. The median PFS was significantly longer in patients receiving abemaciclib plus fulvestrant compared with fulvestrant alone (16.4 vs 9.3 months; hazard ratio, 0.553; 95% CI, 0.449-0.681; P <.001). The ORR was also higher in patients with measurable disease who received the combination compared with fulvestrant alone (48.1% vs 21.3%).

An interim analysis of the phase III MONARCH-3 trial, designed to evaluate the effectiveness of non-steroidal aromatase inhibitors (NSAIs) plus abemaciclib in 450 postmenopausal patients with HR-positive, HER2-negative advanced breast cancer patients without prior therapy, demonstrated significantly improved PFS in patients receiving abemaciclib plus anastrozole or letrozole compared with patients receiving placebo plus anastrozole or letrozole (not reached vs 14.7 months). The ORR was also significantly improved in patients receiving abemaciclib vs placebo (59% vs 44%;

The phase III MONARCH plus trial was designed to evaluate abemaciclib combined with NSAI or letrozole in 450 postmenopausal patients with HR-positive, HER2-negative locoregionally recurrent or advanced breast cancer who received no more than 1 line of endocrine therapy or any prior chemotherapy (NCT02763566).

In a dose-escalation study of 132 patients with retinoblastoma (Rb) proteinpositive solid tumors and 18 breast cancer patients, the maximum-tolerated dose (MTD) of ribociclib was reported to be 900 mg, with the recommended phase II dose of 600 mg/day.

The SIGNATURE trial was designed to evaluate the efficacy of ribociclib in patients with solid tumors with CDK4&6 pathway activation who have received at least 1 prior treatment and do not have any standard therapy options remaining (NCT02187783). An ongoing randomized double-blind trial includes 132 patients with HR-positive, HER2-negative breast cancer who progressed on an aromatase inhibitor and a CDK4&6 inhibitor. Primary results are expected in May 2018.

In the advanced setting, phase I/II studies are ongoing, exploring combinations with ribociclib. The TRINITI-1 trial was designed to determine the MTD and CBR of ribociclib with everolimus (Afinitor) and exemestane (NCT02732119). Another trial was designed to determine the MTD and CBR of ribociclib with trastuzumab or trastuzumab emtansine (T-DM1; NCT02657343). A trial was designed to compare dose-limiting toxicities and PFS of ribociclib plus fulvestrant, ribociclib plus BKM120 plus fulvestrant, and ribociclib plus BYL719 plus fulvestrant (NCT02088684).

In the MONALEESA-2 trial, 668 postmenopausal, treatment-na&iuml;ve women with HR-positive, HER2-negative breast cancer were enrolled and randomized to receive ribociclib plus letrozole or placebo plus letrozole. An interim analysis demonstrated a 44% improvement in PFS in patients receiving the combination compared with placebo plus letrozole.16 The CBR and ORR were also significantly improved in patients receiving the combination compared with placebo plus letrozole (53% vs 37% and 80% vs 72%, respectively). The PFS rate at 18 months was 63% with the combination versus 42% with letrozole and placebo.

The MONALEESA-3 trial was designed to evaluate the PFS of ribociclib combined with fulvestrant in 725 men and postmenopausal women with HR-positive, HER2-negative breast cancer who received 1 or no previous lines of endocrine treatment (NCT02422615). COMPLEEMENT-1 was designed to collect additional safety and efficacy data for the combination of ribociclib plus letrozole (NCT02941926). A total of 3000 men and pre-/postmenopausal women with HR-positive, HER2-negative advanced breast cancer without prior hormonal therapy will be enrolled to assess the number of grade 3/4 AEs to determine safety and tolerability.

Palbociclib induces a G1-S cell cycle block by blocking Rb and related protein phosphorylation, followed by the downregulation of S-phase cyclins and mitotic regulatory genes and the suppression of DNA replication and nucleotide biosynthesis.

The inhibition of the phosphorylation of Rb protein and subsequent downregulation of E2F-targeted genes account for cell cycle arrest.

The antitumor effects of palbociclib are limited based on the dependence on active Rb protein presence.

Palbociclib has also been implicated to have a role in the inactivation of FOXM1, a transcription factor, and its transcription targets that induce cellular proliferation.

Palbociclib has also demonstrated sensitization effects on cancer cells to other treatments used in combination, including ionizing radiation and chemotherapy.

Abemaciclib, conversely, has been reported to have increased selectivity for CDK4 versus CDK6.

The most frequently reported toxicity associated with palbociclib is neutropenia, with other reported AEs including leukopenia, anemia, fatigue, back pain, diarrhea, and pulmonary embolism.

Neutropenia has been shown to be the only dose-limiting effect, with common non-hematological AEs including nausea, diarrhea, and fatigue.

The AE profile of ribocicilb is similar to that of palbociclib.

Of patients treated with ribociclib, 10% exhibited asymptomatic QTcF prolongation (>450 ms) at 600 mg/day and 27% exhibited this AE at doses >600 mg/day.

The observed AEs with abemaciclib treatment are different from those reported with palbociclib and ribociclib, which may potentially be a result of a greater selectivity of abemaciclib for CDK4 compared with CDK6.

The dose-limiting toxicity related to abemaciclib is fatigue, with less neutropenia reported compared with palbociclib and ribociclib.

The most commonly reported AEs include fatigue, diarrhea, nausea, vomiting, leukopenia, thrombocytopenia, neutropenia, anorexia, increased creatinine, anemia, and weight loss (TABLE 2).11 Abemaciclib monotherapy treatment has resulted in increased ORRs compared with palbociclib and ribociclib.

Patients receiving palbociclib should avoid simultaneous use of strong CYP3A inhibitors such as ketoconazole, ritonavir (Norvir), clarithromycin, and grapefruit juice. A dose reduction of palbociclib is required if a strong CYP3A inhibitor must be used. Palbociclib use combined with a sensitive CYP3A substrate with a narrow therapeutic index, including fentanyl, everolimus, and midazolam, may require a dose reduction of the CYP3A substrate.

Similar recommendations exist for patients receiving ribociclib. Agents known to prolong the QT interval, including amiodarone, sotalol, and haloperidol (Haldol Decanoate), should be avoided in patients receiving ribociclib.38 Patients receiving abemaciclib should also avoid simultaneous use of strong CYP3A inducers and inhibitors, or a dose reduction of abemaciclib may be warranted.

Following oral administration, palbociclib is slowly absorbed and eliminated in patients.

The median time from dosing to maximum plasma concentration was 4.2 to 5.5 hours. Its half-life was reported to be 23 to 26 hours, with no drug-drug interactions with letrozole.

The MTD recommended for monotherapy and combination strategies was reported as 125 mg once daily over 3 weeks on followed by 1 week off schedule. In a subset of patients, low absorption and drug exposure were observed in the fasted state, which was increased when palbociclib was administered with food. Reduced drug levels and effectiveness may be experienced if palbociclib is taken on an empty stomach.

Following oral administration, ribociclib was absorbed with a median time from dosing to maximum plasma concentration of 1 to 5 hours.

The MTD of ribociclib was reported as 900 mg daily of 3 weeks on and 1 week off over a 28-day schedule.

The median time from dosing to maximum plasma concentration was 1 to 5 hours and the average half-life was found to be approximately 36 hours. The recommended initial dose of ribociclib is 600 mg taken once daily, preferably in the morning, orally.

The absorption of ribociclib is not affected by food.

Abemaciclib has also been shown to be slowly absorbed, with a median time from dosing to maximum plasma concentration of 4 to 6 hours.

Abemaciclib is widely eliminated and distributed, with the average half-life ranging from 17.4 to 38.1 hours. The MTD was reported to be 200 mg every 12 hours, given continuously throughout the cycle.

Abemaciclib has been shown to cross the blood-brain barrier, which led to the design of a clinical trial evaluating the effects of abemaciclib in patients with brain metastases (NCT02308020).

Palbociclib, ribociclib, and abemaciclib have been approved by the FDA for the treatment of patients with breast cancer based on promising clinical trial results. These therapies are similar but have differences related to drug interactions and AEs that should be considered when optimizing individual patient treatment decisions. These trial results have led to the initiation of further studies investigating CDK4&6 combination therapies in an effort to further improve patient outcomes in breast cancer.

Conleth G. Murphy, MD, of Bon Secours Hospital, Cork, Ireland, and Maura N. Dickler, MD, of Memorial Sloan Kettering Cancer Center, New York, New York, commented in The Oncologist, &ldquo;The results of clinical trials with oral CDK4&6 inhibitors to date have offered promising glimpses of significant activity in hormone-sensitive breast cancer. This activity, combined with a favorable toxicity profile, makes this family of novel therapies very exciting. It is to be hoped that the currently accruing phase III studies will build on this promise and confirm the place of these therapies in the breast cancer armamentarium.&rdquo;

Dukelow T, Kishan D, Khasraw M, Murphy CG. CDK4/6 inhibitors in breast cancer.

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Palbociclib (IBRANCE). US Food and Drug Administration website. Posted March 31, 2017. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm549978.htm. Accessed November 20, 2017.

Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer.

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FDA approves new treatment for certain advanced or metastatic breast cancers. US Food and Drug Administration website [news release]. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm578071.htm. Accessed November 20, 2017.

Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. J Clin Oncol. 2016;34(suppl; abstr 510).

Ribociclib (Kisqali). US Food and Drug Administration website. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm546438.htm. Accessed November 20, 2017.

Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro.

Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of estrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.

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Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.

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Patnaik A, Rosen LS, Tolaney SM, et al. LY2835219, a novel cell cycle inhibitor selective for CDK4/6, in combination with fulvestrant for patients with hormone receptor positive (HR+) metastatic breast cancer.

Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors.

2016;6(7):740-753. doi: 10.1158/2159-8290.CD-16-0095.

Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer.

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Sledge Jr GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy.

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Di Leo A, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer.

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Infante JR, Cassier PA, Gerecitano JF, et al. A phase I study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas.

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Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer.

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Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure.

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The development of CDK4&amp;6 inhibitors has provided promising data regarding this new therapeutic option for patients with cancer, particularly for patients with breast cancer. Currently, there are 3 FDA-approved CDK4&amp;6 inhibitors for the treatment of patients with breast cancer.

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