CDK4/6 Inhibitors: Game Changers in Metastatic Breast Cancer Therapy

Kate M. O'Rourke

Disclosures

March 18, 2020

The combination of CDK4/6 inhibitors with endocrine therapy for estrogen receptor (ER)-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) continues to be among the most successful stories in treatment for advanced disease.

How have these drugs changed the MBC treatment landscape? "Most people use cyclin-dependent kinase (CDK) 4/6 inhibitors at the time of first metastatic diagnosis because they are tolerable and double the progression-free survival (PFS) interval." said Lisa Carey, MD, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research, chief of the Division of Hematology/Oncology, and deputy director of clinical sciences at University of North Carolina-Chapel Hill.

To learn more about how these drugs are used, Medscape reached out to experts to discuss practical tips about agent selection and patient monitoring.

Impact on Therapy

Five years ago, the first CDK4/6 inhibitor palbociclib was approved for use in MBC in combination with letrozole for treating ER-positive, HER2-negative MBC as initial endocrine-based therapy in postmenopausal women. Subsequently, the drug was approved in 2016 in combination with fulvestrant with disease progression after endocrine therapy in women with ER-positive, HER2-negative MBC.[1] Since then, two more CDK4/6 inhibitors, ribociclib and abemaciclib, have been approved.[2,3,4]

CDK4/6 inhibitors work chiefly through inhibiting retinoblastoma protein phosphorylation, thereby inducing cell cycle arrest, but the drugs also alter cancer cell biology in other ways, including interfering with mitogenic kinase signaling, inducing a senescence-like phenotype, and enhancing cancer cell immunogenicity.[5] CDK4/6 inhibitors are indicated with endocrine therapy as first-line or second-line treatment for ER-positive, HER2-negative advanced or MBC, and adding these agents doubles median PFS compared with endocrine therapy alone.[6,7]

In April 2019, the US Food and Drug Administration (FDA) extended the indication of palbociclib in combination with specific endocrine therapies for ER-positive, HER2-negative MBC in male patients.[8] The expansion was based on data from postmarketing reports and electronic health records that demonstrated that the safety profile was similar for men and women treated with the drug.

"Now that it has been 5 years since the approval of palbociclib, and we have seen all the additional data with ribociclib and abemaciclib, it's very striking to see how a mechanism that was somewhat overlooked for many years has really changed the treatment landscape and very quickly," said Richard Finn, MD, an assistant professor of medicine at the Geffen School of Medicine at UCLA in the Department of Medicine, Division of Hematology/Oncology. All three CDK4/6 inhibitors are currently being tested in early breast cancer trials, and Finn said he was excited to see the results.[9,10,11,12,13]

In the latest study to show benefit, FDA researchers conducted the first pooled analysis of seven randomized phase 3 clinical trials of all marketed CDK4/6 inhibitors, to assess efficacy in subgroups of patients with ER-positive MBC.[7] In the trials, the targeted agents increased median PFS by 8.8 months and benefit was seen in all clinicopathological patient subgroups.

Whereas many patients exhibit primary resistance to CDK4/6 inhibition and often have to switch to chemotherapy within 6 months, other patients may initially benefit from treatment, but later develop secondary resistance.[6]

Selection and Management

In terms of choosing an agent, Sarah Tolaney, MD, PhD, a medical oncologist at Dana-Farber Cancer Institute in Boston, said clinicians should select a CDK4/6 inhibitor on the basis of toxicity profiles in individual patients. The agents have varied toxicity profiles.[14,15] "Although there are no randomized trials comparing these three drugs, if you look at the individual registration trials conducted with each agent, and you put the data side-by-side next to each other, they are almost identical in terms of benefit and in terms of PFS and even overall survival," explained Tolaney. "You can't judge on the basis of an efficacy standpoint, but can pick on the basis of toxicity profile."

All of the CDK4/6 inhibitors, added Finn, cause bone marrow suppression to some extent and neutropenia, which is more common with palbociclib and ribociclib than abemaciclib.[14,15,16] In the PALOMA and MONALEESA-7 trials, neutropenia occurred in about 80% of patients on palbociclib and ribociclib; only roughly half of patients on abemaciclib experience neutropenia.[14,15] A recent analysis revealed that 61% of patients taking palbociclib or ribociclib experienced neutropenia, but neutropenic fever (1%) and infections (3%) were rare.[16] "Over time, we have all gotten very comfortable with managing the neutropenia with either dose reductions or dose delays," said Finn.

Abemaciclib's most significant toxicity is gastrointestinal toxicity, with diarrhea affecting between 80% and 90% of patients and grade 3/4 diarrhea occurring in up to 20%.[14] "About 40% of patients [on abemaciclib] require dose modification owing to the diarrhea," said Tolaney. Patient education is key. "Patients on abemaciclib need to call if they have the onset of diarrhea, and we usually counsel them on the use of loperamide," continued Tolaney. "We certainly counsel them that if the loperamide is not controlling the diarrhea to also call, because that can lead to dose holds and modifications, and you also need to make sure that you are monitoring patients on abemaciclib, usually every 2 weeks for the first 2 months, in terms of blood counts and liver function enzymes."

According to Tolaney, for a patient who has underlying issues, such as irritable bowel syndrome or ulcerative colitis, she would select palbociclib or ribociclib. If a patient had significant bone marrow involvement from breast cancer and had difficulties with blood counts, abemaciclib would be a better choice. Finn added that if a patient was on a drug that already prolongs QT, then he probably wouldn't use ribociclib. Ribociclib prolongs QT, whereas the other two agents do not.[17]

Tolaney explained that palbociclib and ribociclib are dosed intermittently, 21 days out of 28 days,[15] so patients need to understand that they have to carefully track their days off and remember to restart, and come up with a system to make sure they have good compliance. "Abemaciclib, as opposed to palbociclib and ribociclib, is dosed twice daily instead of once daily, and it is dosed continuously, so there is no week off," continued Tolaney.

Finn said that one downside to the CDK4/6 inhibitors is the frequent monitoring required. "Patients who are on endocrine therapy alone do not need to come into the clinic for blood count checks," said Finn. "If you are a patient who is frail and has problems traveling or accessing transportation, it can be a barrier for using these drugs." Patients on ribociclib require EKG monitoring, which may be tricky for some patients.[14]

A critically important factor in drug choice is that doctors are comfortable with them. "The docs need to be comfortable with managing the drug and its toxicities," said Finn.

Financial issues can pose a barrier to using CDK4/6 inhibitors. "My Medicare patients have high copays for these agents, and they don't qualify for the pharmacy assist programs because of being Medicare patients, so this has been a challenge, particularly if they don't have the low income to qualify for a lot of other programs that exist to help with these copays," said Tolaney. For younger patients, she said, pharmaceutical companies have programs that can help with the burden of cost.

Tolaney agreed with the other experts that CDK4/6 inhibitors have radically changed the treatment paradigm for patients with ER-positive, HER2-negative MBC. "These agents allow the disease to be controlled for a median of 2-3 years. I have some patients who have been on these agents since the first phase 1 trials with these drugs, and they have been out now over 7 years for first-line therapy," said Tolaney. "It is really incredible how these drugs have changed our patient survival with metastatic ER-positive, HER2-negative disease."

Dr Tolaney disclosed consultancy for Pfizer, Novartis and Lilly. Dr Carey has no relevant disclosures. Dr Finn disclosed consultancy for AstraZeneca, Bayer, Eisai, Eli Lilly, Genentech, Merck, Novartis, Pfizer, and Roche.

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