Managing AEs Associated With CDK4/6 Inhibitors

Deciding which oral cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to add to endocrine therapy in any particular patient with advanced hormone receptor-positive breast cancer is based on the preferences of individual clinicians and their patients, say experts.

Given the overlapping indications approved by the U.S. Food and Drug Administration for palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), and the absence of head-to-head clinical trial comparisons or specific National Comprehensive Cancer Network (NCCN) guidelines about which to use, clinicians and patients must decide for themselves, based on dosing, convenience, and the side effect profile of each agent.

“Clinicians must now decide whether to use CDK4/6 inhibitors as part of first- or later-line therapy (approved in both settings) and how to sequence therapies after progression,” said Vered Stearns, MD, co-director of the breast cancer program at Sidney Kimmel Comprehensive Cancer Center in Baltimore, and colleagues, writing in a review in Oncology.

They pointed out that there are already a number of treatment options for patients with hormone receptor-positive advanced breast cancer. These include tamoxifen (Nolvadex), nonsteroidal aromatase inhibitors (AIs) such as anastrozole (Arimidex) and letrozole (Femara), fulvestrant (Faslodex), the steroidal AI exemestane (Aromasin) — with or without the mTOR inhibitor everolimus (Afinitor) — and chemotherapy.

“Usually patients receive sequential endocrine therapies until they develop resistance or experience a visceral crisis that requires chemotherapy,” Stearns and co-authors noted.

They added that since the efficacy data for CDK4/6 inhibitors do not support the use of one agent over another, the “somewhat different” safety profiles may guide clinicians when selecting the best treatment.

“We think that efficacy is pretty similar, so clinicians should consider the schedule and toxicity,” Stearns told MedPage Today. Some patients may like the idea of taking a medication every day, while others may find this increases anxiety, she noted. “There are strong opinions either way.”

In an interview, Shom Goel, MD, of the Dana-Farber Cancer Institute in Boston, said that most clinicians “familiarize themselves with one CDK4/6 inhibitor, the side effects, the requirements for monitoring, the rules about dose modifications, and then stick with that drug.”

While experts agree that CDK4/6 inhibitors are fairly well-tolerated and that toxicities can be managed with dose reductions and treatment breaks, however, “there are certain circumstances in which one might want to use one drug over another,” Goel said.

In the patient with a history of irritable bowel syndrome or gastrointestinal disease, deep vein thrombosis or pulmonary embolism, for instance, clinicians may want to consider a CDK4/6 inhibitor other than abemaciclib. Similarly, in a patient with a history of cardiac disease or other medications that could prolong QT interval, the use of ribociclib would not be indicated.

The side effects observed with other breast cancer treatments, including fatigue and nausea, are seen with CDK4/6 inhibitors. However, the most common grade 3/4 toxicities seen with palbociclib and ribociclib are neutropenia and leukopenia. These toxicities tend to emerge within 15 days of the initial dose, noted Marc Thill, MD, PhD, of the Agaplesion Markus Hospital in Frankfurt, and Marcus Schmidt, MD, of the University Medical Center in Mainz, Germany.

Dosing regimens for palbociclib and ribociclib feature a 1-week treatment-free interval every 3 weeks, they pointed out in an online report in Therapeutic Advances in Medical Oncology.

“[E]arly and sufficient monitoring with regular clinical assessments and management of the side effects is crucial and the key to treating patients successfully, minimizing side effects and treatment interruptions, and avoiding a lack of confidence for this innovative treatment,” Thill and Schmidt wrote. “Clear communication between the patient and the therapist is mandatory to minimize any misunderstandings.”

In all three PALOMA trials, 125 mg oral palbociclib was given daily with food for 3 weeks followed by 1 week off. Grade 3/4 neutropenia was seen in 54% of patients receiving palbociclib plus letrozole (PALOMA-1), in 66% of patients receiving the same regimen (PALOMA-2), and in 65% of patients treated with palbociclib plus fulvestrant (PALOMA-3).

In the MONALEESA trial program, 600 mg daily ribociclib was given every morning for 3 weeks followed by a 1-week treatment break. In MONALEESA-2 (ribociclib + letrozole), 59% of patients developed grade 3/4 neutropenia and 21% developed grade 3/4 leukopenia. QTc prolongation to >480 ms was also experienced by 11 patients (3.3%) including one with cardiac abnormalities at baseline.

“[P]atients who are at risk of developing QTc prolongation should not be treated with ribociclib,” said Thill and Schmidt. They noted that most QTc changes were observed early in the course of treatment and limited by dose interruption or reduction. “Interestingly,” they added, “palbociclib had no clinically relevant effect on the QTc interval in advanced breast cancer patients.”

Regarding prescribing information, clinicians must check the cardiac status of any patient being considered for ribociclib, and a history of any concomitant medication that could prolong QTc should be ruled out. ECGs should be assessed prior to initiation of treatment and repeated at Day 14 of the first cycle and at the beginning of the second cycle, or more frequently as indicated, with the patient told to report any related symptoms.

In MONARCH-2 (abemaciclib plus fulvestrant) and MONARCH-3 (abemaciclib plus nonsteroidal aromatase inhibitor), abemaciclib was given at a dose of 150 mg twice daily until disease progression or unacceptable toxicity. Rates of all-grade neutropenia were 50% lower compared with palbociclib and ribociclib.

Thill and Schmidt pointed out that the rates of subsequent febrile neutropenia are relatively rare with any of the CDK4/6 inhibitors. And unlike the neutropenia seen in patients treated with chemotherapy, CDK4/6-associated neutropenia is reversible with dose reduction or a 1-week treatment-free period that allows hematopoietic stem cells to resume proliferation.

Abemaciclib-treated patients are at higher risk of gastrointestinal side effects, especially diarrhea. This was seen in 86% of patients in MONARCH-2 and 81.3% of patients in MONARCH-3.

Goel said he counsels each new abemaciclib patient carefully about the risk of diarrhea: “I write them a prescription for loperamide (Imodium). Patients don’t have to take it right away but should leave with it in hand, knowing that should diarrhea develop, they can manage it adequately.”

The average length of time on abemaciclib in the first-line setting is approximately 2 years, he noted. During this time, some patients will experience mild to moderate diarrhea that may develop early on in the course of treatment and then resolve. In patients who develop severe diarrhea, the dose of abemaciclib is reduced.

An asymptomatic increase of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) has also been observed with CDK4/6 inhibitors. Thill and Schmidt noted that hepatic failure and liver-related death was documented in two patients treated with palbociclib and letrozole, although a grade 3 ALT increase was observed in only 3% of patients in the PALOMA-3 trial.

In patients treated with ribociclib and letrozole in MONALEESA-2, grade 3/4 ALT and AST elevations occurred in 9.3% and 5.7%, respectively, along with a concurrent elevation of total bilirubin. These were reversed after treatment interruption.

In the MONARCH-3 trial, 5.8% of patients treated with abemaciclib and a non-steroidal aromatase inhibitor experienced a grade 3 ALT increase and 0.6% had a grade 4 ALT increase. An AST increase of grade 3 was also observed in 3.8% of patients. Again, most cases were reversible with dose adjustment, Thill and Schmitt pointed out.

Nevertheless, every patient must undergo regular liver function testing during CDK4/6 inhibitor-based treatment along with a careful history of complementary and alternative concomitant medication, alcohol abuse, and hepatitis. Any patient being considered for ribociclib therapy should have a liver function test prior to the start of treatment and every 2 weeks for the first two cycles, at the beginning of each subsequent four cycles, and as otherwise clinically indicated.

Although there are currently no efficacy data regarding use of CDK4/6 inhibitors beyond progression, the New York University Langone Health Perlmutter Cancer Center is participating in the MAINTAIN trial to address this question, said Francisco J. Esteva, MD, director of the center’s breast medical oncology program.

“In this study, patients progressing on front-line CDK4/6 inhibitor in combination with endocrine therapy (aromatase inhibitor or fulvestrant) are randomized to second-line endocrine therapy alone versus endocrine therapy in combination with continuation of ribociclib,” he told MedPage Today. “Outside of a clinical trial, the standard of care is to discontinue these drugs at the time of progression.”