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CDK4/6 Inhibitors Changing Course of Care in HR+/HER2- Breast Cancer

Caroline Seymour
Published: Friday, Feb 08, 2019

Neelima Denduluri, MD

Neelima Denduluri, MD

Earlier diagnosis and more effective therapeutic options are enabling physicians to deliver better rates of disease control and improved quality of life (QoL) to patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, explained Neelima Denduluri, MD.

“Our goals of therapy are disease control while maintaining the QoL, [all the while delaying the need for] chemotherapy for as long as possible,” said Denduluri in a presentation during the 2018 OncLive® State of the Science Summit™ on Breast Cancer.

Such progress is, in large part, due to the advent of CDK4/6 inhibitors, 3 of which have received FDA approval for this patient population: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). During her presentation, Denduluri reviewed each CDK4/6 inhibitor as potential first-line and second-line therapies based on the data from the PALOMA-2, MONALEESA-2 and -7, and MONARCH 3 trials, which led to their approvals.

In the PALOMA-2 study, postmenopausal patients with advanced treatment-naïve estrogen receptor (ER)–positive, HER2-negative disease (n = 666) were randomized 2:1 to receive either 125 mg of palbociclib twice daily on a 3-weeks-on, 1-week-off schedule plus 2.5 mg of letrozole twice daily or placebo plus letrozole. Results demonstrated the superiority in median progression-free survival (PFS) and risk reduction with palbociclib/letrozole, at 24.8 months, compared with placebo at 14.5 months (HR, 0.58; 95% CI, 0.46-0.72; P <.001).1 In 2017, the FDA granted a full approval to the combination as frontline therapy for postmenopausal women with ER-positive, HER2-negative metastatic disease.1

In MONALEESA-2, postmenopausal patients with advanced, treatment-naïve, ER-positive, HER2-negative disease (n = 668) were randomized 1:1 to receive 600 mg of ribociclib twice daily on a 3-weeks-on, 1-week-off schedule plus 2.5 mg of letrozole twice daily or placebo plus letrozole.2 The same randomization and dosing schedule were used in the MONALEESA-7 trial, in which all patients had previously received a GnRH agonist, noted Denduluri. Although the study was restricted to pre-/perimenopausal patients (n = 672),3 women could have had prior exposure to tamoxifen or an aromatase inhibitor (AI), explained Denduluri.

However, due to a prolongation of the QTc prolongation with tamoxifen, physicians caution against its use in combination with ribociclib in practice, explained Denduluri, advising only an AI or fulvestrant.

In March 2017, the FDA approved the combination of ribociclib and an AI for frontline therapy, based on results from the MONALEESA-2 trial, which demonstrated a similar improvement in median PFS as was seen in the PALOMA-2 trial. In July 2018, the label for ribociclib was expanded to patients with pre-/perimenopausal HR-positive, HER2-negative advanced or metastatic breast cancer based on the results of MONALEESA-7, which indicated a 14-month improvement in median PFS with the combination versus AI monotherapy at 27.5 months and 13.8 months, respectively (HR, 0.569; 95% CI, 0.436-0.743).

Abemaciclib was examined in the MONARCH 3 trial, in which postmenopausal women with HR-positive, HER2-negative metastatic or locally advanced breast cancer who had not yet received systemic therapy (n = 493) were randomized 2:1 to receive either 150 mg of abemaciclib twice daily plus 1 mg of anastrozole or 2.5 mg of letrozole daily, or placebo plus anastrozole or letrozole. The median PFS rates were 28.2 months and 14.8 months with abemaciclib versus an AI, respectively (HR, 0.54; 95% CI, 0.418-0.698; P <.0001).4

“No matter which endocrine therapy backbone you use and which CDK4/6 inhibitor you use, the hazard ratios seem to be very similar,” said Denduluri. “They seem to improve PFS across the board.”

In terms of toxicity, all 3 agents are associated with neutropenia and fatigue, although ribociclib and abemaciclib are associated with hepatotoxicity. Distinct from the other 2 agents, however, abemaciclib is associated with a higher rate of early-onset diarrhea as well as venous thromboembolic events, reported Denduluri.

“We may have to dose reduce, but patients are likely going to derive the same degree of benefit from the drug if the dose reduction is necessary,” said Denduluri.

Apart from their use in combination, all 3 inhibitors show single-agent activity as well, although, abemaciclib seems to show the most single-agent activity, according to Denduluri. As the only FDA-approved CDK4/6 monotherapy, abemaciclib should be administered at a modified dose of 200 mg twice daily, when given as a single agent.


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Community Practice Connections™: How Do We Leverage PARP Inhibition Strategies in the Contemporary Treatment of Breast Cancer?May 31, 20191.5
Community Practice Connections™: A Better Way to Stop Pain: Paths Toward Responsible Postsurgical Pain Management for Patients With Breast CancerMay 31, 20191.5
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