CDK4/6 Inhibitors Make Impact in HR-Positive Metastatic Breast Cancer

Christin L. Melton, ELS
Published: Tuesday, Dec 19, 2017
Adam M. Brufsky, MD, PhD
Adam M. Brufsky, MD, PhD
The introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors has resulted in a significant paradigm shift in the treatment of hormone receptor–positive breast cancer, helping to make the new agents part of rapidly developing improvements in personalized care for patients, according to an OncLive® Peer Exchange panel of experts.

CDK4/6 inhibitors, a category that currently consists of 3 FDA-approved agents, has taken the “estrogen receptor (ER)-positive part of the metastatic breast cancer world by storm,” noted Adam M. Brufsky, MD, PhD, who served as moderator of the program.

Anti-CDK4/6 Agents

Cyclin family proteins activate CDKs to help regulate cell cycle progression.1 More than 50% of women with breast cancer have alterations in the cyclin D/CDK/retinoblastoma (Rb) pathway that cause overexpression of cyclin D, a protein family implicated in disease pathogenesis and progression.1 Studies have also documented overexpression of other cyclins and of CDK4.1 “Cyclin D is an important transcriptional product of the ER,” said panel member Joyce A. O’Shaughnessy, MD. In women with ER-positive breast cancer, amplification of cyclin D is associated with poor response to standard endocrine therapies,1 especially in women with luminal B tumors, O’Shaughnessy said. “Our endocrine agents, even really good aromatase inhibitor inhibition or really good degradation of ER, are still not perfect in terms of totally clamping down on that pathway,” she said.

The need for better targeting of the cyclin D/ CDK/Rb pathway led to the development of first-generation CDK inhibitors.2 These pan-CDK inhibitors had low selectivity, and clinical trials in ER-positive breast cancer proved disappointing.2 As accumulating data emphasized the important role of CDK4 and CDK6 activity in ER-positive breast cancer, new agents were introduced that were highly selective for these 2 kinases. The FDA has now approved 3 CDK4/6 inhibitors for women with advanced or metastatic hormone receptor–positive, HER2-negative breast cancer: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). All 3 are oral medications; ribociclib and palbociclib are given in 28-day cycles, with 21 days on and 7 days off, while abemaciclib is given twice daily without interruption.

The European Medicines Agency has approved palbociclib and ribociclib, while abemaciclib remains under consideration. “We were waiting… for this kind of drug for more than 10 years because in the era of endocrine treatment of breast cancer patients, the last innovation has been aromatase inhibition ...I’m very happy to have these drugs on the market,” said Michael Untch, MD.

New First-Line Therapies


The FDA granted accelerated approval to palbociclib in February 2015 based on progression-free survival (PFS) findings from the phase II PALOMA-1 trial in which 165 patients were randomized to receive letrozole with or without palbociclib.3 Brufsky described the decision as highly unusual, but panelist Hope S. Rugo, MD, said the agency was on solid footing. “I think that in this situation it was quite reasonable—it gave people access to the drug,” said Rugo. She pointed out that the phase III study she was involved with, PALOMA-2, had already completed accrual, so the FDA could be confident it would receive more extensive data. “They didn’t have safety concerns that hadn’t been well described… and there was evidence of a significant prolongation of progression-free survival,” Rugo added. Final data from PALOMA-1, presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, showed a median PFS of 20.2 months in the palbociclib arm compared with 10.2 months in the letrozole-only arm (HR, 0.488). No significant difference in overall survival (OS) was observed between treatment groups.4

Although palbociclib is approved in the European Union, Untch said Germany’s Federal Joint Committee, which acts as a cost-effectiveness watchdog, ruled that the drug offered no benefit over existing therapies partly because the agency was dissatisfied with use of PFS as the primary endpoint. Untch said he believes PFS is an adequate endpoint and noted that a growing number of German oncologists are prescribing palbociclib.

Michael Gnant, MD, criticized regulatory agencies for insisting on OS data when evaluating the drugs. “Maybe it’s super provocative, but I would suggest that we should make a clear statement: OS in luminal breast cancer is not a rational endpoint any longer,” he said.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
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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