In Metastatic Breast Cancer Treatment, Not All CDK Inhibitors Are Equal

Doctors prescribe drugs known as CDK inhibitors to treat some women with estrogen-receptor-positive (ER+) metastatic breast cancer. Research into these drugs is ongoing, and new, promising CDK inhibitor options are on the horizon. Here, I address the current outlook for CDK inhibitors in ER+ breast cancer.

First, some background: ER+ breast cancers comprise about 70% of all breast cancers. The name reflects the fact that cells of these cancers express estrogen receptors (ERs), which are protein features targeted by many treatment strategies for this cancer type. The estrogen receptor (ER) protein is a treatment target not only because “it is there,” but mainly because it drives tumor cell proliferation in ER+ breast cancer. The activity of the ER depends on its binding to the hormone estrogen, and treatments known as endocrine drugs aim to prevent this interaction. Some endocrine drugs inhibit the synthesis of estrogen in the body (e.g., aromatase inhibitors, such as letrozole and anastrozole), and others prevent the interaction of estrogen with ERs (e.g., ER modulators such as tamoxifen, or the pure anti-estrogen drug fulvestrant). The problem of course is that, in metastatic breast cancer, resistance develops to each and every endocrine drug used.

ERs rely on the normal cellular machinery that drives cell division, and this involves a number of proteins that normally initiate cell proliferation. ER+ breast cancers often have high levels of cyclin D1, a key proliferation protein that interacts with proteins known as CDK4 and CDK6 (collectively called CDK4/6). CDKs (cyclin-dependent kinases), in complex with cyclin D1, drive cell division when levels of cyclin D are elevated by the activated ER.

The discovery that the ER drives cell proliferation through activation of CDK4/6 complexes prompted development of treatment strategies that rely on inhibition of these enzymes; i.e., tackling ER-driven proliferation from the “bottom end.” There was also much hope that inhibiting CDK4/6 may prevent or at least delay the development of resistance to endocrine drugs. CDK4/6, as kinase proteins amenable to inhibition, have been long a target of drug development, but the initial inhibitors were either inactive, toxic, or both.

The CDK4/6 inhibitor palbociclib (Ibrance) was the first to show encouraging results in ER+ breast cancers. Palbociclib, in combination with letrozole, became the first U.S. Food and Drug Administration (FDA)-approved CDK 4/6 inhibitor in February 2015. Based on the results of the PALOMA II clinical trial, this combination showed a doubling of progression-free survival compared to letrozole alone. In March 2016, the FDA approved the combination of palbocicilb with another endocrine drug, fulvestrant, based on PALOMA III results. This combination is now used as a second-line treatment, prescribed if initial treatment does not work or stops working.

In November 2016, another CDK4/6 inhibitor, ribociclib (LEE001), was granted a Breakthrough Therapy designation by the FDA in combination with letrozole, based on the positive results of the phase III MONALEESA-2 trial in postmenopausal women who had received no prior therapy for their advanced disease. After 18 months, 63 percent of women treated with both of these drugs had disease that did not get worse. That was a 44% improvement over disease progression seen in women who received only letrozole.

A third inhibitor, abemaciclib, entered the race later but is now quickly advancing to the forefront. It received a Breakthrough Therapy designation from the FDA in October 2016. This was based on results of the MONARCH 1 trial, in which abemacicilb showed promising activity when given on its own (as a single agent). In the MONARCH 1 trial, 42% of women experienced a clinical benefit (either tumor burden reduction or stable disease). The important point about this trial is that many women in the study had already received multiple lines of endocrine treatment, developed resistance to all of these treatments, and progressed. These women had exhausted all options for endocrine treatments, and many had already received chemotherapy. Abemaciclib therefore presents an entirely new treatment option as a single agent for patients who have preciously few—if any—options left. The potential benefit of chemotherapy in this heavily pretreated population is historically only 10 to 20 percent, and responses to it have a short duration, which compares unfavorably to abemaciclib. The results of MONARCH 1 are therefore really very exciting. Abemaciclib is now in trials with endocrine drugs as well (letrozole in MONARCH 2 and fulvestrant in MONARCH 3), with results forthcoming hopefully this year.

The major problem with CDK4/6 inhibitors is their side effects, the most common one being neutropenia (loss of white blood cells). Palbociclib induces neutropenia in more than half of women who receive this drug, necessitating dose interruptions and sometimes reductions. Ribociclib is not much better regarding neutropenia, at least according to the results available so far.

Abemaciclib, however, appears to be more promising in this regard. It is apparently more specific in inhibiting CDK4, and most likely because of that, the incidence of neutropenia is much lower. It does induce diarrhea initially, but this is quite manageable. There is much to look forward to with this new treatment option for ER+ breast cancer. Further development also includes combining abemacilcib with the immune checkpoint inhibitor pembrolizumab in a clinical trial (NCT02779751). This presents a glimmer of hope to extend the option of immunotherapy interventions to ER+ breast cancer, a type so far not know to be responsive to immune checkpoint drugs.

Image Credit: Metastatic breast cancer in the stomach, with cells stained for the estrogen receptor. Credit: Ed Uthman