Matthew J. Ellis, MD, PhD, discusses the use of CDK4/6 inhibitors in the treatment of patients with hormone receptor–positive breast cancer.
Matthew Ellis, MD, PhD
Endocrine therapy has long been a staple for treatment of patients with hormone receptor (HR)—positive breast cancer; however, most patients will develop acquired resistance or harbor intrinsic resistance to the treatment, said Matthew J. Ellis, MD, PhD.
Nevertheless, CDK4/6 inhibitors have been an impactful addition to this landscape over the past few years.
In September 2017, abemaciclib (Verzenio) became the third CDK4/6 inhibitor to be FDA approved for the treatment of patients with HR-positive, HER2-negative breast cancer following endocrine therapy. The indication was expanded to the frontline setting in February 2018; the decision was based on data from the phase III MONARCH 3 trial. In the study, the addition of abemaciclib to anastrozole or letrozole decreased the risk of progression or death by 46% compared with a nonsteroidal aromatase inhibitor (AI) alone.1
In March 2017, the FDA approved frontline ribociclib (Kisqali), another CDK4/6 inhibitor, in combination with an AI for patients with HR-positive, HER2-negative advanced or metastatic breast cancer. The indication was expanded in July 2018 for use in combination with an AI for the treatment of pre-, perimenopausal, or postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer. The FDA also approved ribociclib for use in combination with fulvestrant for the treatment of postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer, in the frontline setting or after disease progression on endocrine therapy.
The expanded approvals for ribociclib in combination with an AI and fulvestrant were announced following the results of the phase III MONALEESA-7 and MONALEESA-3 trials, respectively. The combination of ribociclib and an AI induced a 14-month improvement in median progression-free survival (PFS) versus AI monotherapy (27.5 vs 13.8 months; HR, 0.569; 95% CI, 0.436- 0.743).2 The median PFS with ribociclib and fulvestrant versus fulvestrant and placebo was 20.5 months and 12.8 months, respectively (HR, 0.593; 95% CI, 0.480-0.732; P =.00000041).3
In 2017, palbociclib (Ibrance) received FDA approval in combination with letrozole as a frontline treatment for postmenopausal women with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer. The approval followed the results of the phase III PALOMA-2 trial, which demonstrated a 42% reduction in the risk of disease progression compared with letrozole alone and a 10-month improvement in median PFS.4
In an interview during the 2018 OncLive® State of the Science Summit™ on Breast Cancer, Ellis, professor and director, Lester and Sue Smith Breast Center; associate director of Precision Medicine, Dan L. Duncan Comprehensive Cancer Center; and professor of medicine and cellular and molecular biology, Baylor College of Medicine, explained that although these agents have shown strong signals of activity, demonstrating efficacy is merely the first aspect in overcoming resistance to endocrine therapy in patients with HR-positive breast cancer.Ellis: The landscape of endocrine therapy for advanced disease has been a settled question for a long period of time. Major forms of therapy have been anti-estrogens and estrogen deprivation therapy. These drugs have relatively low toxicity. Patients do well on them for various periods of time, but resistance is the problem. Except in rare circumstances, most patients will meet an endocrine therapy resistance “wall” in their treatment between the first few months on therapy when it doesn’t work at all to progression—that could be 3 to 5 years down the line.
When we think about resistance, we think about it in 2 broad phases—intrinsic resistance and acquired resistance. We have been studying the molecular biology of acquired resistance to endocrine therapy for some time, and it’s clear that recurring events within ER itself are a cause of acquired resistance. As many as 30% to 40% of patients who become resistant to AIs and tamoxifen have mutations in ER that cause ligand independent activity. We have recently discovered another recoding event in the ER involving ER translocations. [These translocations] are really interesting. When those events occur, all endocrine therapies are off the table because there’s no drug-binding domain. It’s replaced with a chunk of coding sequence from another gene.
Interestingly, experimental systems and patients who have ER mutations or fusions can respond to CDK4/6 inhibitors. These drugs block the cell cycle downstream of the ER. Even if the ER is constitutive or translocated, CDK4/6 inhibitors can block proliferation.
As we move into the adjuvant setting with CDK4/6 inhibitors, intrinsic resistance to endocrine therapy becomes a very interesting thing to consider. If you have an ER-positive tumor that is already programmed to be resistant, a CDK4/6 inhibitor could save the day. We’ve been studying this patient population in some detail. At least some of this intrinsic resistance can be explained by subsets of tumors that have specific defects in DNA repair. [These defects] sever the link between the ER and cell cycle control in ways that still allow [patients] to be treated with CDK4/6 inhibitors.
CDK4/6 inhibition is a sort of broad spectrum downstream inhibitor of all sorts of complicated upstream biology that prevents endocrine drugs from being fully effective.Basically, every trial of a CDK4/6 inhibitor in ER-positive disease has been positive. Regardless of which drug is in question, in the 3 approved drugs—abemaciclib, ribociclib, and palbociclib—the statistics look very similar. They cut the hazard of progression by about 50%, which is a pretty large effect for endocrine therapy drugs. In the first-line setting, a patient can expect an average duration of disease control of more than 2 years. That’s impressive.Of course, there are lots of remaining questions. In the metastatic setting, there’s the issue of whether these drugs affect overall survival. Should one drug be favored over another in certain circumstances? What are the mechanisms of intrinsic and acquired resistance? Are there other combinations that we could consider in both ER-positive disease but also other subsets of breast cancer? [These may be] combinations with CDK4/6 and HER2-targeting drugs, for example.
Are there patients who will have such a good response to endocrine monotherapy, [so good that could] treat them with that first and reserve the CDK4/6 inhibitor for the acquired resistance setting? Some patients would be fine with endocrine monotherapy and perhaps with fulvestrant as a third-line choice. Then, you could reserve the CDK4/6 inhibitor for later lines of therapy.We don’t know how effective these drugs are going to be in the adjuvant setting. We can be absolutely sure that they will eventually show some efficacy there. The question is, “To what degree?” For example, you couldn’t have predicted the effectiveness of tamoxifen in the adjuvant setting from the metastatic data. It’s remarkably effective against micrometastatic disease with survival benefit still appearing many years after patients have been treated with tamoxifen.
One can only hope that CDK4/6 inhibitors could produce similar kinds of effects. There is quite good evidence that CDK4/6 inhibitors perturb the immune system in viable ways and may perhaps alter the immunogenicity of ER-positive tumors in ways that are favorable for T-cell responses. That may work out very nicely. We need to understand why these drugs eventually fail and how that failure might be circumvented with other agents.Pretty soon all of the approvals are going to be pretty equivalent with first- and second-line data and combinations with both AIs and fulvestrant. The trials have just about completed at this point and the drugs are efficacious in premenopausal women and postmenopausal women.
I’m interested in abemaciclib as a later-line therapy in patients who haven’t had an opportunity to be treated with a CDK4/6 inhibitor. Because of that approval, the 1 place where abemaciclib gets favored treatment in my practice is in patients who come to me with multiple resistance to multiple endocrine agents. They’ve already had fulvestrant and/or an AI, perhaps even tamoxifen. There, I might use abemaciclib monotherapy. My preclinical data with ESR1 mutations and ESR1 fusions indicate that downstream inhibition is quite effective with CDK4/6 even when the ER is mutationally interrupted.
We are making some of these diagnoses with liquid biopsy analyses. That might be a situation where, if I see a high-allele fraction of an ESR1 mutation and the patient has had an AI and fulvestrant, it’s logical to consider abemaciclib as third-line monotherapy because there isn’t an obvious endocrine partner. Why would you give the patient more intramuscular injections when they can take just a pill?Broadly speaking, a cure for ER-positive metastatic breast cancer. We’re not there, even though we have some effective agents that are pushing progression out. We don’t really know how much survival benefit we’re going to get from CDK4/6 inhibitors. [We need to understand] the intersection between the tumor genome, the DNA repair mechanisms, and the immune responses to mutation presentation and mutational load. The optimal treatment of CDK4/6 inhibitors may lie in combination with drugs that interrupt immune checkpoints. You can begin to see the shape of some combinations that might produce durable remissions in some patients.