Expert Explores Future of CDK4/6 Inhibitors in Breast Cancer

Matthew Goetz, MD

FDA approvals of 3 CDK4/6 inhibitors have added important treatment options to the armamentarium for patients with hormone receptor (HR)—positive breast cancer, but the future will focus on defining mechanisms of acquired and de novo resistance to these agents, said Matthew P. Goetz, MD.

Palbociclib (Ibrance) received an accelerated approval from the FDA in 2015 for use in combination with letrozole as a frontline treatment for postmenopausal women with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer. A full approval was granted by the FDA in March 2017. This CDK4/6 inhibitor is now also indicated for use in combination with fulvestrant or an aromatase inhibitor (AI) in this setting.

Additionally, frontline ribociclib (Kisqali) was approved by the FDA in July 2018 for use in combination with an AI for the treatment of pre-, peri-, or postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer, and for use in combination with fulvestrant for the treatment of postmenopausal women with this subtype of advanced or metastatic breast cancer, in the frontline setting or after disease progression on endocrine therapy. This regulatory decision follows ribociclib’s initial approval in March 2017 for treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an AI as initial endocrine therapy.

Third, the FDA approved abemaciclib (Verzenio) in combination with fulvestrant in September 2017 for patients with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. At this time, it was also approved as a single agent for those who previously received endocrine therapy and chemotherapy. In February 2018, this CDK4/6 inhibitor was approved in combination with an AI as initial endocrine-based therapy for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast disease.

OncLive: What is the current standard of care for patients with metastatic HR-positive breast cancer?

What has been the impact of CDK4/6 inhibitors in this field?

What is your approach for choosing a CDK4/6 inhibitor for patients?

Are there any patient factors that would prevent you from using CDK4/6 inhibitors?

Are there other pathways being explored in HR-positive disease?

Where do you see the field heading in the next few years?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Goetz, chair of the Breast Cancer Disease-Oriented Group and co-leader of the Women’s Cancer Center at the Mayo Clinic, discussed the impact of CDK4/6 inhibitors and their future role in the treatment of this patient population.Goetz: This has really evolved over the last several years. The current standard of care is to use an AI in combination with a CDK4/6 inhibitor in the frontline setting. There are also data suggesting that fulvestrant can be used in combination with a CDK4/6 inhibitor. Additionally, for patients who have progressed on a CDK4/6 inhibitor in the adjuvant setting, the current standard of care would be to try fulvestrant with a CDK4/6 inhibitor.CDK4/6 inhibitors have impacted the landscape in several different ways. First of all, as we look across the 3 agents that have been approved—palbociclib, ribociclib, and abemaciclib—we see very similar hazard ratios and comparable absolute benefits. These are not small benefits, rather, they are relatively large, with survival gains of approximately 1 year. The other thing that we know about the CDK4/6 inhibitors is that they are generally well tolerated. When we think about the benefit of these drugs, we are doing so in a way where quality of life is not being detrimentally affected.The fact that we have 3 CDK4/6 inhibitors and that they are each slightly different from each other is very helpful. Palbociclib is a CDK4/6 inhibitor in which one of the main adverse events (AEs) we see is neutropenia; this is usually not problematic, but it can sometimes cause dose reductions. In contrast, with the use of abemaciclib, we see a lot of diarrhea. Neutropenia is actually much less of a problem. As clinicians, we can distinguish between these 3 agents by [taking into consideration] their AEs.There are definitely some toxicities that are unique to CDK4/6 inhibitors. For example, abemaciclib has a slightly increased risk for venous thromboembolism. If I had a patient with a strong family or personal history of this, I would probably shy away from that drug. Palbociclib does have the issue with neutropenia, so if I have a patient who has difficulty dosing on that agent I would switch. Ribociclib actually has a very similar toxicity profile to palbociclib; neutropenia is very common.The pathways we know are important include the PI3K pathway. We have to determine where these drugs fit in the treatment sequence. They will have their biggest role after patients progress on a CDK4/6 inhibitor or in combination with a CDK4/6 inhibitor. There are ongoing studies looking at this.There are 2 major areas we need to focus on. I like to think of it this way—we focused on it like this with endocrine resistance—we need to know more about de novo resistance. When patients are diagnosed with ER-positive breast cancer and we think about putting them on a CDK4/6 inhibitor, we need to understand why they will rapidly progress. We need new treatment options for these patients. The major issue we will have to deal with is acquired resistance. Like hormonal therapy alone, most patients on a CDK4/6 inhibitor will eventually progress, even those who have prolonged benefit.

Is there anything else you would like to add?

What we need to understand are the mechanisms by which the cancer cells are developing ways to fight off these targeted agents. Will we introduce drugs at the time of progression, or combine drugs with CDK4/6 inhibitors?One of the areas I focused on in my presentation was the early survival data with palbociclib. There was recently an article published in the New England Journal of Medicine from the PALOMA-3 study. What they did in that study was a randomization of fulvestrant alone versus fulvestrant plus palbociclib in patients who progressed on endocrine therapy. The write-up was quite provocative because it showed a clear trend toward survival. However, they focused on patients who had so-called sensitivity to endocrine therapy—they were on an AI in the adjuvant or metastatic setting for a prolonged period of time. These were the patients who seemed to derive the survival benefit. This begs the question of making significant survival gains with CDK4/6 inhibitors in patients who have sensitivity to endocrine therapy. However, this was just 1 study, so we will need more data.

There were also data with abemaciclib in patients with so-called high-risk disease. These patients had liver metastases, high-grade tumors, and ER-negative disease. These patients have large benefit from abemaciclib. This makes us wonder if these CDK4/6 inhibitors are the same. As clinicians, we should be thinking about one versus the other.