CDK4/6 Inhibitors Are Transforming Treatment in HR+ Breast Cancer

Terry L. Evans, MD

CDK4/6 inhibitors have been game-changing treatments for patients with hormone receptor (HR)—positive metastatic breast cancer, said Terry L. Evans, MD.

In the past, patients were treated with either exemestane or fulvestrant (Faslodex) as single agents, but research has shown that adding a CDK4/6 inhibitor to fulvestrant can improve progression-free survival (PFS) and clinical benefit rates in this population.

For example, data from the phase III PALOMA-3 trial, which were the basis for the FDA approval of palbociclib (Ibrance) in February 2016, demonstrated that the combination of the CDK4/6 inhibitor palbociclib with fulvestrant led to a clinically meaningful benefit in overall survival (OS) in patients with HR-positive, HER2-negative advanced breast cancer who progressed or relapsed on prior endocrine therapy.

At a median follow-up of 44.8 months in the intent-to-treat population, the combination led to a median OS improvement of 6.9 months compared with fulvestrant plus placebo (stratified hazard ratio, 0.81; 95% CI, 0.64-1.03; 1-sided P = .043). The median OS with the combination was 34.9 months (95% CI, 28.8-40.0) compared with 28.0 months (95% CI, 23.6-34.6) with fulvestrant/placebo.

In addition to palbociclib, abemaciclib (Verzenio) and ribociclib (Kisqali) are 2 other CDK4/6 inhibitors available to treat patients with HR-positive, HER2-negative advanced breast cancer.

In September 2017, the FDA initially approved abemaciclib in combination with fulvestrant for patients with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. It was simultaneously approved as a monotherapy for those with this breast cancer subtype who previously received endocrine therapy and chemotherapy. In February 2018, abemaciclib was approved for use in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

Frontline ribociclib 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.

OncLive: Is there an optimal partner for each of these CDK4/6 inhibitors?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Evans, a medical oncologist and clinical assistant professor of medicine at the University of Pittsburgh Medical Center, discussed the impact of CDK4/6 inhibitors in the metastatic breast cancer space and challenges that still need to be addressed.Evans: I don’t think it matters. All of the trials used letrozole or anastrozole [as partner drugs]; I don’t think there’s any difference. In MONALEESA-7, the premenopausal study, everybody had to receive goserelin monthly and then investigators paired it either with tamoxifen, letrozole, or anastrozole, and it seemed to make no difference what the partner drug was.

Could you discuss the impact of trials such as PALOMA-3 on the space?

Is toxicity an issue with this class of agents?

These drugs in partnership with tamoxifen or an AI are useful in patients who are pre-, peri-, and postmenopausal, so I wouldn’t hesitate to use them in any subgroup.The PALOMA-3, MONALEESA-3, and MONARCH 2 trials all paired a different CDK4/6 inhibitor with the same secondline therapy, which was fulvestrant. All the data are the same; I don’t think there’s a bit of difference in terms of efficacy among palbociclib, ribociclib, and abemaciclib. The cost is the same as well. In practice, [physicians] have to decide which group of patients they feel the most comfortable giving [each inhibitor to] because of toxicity.The tolerability is a big issue. My own sense is that abemaciclib may be a more potent drug when it comes to inhibiting breast cancer metastases. In MONARCH 3, when abemaciclib was combined with fulvestrant, there were tumor shrinkages in 14 of the patients. You hardly ever see tumor shrinkage with cytostatic drugs, and so, it may be a better drug. We need to get more data on that particular issue, but from the standpoint of adverse events, that is where clinical judgment comes into play.

Palbociclib seems to be the safest of the 3 inhibitors. With ribociclib, physicians have to consider the cardiac adverse events. If a patient has cardiac issues and they’re on other drugs that could prolong the QTC, I would be a little be wary about using ribociclib.

What are some questions that still need to be answered with these inhibitors?

What are the biggest challenges with these drugs?

Where does research need to go in this space to keep moving the needle forward?

Similarly, if [physicians are considering] abemaciclib, and [they] have a patient who has bowel issues to begin with, or they have inflammatory bowel disease or a spastic colon, they have to let them know that diarrhea could be a real issue. Is there any rationale for using a different CDK4/6 inhibitor when [a patient has] progressed on one? We need to get those data. It’s similar to non—small cell lung cancer to some extent, in that there are trials looking at one of the other CDK4/6 inhibitors that [had not been] originally used to see if there is cross-resistance between these drugs. Right now, we don’t really have those data.Paying for them. They are all equally effective in my view, but they’re also very costly. They’re in the range of $14,000 to $15,000 a month. Fortunately, a lot of the insurances will cover that cost, but if there are copayments of any sort involved, patients and families are going to bring that to their physician’s attention. That is not just for the CDK4/6 inhibitors—that’s for all of these expensive drugs that we use now. Secondly, there’s no survival advantage yet. I don’t want to say [these inhibitors are] a “home run,” but it’s probably a double in the treatment of patients with estrogen receptor—positive metastatic breast cancer. However, we have a long way to go.We need more information on the mechanisms of resistance. In my presentation, I discussed 1 patient who had a long disease-free interval—10 to 12 years—between her adjuvant therapy and recurrence. She is now almost 4 years into the palbociclib and letrozole treatment and has had a complete remission. What makes her different from the next patient who gets a response for 4 months and then has progression?

[Numerous possible explanations have been considered and] are being looked at, including the gene encoding for cyclin D1 overamplification and discerning whether the Rb protein is there. But to my knowledge, there are still no clear-cut ideas as to why some patients do well [on treatment] and some patients do not.

Cristofanilli M, Slamon DJ, Ro J, et al. Overall survival (OS) with palbociclib plus fulvestrant in women with hormone receptor—positive (HR+), human epidermal growth factor receptor 2– negative (HER2–) advanced breast cancer (ABC): analyses from PALOMA-3. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA2_PR. academic.oup.com/annonc/article/29/ suppl_8/mdy424.009/5141510.