CDK4/6 Inhibitors Continue to Revolutionize ER+ Breast Cancer Care

Yelena Novik, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Yelena Novik, MD

FDA approvals of the 3 novel CDK4/6 inhibitors— palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) have given oncologists a tool in their armamentarium against metastatic estrogen receptor (ER)-positive breast cancer, according to Yelena Novik, MD.

The agents have demonstrated efficacy in combination with endocrine therapy or an aromatase inhibitor (AI) in the first-line setting for patients with metastatic and advanced disease in studies such as PALOMA-2, MONALEESA-3, and MONARCH 2.

Updated findings from the PALOMA-2 study showed the superiority in median progression-free survival (PFS) with frontline palbociclib and letrozole in patients with metastatic ER-positive disease compared with placebo (24.8 vs 14.5 months; HR, 0.58; 95% CI, 0.46-0.72; P <.001).¹

Additionally, women with advanced hormone receptor (HR)-positive breast cancer experienced a 41% reduction in the risk of disease progression (P = .00000041) when ribociclib was added to fulvestrant (Faslodex) in the first- or second-line setting. The combination led to an improved median PFS of 20.5 months versus 12.8 months with placebo in the phase III MONALEESA-3 trial.²

Data from the phase III MONARCH 2 trial showed that the addition of abemaciclib to fulvestrant versus fulvestrant alone led to an improvement in median PFS of 7.1 months in pretreated patients with advanced HR-positive/HER2-negative disease (HR, 0.553; 95% CI, 0.449-0.681; P <.0000001).³ More recently, the combination plus a GnRH agonist was found to improve PFS and overall response rates in a subgroup analysis in both pre- and perimenopausal women with HR-positive advanced breast cancer.⁴ Abemaciclib is also approved in the frontline setting in combination with an aromatase inhibitor for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

Additionally, Novik said, ongoing adjuvant trials could even further enhance the impact of CDK4/6 inhibitors in breast cancer.

OncLive: Please provide an overview of your presentation.

In an interview during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Novik, associate professor, NYU Langone’s Perlmutter Cancer Center, discussed the application of CDK4/6 inhibition and methods to overcome resistance in ER-positive breast cancer.Novik: We discussed overcoming hormone resistance in the treatment of [patients with] advanced and metastatic breast cancer. Over the last few years, we've been lucky to have access to new targeted agents of cell-cycle inhibitors. Currently, we have 3 FDA-approved agents—palbociclib, ribociclib, and abemaciclib. They have been shown in randomized controlled studies to be superior to hormonal agents in improving PFS, as well as responses in women with advanced breast cancer.

What is the impact of the MONALEESA-7 trial?

I discussed the PALOMA, MONALEESA, and MONARCH randomized studies. PALOMA-2 compared palbociclib versus placebo in combination with letrozole. MONALEESA-3 combined ribociclib versus placebo. MONARCH 2 examined abemaciclib versus placebo in both the first-line and second-line treatment of metastatic breast cancer with fulvestrant. These drugs work through the D1 cycle mechanism to significantly improve PFS in advanced breast cancer. We are very lucky to be able to offer these options to our patients.Most of the trials in advanced breast cancer specifically target women who are menopausal or postmenopausal. It's much more difficult to conduct trials that specifically target premenopausal women. The MONALEESA-7 trial was directed to premenopausal women.

Are there any preemptive means of overcoming resistance?

Premenopausal women were randomized to receive either hormonal therapy alone—which is ovarian suppression and either tamoxifen or an AI–or the combination of hormonal therapy and ribociclib. The women were followed for a number of years and followed for PFS as well as overall responses. Not surprisingly, the PFS was significantly superior in the combination group with ribociclib compared with standard therapy.Now that we have the FDA approval of those first-line therapies, we can offer them to women at the first presentation of metastatic disease. However, a patient who presents with advanced cancer may already have resistance. We are also studying these agents in adjuvant trials, so we may be able to potentially increase the time before metastatic disease can develop.

Are there any preliminary data with CDK4/6 inhibitors in combination with MEK inhibitors and immunotherapy?

We are also looking at secondary resistance to see what options we can rotate in the second-line setting. Can we add either new targeted agents like PI3K inhibitors and others? There's a lot of research going on, which makes us hopeful.Those data are still in development. There is not very much published at this point. There's definitely a lot of interest [in this combination]. There are some data coming out in other malignancies, and there is some theoretical rationale to look into this [in breast cancer].

Could neratinib (Nerlynx) be a part of reversing hormone resistance?

Immune therapy in HR-positive breast cancer has been difficult. We may be seeing more in other malignancies that may show us a way to incorporate different strategies of [selecting therapy] in particular subtypes of breast cancer.Neratinib is an anti-HER2 agent, but also a tyrosine kinase inhibitor (TKI). Neratinib was involved in trials that showed superiority in patients who had ER-positive in addition to HER2-positive tumors. That doesn’t make that much sense scientifically and may be related to [whether] these patients recur later or earlier.

What is an area of research you would like to see addressed moving forward?

There may be a potential TKI blockade that may be related. There are more questions than answers at this point. We're collecting more data and looking at some of the molecular pathways in breast cancer, which is something we did not do [before] because we were so lucky to have ER, progesterone receptor, and HER2 for so many years. We're now trying to look at some other pathways that will hopefully give us more answers.I was a skeptic when cell-cycle inhibitors were just coming along because we tried combining so many different targets with hormonal therapy for so many years. However, none of them showed progress. When the first PALOMA study showed such a big change, it was a big discovery for me. These drugs really changed how we treat advanced breast cancer.

What would you like community oncologists to take home with them from this lecture?

I hope to see more novel hormonal drugs. We didn't have a new hormonal agent for decades. We need to understand how to harness immunotherapy. We develop new drugs, but we need to understand how they work and what they can bring. That's not modest.There were updates on the MONARCH studies with abemaciclib at the 2018 ASCO Annual Meeting. We saw some concern in cost issues related to cell-cycle inhibitors and they are real issues, but these drugs are here to stay. They definitely have their place as a first- and potentially second-line treatment for [patients with] advanced breast cancer. They clearly prolong disease-free survival and improve quality of life. Managing toxicity does not seem to be a very difficult task, and it has moved the whole algorithm of how we treat patients.

Premenopausal women should be offered the combination with ovarian suppression as their first-line treatment. If they didn't get it in the second-line setting, hormonal therapy will also extend their longevity and time to progression. We will potentially see some neoadjuvant therapy with this combination with hormonal therapy. That is still a very much unexplored area, especially in older women. ER-positive breast cancer is becoming more prevalent, so that will keep us busy.

References

1. Finn RS, Gelmon KA, Ettl J, et al. Impact of prior treatment on palbociclib plus letrozole efficacy and safety in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) first-line advanced breast cancer: a PALOMA-2 subgroup analysis. In: Proceedings from the 35th Annual Miami Breast Cancer Conference^® (MBCC); March 8-11, Miami Beach, FL. Abstract 591.
2. Slamon DJ, Neven P, Chia SKL, et al. Ribociclib (RIB) + fulvestrant (FUL) in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2—) advanced breast cancer (ABC): results from MONALEESA-3. J Clin Oncol. 2018;36 (suppl; abstr 1000).
3. Sledge GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy. J Clin Oncol 35, 2017 (suppl; abstr 1000).
4. Neven P, Rugo HS, Tolaney SM, et al. Abemaciclib for pre/perimenopausal women with HR+, HER2- advanced breast cancer. J Clin Oncol. 2018;36 (suppl; abstr 1002).