Experts Discuss Frontline CDK4/6 Inhibitors in ER+ Breast Cancer

Dennis J. Slamon, MD, PhD

The discovery of the estrogen receptor in the mid-twentieth century by Elwood V. Jensen, PhD, marked a new era of treatment for patients with hormone receptor (HR)-positive breast cancer. As researchers continue to learn how to best target the estrogen receptor, new treatments are emerging in this landscape.

Presently, ASCO and NCCN guidelines suggest the use of hormonally targeted therapies rather than chemotherapy for patients with HR-positive breast cancer. In a lecture during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Sara A. Hurvitz, MD, and Dennis J. Slamon, MD, PhD, discussed the impact of one of the most impactful treatment options for these patients—CDK4/6 inhibitors.

"It is our knee-jerk reaction as oncologists to give them chemotherapy to get it under control," said Hurvitz, director of the Breast Oncology Program at the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center. "That really is not the most appropriate way. The most toxic therapy is not always the most effective therapy."

Hurvitz said that in a hormonally driven cancer, hormonally targeted therapies should be used until exhausted in all but the most unusual circumstances of visceral crisis. Response rates with chemotherapy span from 50% to 60%, which does not last long, noted Hurvitz. The time to treatment failure has been recorded as less than 1 year in multiple clinical trials.

The Introduction of CDK4/6 Inhibitors

Clinical studies of the hormonal therapy fulvestrant (Faslodex) offered the first glimmer of hope that something other than chemotherapy could induce durable, lasting responses in these patients, said Hurvitz. Since then, fulvestrant has become a staple in the treatment of postmenopausal patients with HR-positive breast cancer. For HR-positive patients with estrogen receptor (ER)-positive breast cancer, CDK4/6 inhibitors have emerged as a very potent therapy. Slamon, the director of Clinical/Translational Research, Revlon/UCLA Women's Cancer Research Program, Jonsson Comprehensive Cancer Center, said that this was based on a breakthrough therapy that almost did not happen.

This breakthrough was PD-0332991, which ultimately became known as palbociclib (Ibrance). PD-0332991 had been developed for mantle cell lymphoma and hematopoietic malignancies where cyclin-D amplification is a molecular hallmark. The agent had some activity in these malignancies, but it ultimately was shelved due to safety issues, said Slamon.

"We wanted to look at it in breast cancer, because we had a concept that it might have an impact on some rapidly proliferating cancers," Slamon said.

Palbociclib is an oral, small molecule, selective, potent, reversible inhibitor of CDK4/6. This was one of the first inhibitors specific to CDK4/6, as the previous generation of these inhibitors were considered pan-CDK inhibitors targeting multiple CDKs in the cell cycle.

"There is an incredibly well-orchestrated phenomenon that goes on every time a cell divides,” said Slamon. “This was one of the first inhibitors that hit something specifically, as opposed to multiple CDKs throughout the cell cycle.”

In an evaluation of palbociclib in various cell lines, the drug was shown to be most effective in inhibiting growth in breast cancer, particularly at lower doses. A breast panel compiled by UCLA showed that ER-positive luminal breast cancer was exquisitely sensitive to palbociclib, while a significant number of triple-negative tumors were resistant.

"We were scratching our heads as to why we were seeing what we were seeing. It became very obvious when we looked at the molecular analysis," said Slamon. "When you look at the amount of retinoblastoma protein in these cells relative to their counterparts, it is the ER-positive subsets that have had these incredible high levels of retinoblastoma, which explains why the drug had such unique activity in the group."

This allowed investigators to propose a phase Ib clinical trial with palbociclib specifically targeting recurrences in patients with metastatic ER-positive breast cancer. Slamon said that responses were seen in this initial 12-patient trial, although investigators were strictly evaluating safety.

These findings led to the open-label phase II PALOMA-1 study, which evaluated the safety and efficacy of the combination of palbociclib plus letrozole versus letrozole alone in patients with postmenopausal ER-positive/HER2-negative breast cancer. About halfway to accrual, patients were coming off study because of progressive disease at about a 2:1 ratio in the letrozole alone arm. Slamon said that they then looked at the Kaplan-Meier curves, which showed a huge difference between the 2 arms.

Findings from PALOMA-1 led to the February 2015 FDA accelerated approval of palbociclib for use in combination with letrozole as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer. This was the biggest impact on this setting since the introduction of tamoxifen, said Slamon.

Subsequently, the phase III PALOMA-2 trial further investigated the palbociclib in combination with letrozole. This combination reduced the risk of disease progression by 42% compared with letrozole alone in patients with ER-positive/HER2-negative advanced or metastatic breast cancer.¹ The addition of palbociclib improved the median PFS by more than 10 months.

Current Use of CDK4/6 Inhibitors

Findings from PALOMA-2 led to the March 2017 full approval of palbociclib plus letrozole as a frontline combination treatment for postmenopausal women with ER-positive/HER2-negative metastatic breast cancer.In March 2017, the FDA approved the CDK4/6 inhibitor ribociclib (Kisqali) for use in combination with an aromatase inhibitor (AI) for the frontline treatment of postmenopausal women with HR—positive/HER2-negative advanced breast cancer.

The approval of ribociclib was based on findings from the phase III MONALEESA-2 trial, in which combining ribociclib with letrozole reduced the risk of progression or death by 44% compared with letrozole alone in the first-line setting for HR-positive/HER2-negative advanced breast cancer (HR, 0.556; 95% CI, 0.43-0.72; P <.0001).^2,3

Ribociclib was granted a breakthrough therapy designation by the FDA in January 2018 for use in combination with tamoxifen or an AI as frontline therapy for pre- or perimenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer.

Then in February 2018, the FDA approved abemaciclib (Verzenio) for use in combination with an AI for the frontline treatment of postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer. This was based on data from the phase III MONARCH 3 trial. Abemaciclib was previously approved as a single agent in September 2017 based on data from the MONARCH-1 trial.

Findings from the MONARCH 3 study showed that the addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46% compared with the nonsteroidal AI (NSAI) alone for previously untreated patients with HER2-negative/HR-positive advanced breast cancer.⁴ The median PFS was 28.2 months (95% CI, 23.5 to not reached) in the abemaciclib arm versus 14.8 months (95% CI, 11.2-19.2) with the NSAI alone (HR, 0.54; 95% CI, 0.418-0.698; P <.0001).

The CDK4/6 inhibitors palbociclib and abemaciclib have been studied in the second-line setting in the PALOMA-3 and MONARCH-2 trials, respectively. Both agents have FDA indications in this setting.

“In my opinion, we should be using a CDK4/6 inhibitor paired with an AI in the frontline setting," said Hurvitz. "Right now, we do not have a good indicator as to which [agent] we should be selecting because the data look so similar, and we do not have randomized data."

Hurvitz said that with such comparable data, patient-focused decision making is critical. This involves looking at a patient's comorbidities, such as cardiac- and gastrointestinal-related, as well as copay comorbidities. Additionally, careful follow-up and management of adverse events are important considerations for treatment.

Another unaddressed question is what to do when a patient progresses on a CDK4/6 inhibitor. This is an area that is under clinical trial evaluation currently, Hurvitz said.

References

1. Finn RS, Martin M, Rugo HS, et al. PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2— advanced breast cancer (ABC). J Clin Oncol. 2016;34(suppl; abstr 507). doi: 10.1200/JCO.2016.34.15_suppl.507.
2. Hortobagyi GN, Stemmer SM, Burris HA, et al. First-line ribociclib + letrozole for postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA1.
3. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer [published online October 8, 2016]. N Engl J Med. doi: 10.1056/NEJMoa1609709.
4. Di Leo A, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 236O_PR.