Joseph F. Stilwill, MD
All 3 FDA-approved CDK4/6 inhibitors—palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)—show a consistent progression-free survival (PFS) advantage for patients with metastatic hormone receptor (HR)–positive, HER2-negative breast cancer, irrespective of endocrine therapy use, line of therapy, menopausal status, and clinical and pathologic features.
“CDK4/6 inhibitors have really become the standard of care in first-line therapy for patients with estrogen receptor (ER)–positive disease,” said Joseph F. Stilwill, MD, in a presentation during the 2019 OncLive®
State of the Science Summit™ on Breast Cancer.
Stilwill, a hematologist/oncology specialist at Sarah Cannon Cancer Institute, HCA Midwest Health, shared insight on the clinical benefit seen with CDK4/6 inhibitors in patients with advanced HR-positive, HER2-negative breast cancer and highlighted ongoing research aimed at overcoming acquired resistance.
The first 2 phase III trials to examine the use of palbociclib and ribociclib in the frontline setting were the PALOMA-2 and MONALEESA-2 trials, respectively. In PALOMA-2 and MONALEESA-2, postmenopausal patients with advanced HR-positive, HER2-negative breast cancer were randomized to palbociclib or ribociclib, respectively, plus letrozole or placebo plus letrozole.
PFS served as the primary endpoint of both studies, said Stilwill. The median PFS with palbociclib/letrozole was 24.8 months (hazard ratio, 0.58; 95% CI, 0.46-0.72; P
<.000001) and the median PFS with ribociclib/letrozole was 25.3 months (hazard ratio, 0.568; 95% CI, 0.457-0.72), outperforming endocrine therapy alone by approximately 10 months in both studies.1,2
In 2017, both palbociclib and ribociclib received approvals from the FDA for use in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for the treatment of postmenopausal women with ER-positive, HER2-negative advanced or metastatic breast cancer.
Subsequently, abemaciclib was examined in the MONARCH 3 trial, in which investigators randomized postmenopausal women with metastatic or locally recurrent disease 2:1 to receive either abemaciclib plus physician’s choice of anastrozole or letrozole or placebo plus AI therapy. Although prior exposure to neoadjuvant or adjuvant endocrine therapy was allowed, patients had to have a disease-free interval >12 months after completing treatment.
Similarly, the median PFS was 28.2 months with abemaciclib/ AI and 14.8 months with an AI alone (hazard ratio, 0.54; 95% CI, 0.418-0.698; P
The benefit of CDK4/6 inhibition with ribociclib was later replicated in the MONALEESA-7 trial, specifically in the premenopausal/perimenopausal population, said Stilwill, which served as the basis for the FDA’s decision to expand its indication in July 2018.
In the trial, patients without prior exposure to endocrine therapy for advanced disease and ≤1 line of chemotherapy for advanced disease were randomized 1:1 to ribociclib, tamoxifen/ nonsteroidal AI (NSAI), and the GnRH agonist goserelin (Zoladex) or tamoxifen/NSAI and goserelin. The results indicated a 10.8- month improvement in median PFS with ribociclib compared with an AI alone at 23.8 months and 13.0 months, respectively (hazard ratio, 0.55; 95% CI, 0.44-0.69; P
“This tells us that there is not a substantial difference among the 3 drugs. Choosing which one [to use] really comes down to adverse events and which dosing schedule you’re most comfortable with,” explained Stilwill.
In terms of dosing, both palbociclib and ribociclib are administered on a 3-weeks-on/1-week off schedule with corresponding doses of 125 mg daily and 600 mg daily, whereas abemaciclib can be given twice daily at 150 mg with endocrine therapy or at 200 mg as monotherapy.
Abemaciclib is the only CDK4/6 inhibitor to be granted an approval from the FDA for single-agent use in the treatment of patients with advanced or metastatic disease progression following prior endocrine therapy and chemotherapy. The approval was based on positive data from the MONARCH 1 trial, which indicated an objective response rate of 19.7%, a clinical benefit rate of 42.4%, a median PFS of 6 months, and a median overall survival (OS) of 17.7 months.5
In terms of toxicity, neutropenia with palbociclib and diarrhea with abemaciclib pose the biggest challenge to clinicians, although both adverse events can be effectively managed, said Stilwill.
If ribociclib is given, physicians should be prepared to monitor the patient’s electrocardiogram at baseline and on days 1 and 15 of the first cycle of therapy as well as on the first day of every cycle thereafter due to a prolonged corrected QT interval.
All three CDK4/6 inhibitors were also examined as second- line therapy in combination with fulvestrant, explained Stilwill.