Joseph F. Stilwill, MD, shares insight on the 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.
Joseph F. Stilwill, MD
CDK4/6 inhibitors have shown significant clinical benefit 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, explained Joseph F. Stilwill, MD.
All 3 FDA-approved CDK4/6 inhibitorspalbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)—show a consistent progression-free survival (PFS) advantage.
“CDK4/6 inhibitors have really become the standard of care in first-line therapy for patients with estrogen receptor (ER)positive disease,” said Stilwill.
Stilwill, a hematologist/oncology specialist at Sarah Cannon Cancer Institute, HCA Midwest Health, shared insight on the 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.1,2In 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<.0001).3
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<.0001).4
“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.
In the PALOMA-3 trial, investigators observed a statistically significant benefit in both PFS and OS with the combination of palbociclib and fulvestrant. Positive preliminary results from the trial led to the combination’s approval by the FDA in 2016 for use in patients with disease progression following endocrine therapy. Notably, the median time to chemotherapy was 17.6 months in the experimental arm and 8.8 months in the placebo arm (hazard ratio, 0.58;P<.0001).6
Furthermore, data from the MONALEESA-3 trial showed a clear extension in PFS with the addition of ribociclib to fulvestrant as second-line therapy versus fulvestrant alone at 20.5 months versus 12.8 months, respectively (hazard ratio, 0.593; 95% CI, 0.480-0.732;P= .001).7
“There’s clearly a benefit regardless of progesterone receptor status, whether it’s lobular or ductal, whether they have bone-only or visceral metastases, whether it’s de novo metastatic, or whether patients have received prior adjuvant endocrine therapy with a 12-month treatment-free interval,” said Stilwill.
Even so, mechanisms of resistance are an inevitable reality for many patients.
“[The acquired mutation] makes a difference in terms of choosing the next line of therapy,” added Stilwill. “This is a reason to really think about next-generation sequencing upon progression.”
Through decreased ER dependence, patients may developESRmutations,RBmutations, andPIK3CA-activating mutations, for which FGFR inhibitors and the PI3K inhibitorsbuparlisib (BKM120), taselisib (GDC-0032), alpelisib (BYL719), and gedatolisib (PF-05212384)—are being investigated.
Specifically, for those who develop PIK3CA mutations following prior endocrine therapy with CDK4/6 inhibition, interim data from the SOLAR-1 trial showed that alpelisib induced a prolonged OS when added to fulvestrant compared with fulvestrant alone (hazard ratio, 0.73; 95% CI, 0.48- 1.10;P= .06).8
Looking toward the future, Stilwill explained that CDK4/6 inhibition has shown preclinical synergy with PD-1 inhibitors, but whether it can enhance response rates in these patients remains to be seen.