Peter A. Kaufman, MD
The treatment options for women with hormone receptor (HR)–positive metastatic breast cancer have evolved rapidly in the past decade, with the introduction of the CDK4 and CDK6 inhibitors representing a major advance, according to Peter Kaufman, MD, during a lunch symposium at the 36th Annual CFS®
"The CDK4/6 inhibitors have been the most recent therapies added to our armamentarium," said Kaufman, associate professor of medicine, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center. "CDK4/6 inhibitors have really had a dramatic impact on the treatment of hormone receptor–positive, HER2-negative metastatic patients. It has had a huge impact therapeutically."
Inhibition of CDK4 and CDK6 prevents the phosphorylation of Rb, which halts cell cycle progression from G1 to S phase. Continuous inhibition of CDK4 and CDK6 leads to prolonged cell cycle arrest and initiation of apoptosis and senescence, with a potential rebound effect in Rb phosphorylation and cell cycle activity when inhibition is withdrawn, according to Kaufman. Among the approved CDK4 and CDK6 inhibitors, he noted that abemaciclib (Verzenio) was the only agent approved for continuous dosing.
"In the lab in a variety of preclinical experiments it was shown that intermittent inhibition of the cell cycle results in rebound activation of Rb and reactivation of the cell cycle, whereas continuous inhibition of this pathway leads to apoptosis and senescence," Kaufman said.
Abemaciclib has quickly gained 3 indications, since its initial approval in 2017. The agent is approved for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor (AI) as initial endocrine therapy and in combination with fulvestrant (Faslodex) following progression on endocrine therapy. Moreover, abemaciclib has a single-agent approval following endocrine therapy and prior chemotherapy in the metastatic breast cancer setting.
"Abemaciclib is approved as a single agent. This is unique to abemaciclib in this class of CDK4 and 6 inhibitors," he noted. "It is the only CDK4 and 6 inhibitor given on a continuous schedule."
In his presentation, Kaufman noted that abemaciclib is ideal for patients with disease characteristics that typically confer a less favorable prognosis, such as liver metastases or primary resistance to endocrine therapy. He highlighted the benefits seen in this group during a review of findings from the phase III MONARCH 2 and MONARCH 3 studies and the phase II MONARCH 1 trial.
In the MONARCH 2 trial, patients were randomized to abemaciclib plus fulvestrant (n = 446) or fulvestrant plus placebo (n = 223). All patients had recurred or progressed on or after endocrine therapy. The study primarily included postmenopausal women (82%), with the remainder being pre- or perimenopausal. For this group, patients received the gonadotropin-releasing hormone agonist goserelin throughout the trial and for at least 4 weeks prior to entering the study.
Overall, the median progression-free survival (PFS) was 16.4 months in the abemaciclib arm versus 9.3 months in the fulvestrant-alone group (HR, 0.553; 95% CI, 0.449-0.681; P
<.001). For those with primary resistance, the median PFS was 15.3 months in the abemaciclib group and 7.9 months in the control arm (HR, 0.454; 95% CI, 0.306-0.674). In the visceral disease group, the median PFS was 14.7 and 6.5 months, respectively (HR, 0.481; 95% CI, 0.369-0.627).
"This is a group historically that had not done as well with hormonal therapy," Kaufman said. "The median PFS for fulvestrant alone is numerically somewhat lower than the overall population, and you can see a highly clinically significant improvement for abemaciclib in this group."
In the MONARCH 3 trial, 328 women received abemaciclib with their initial endocrine therapy for metastatic or advanced disease and 165 received a nonsteroidal AI plus placebo. Prior to study entry, in the adjuvant or neoadjuvant space, 38% of patients had received chemotherapy and 26% had received an AI.
The median PFS with abemaciclib was 28.2 months versus 14.8 months with the nonsteroidal AI alone (HR, 0.54; 95% CI, 0.418-0.698; P
<.0001). In those with liver metastases (n = 78), the median PFS was 15.0 months in the abemaciclib arm compared with 7.2 months in the placebo group (HR, 0.477; 95% CI, 0.272-0.837).
Kaufman noted that treatment-free interval could potentially be used for tailoring therapy. In MONARCH 3, those with a recurrent disease-free interval of <36 months experienced a better outcome with abemaciclib than those with an interval of ≥36 months. The hazard ratio in the <36-month group was 0.442 compared with 0.778 in the ≥36-month subgroup.
"This is only hypothesis generating, but this suggests a subgroup of patients who don't derive as great of a benefit with the addition of abemaciclib," Kaufman said. "Those with high-grade disease, liver metastases, and other concerning clinical characteristics do benefit from the addition of abemaciclib."
The monotherapy approval for abemaciclib was based on findings from the phase II MONARCH 1 trial, which enrolled 132 patients with HR-positive/HER2-negative metastatic breast cancer who progressed during or after endocrine therapy and chemotherapy. Overall, 90% of patients had visceral disease, and 51% had 3 or more metastatic sites. Seventy-one percent of patients had liver metastases.
The median PFS in this setting was 5.7 months, and the investigator-assessed objective response rate (ORR) was 19.7%. The median duration of response was 8.6 months. The independently reviewed ORR was 17.4% with a median response duration of 7.2 months.
Across the clinical trials, diarrhea was one of the most common adverse events (AEs) associated with abemaciclib, Kaufman noted. In the MONARCH 3 trial, 81% of patients experienced this event, of which 9% was grade 3. In the MONARCH 2 trial, 86% of patients had all-grade diarrhea and 13% had a grade 3 event, and in the MONARCH 1 trial, 90% of patients had diarrhea, with a grade 3 rate of 20%. Given the frequency of this event, abemaciclib comes with a loperamide kit.
"Diarrhea is the major side effect clinically with abemaciclib. It definitely occurs, there's no question that it occurs, but it is definitely manageable. It tends to occur early, typically within the first week or so from the initiation of therapy," said Kaufman. "The necessity to come off study due to diarrhea was exceedingly low, it was very, very uncommon that a patient had to discontinue treatment from diarrhea. It is important to be aware of it and address it appropriately but, in my experience, it is very manageable."
Neutropenia represents another AE associated with CDK4 and CDK6 inhibition, which occurred in 41%, 46%, and 37% of patients in the MONARCH 3, 2, and 1 trials, respectively. Neutropenia of grade ≥3 severity was experienced by 22%, 32%, and 27%, respectively. Abemaciclib was associated with other AEs of interest, including hepatotoxicity, venous thromboembolism, and embryo-fetal toxicity.
"There is a small incidence of grade 3 transaminitis, it does occur, but it is really quite uncommon. There is also a rise in serum creatinine with abemaciclib, it is thought to be a lab artifact. It is not impacting renal function whatsoever," Kaufman noted. “Information about venous thromboembolism is still evolving.”
As research into abemaciclib continues, one avenue for further exploration is the treatment’s role for patients with brain metastases. Early evidence has suggested that abemaciclib may cross the blood brain barrier, Kaufman said. "In addition to some early data, which is quite interesting, there is some clinical data suggesting that abemaciclib crosses the blood brain barrier," he noted. "This is an area of active interest and exploration."
A phase III study exploring endocrine therapy with or without abemaciclib following surgery for patients with breast cancer (monarchE) is currently enrolling participants. This study is investigating the utility of abemaciclib as an adjuvant therapy, with a primary endpoint of invasive disease-free survival. The trial plans to enroll 4580 participants with an estimate primary completion date of April 2021 (NCT03155997).