Abemaciclib (from Lilly) is heading to become the third of a new class of drugs for use in breast cancer — the cyclin-dependent kinase (CDK) 4/6 inhibitors. The US Food and Drug Administration (FDA) granted the drug priority review on July 10, which means a decision on approval should be forthcoming within 6 months, maybe even before year end.
Already on the market are palbociclib (Ibrance, Pfizer) and ribociclib (Kisqali, Novartis), and now the publication of clinical data on abemaciclib showing similar efficacy is leading to an "embarrassment of riches," experts write in an editorial in the Journal of Clinical Oncology.
The published clinical results for abemaciclib come from the MONARCH 2 trial and show a significant improvement in progression-free survival (PFS) when abemaciclib is used with fulvestrant in women with hormone receptor–positive (HR+), human epidermal growth factor receptor–negative (HER2–) advanced breast cancer.
"To the best of our knowledge, the median PFS [with the combination]….represents the longest reported in a population with ABC [advanced breast cancer] whose disease had progressed while they were receiving prior ET [endocrine therapy]," write the study authors, headed by George W. Sledge Jr, MD, Stanford University School of Medicine, California.
The editorial, however, emphasizes how close the results are to what has been seen with the other two drugs. "The data suggest a drug-class effect, with similar improvements in the hazard ratio for progression-free survival," note the editorialists, Jennifer J. Griggs, MD, MPH, from the University of Michigan Cancer Center, Ann Arbor, and Antonio C. Wolff, MD, from the Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
Currently, palbociclib and ribociclib, each in combination with an aromatase inhibitor, are approved as initial endocrine treatment of postmenopausal women with HR+/HER2– advanced or metastatic breast cancer.
In addition, palbociclib is also approved for use in combination with fulvestrant for the second-line treatment of HR+/HER2– metastatic breast cancer following progression on ET.
The new drug application for abemaciclib is based on results from both the MONARCH 2 and the MONARCH 1 study, in which abemaciclib monotherapy demonstrated objective responses in women with HR+/HER2– advanced or metastatic breast cancer that had progressed after one or more endocrine-based therapy. A third study, MONARCH 3, which is expected to provide a front-line indication for abemaciclib, has yet to read out.
The editorialists ask whether three drugs in the same class are required for the treatment of the same disease, and whether these agents can be used interchangeably.
"Given that the response to the CDK 4/6 inhibitors thus far seems to be a class-specific effect, one would imagine that once a patient experiences progression on one CDK 4/6 inhibitor, there would be no benefit of changing to another," they write. However, this has not been formally tested, they admit.
Approached for comment, Eric P. Winer, MD, director of the Breast Oncology Center at the Dana-Farber Cancer Institute, Boston, echoed a similar sentiment. "A critical piece of information that is relevant to clinical practice is to know whether CKD 4/6 inhibitors continue to work after initial progression," he told Medscape Medical News. Currently, in his own practice, Dr Winer does not continue to use the CDK 4/6 inhibitor when a patient initially progresses on a regimen containing the agent.
Lead author of the MONARCH 2 study, Dr Sledge, added a different slant: "Is the primary resistance that emerges with a CDK 4/6 inhibitor combination centered on CDK 4/6 inhibition or on the hormonal therapy component?" If the resistance is due to the hormonal component, one could possibly switch to another hormonal therapy and retain use of the initial CDK 4/6 inhibitor, he commented to Medscape Medical News.
He recounted that in the era before pertuzumab (Perjeta, Genentech/Roche), it was not uncommon to switch the chemotherapy when resistance emerged to a trastuzumab (Herceptin, Genentech/Roche)–chemotherapy combination.
With respect to dosing, the editorialists note that abemaciclib may be easier for the patient to take because it has continuous dosing, whereas both palbociclib and ribociclib have a 3-week-on and 1-week-off dosing schedule. They also suggest that abemaciclib may have an advantage in the treatment of patients with brain metastases because it is known to penetrate the blood-brain barrier.
"We do not know if the dosing schedule [intermittent vs continuous] provides efficacy differences,” Dr Sledge told Medscape Medical News. He believes there is limited real-world experience with CDK 4/6 inhibitors to bias one against the other. "But clinicians have a comfort level with palbociclib since it has been in the clinic for over 2 years," he said.
Dr Winer agreed. "Currently, palbociclib is the go-to CDK 4/6 inhibitor," he said, but he added that "palbociclib and ribociclib are similar drugs. We do not know how usage will change over time.”
Dr Sledge exclusively uses palbociclib in his practice. "It is not because it is a better drug," he said. "There is no compelling reason beyond the comfort factor." He drew a parallel to the era when three aromatase inhibitors were available and he used "anastrazole exclusively for no compelling reason."
Also approached for comment, William J. Gradishar, MD, Betsy Bransen Professor of Breast Oncology at Northwestern's Robert H. Lurie Comprehensive Cancer Network, Chicago, Illinois, agreed. In his clinic, he admitted to having limited experience with ribociclib. "We have the maximum experience with palbociclib and have a comfort level that is lacking with ribociclib," he told Medscape Medical News. "It is too early to know how these drugs can be sequenced in the clinic," he added.
Unique Side-Effect Profiles
The side-effect profile of each CDK 4/6 inhibitor is unique.
Palbociclib is considered to have the most favorable toxicity profile, according to Dr Sledge.
Ribociclib is noted by the FDA to demonstrate QT-interval prolongation and liver toxicity — two safety concerns unique to this drug. The FDA recommends patients receive electrocardiography [ECG] before starting ribociclib, and that the ECG be repeated at day 14 of the first cycle and the beginning of the second cycle. "This currently poses an inconvenience for the routine use of ribociclib," Dr Sledge said.
Diarrhea has emerged as the major toxicity with abemaciclib. This is an acute toxicity, not cumulative, and occurs fairly early — during the first course, Dr Sledge explained. "Although we are accustomed to managing diarrhea with the routine use of antidiarrhea medicines, such as loperamide, the management of this side effect will add an extra layer of complexity for using abemaciclib," he admitted.
Dr Sledge and Dr Winer both suggested that abemaciclib may be a "different drug." They pointed out that abemaciclib is the only drug that has been shown to have single-agent activity in the refractory setting. Moreover, its toxicity profile is distinct from that of palbociclib or ribociclib. "Time will tell whether abemaciclib will be used over palbociclib or ribociclib to avoid blood count suppression in patients," Dr Winer said.
According to Dr Sledge, the toxicity profile might be related to the mechanism of action. "While all three are CDK 4/6 inhibitors, abemaciclib more potently inhibits CKD 4 than CDK 6," Dr Sledge said. The differential toxicities may be related to differential inhibition of CDK 4 and CDK 6, he postulated.
Cost is a potential issue when physicians write drug prescriptions. When ribociclib was approved, a 28-day supply of the 600-mg dose was noted to cost $10,950 wholesale, with the same supply of the 400-mg dose costing $8760, and the 200-mg dose running at $4380. This wholesale pricing structure provided access to the drug at about 20% discounted price to palbociclib.
However, Dr Sledge did not consider pricing to be a likely factor for clinicians prescribing CDK 4/6 inhibitors. He explained that pharmaceutical companies constantly negotiate drug prices with wholesale and retail pharmacies, and with hospitals. "The first on the market will take the majority share because we are used to it," he reiterated.
The editorialists urge postmarketing surveillance for all the CDK 4/6 inhibitors. "[T]oxicities thus far observed in the controlled setting of clinical trials may become more consequential as use of CDK4/6 inhibitors extends into more routine clinical practice, especially in patients who have received multiple lines of therapy or who would otherwise not have been eligible for the clinical trials by virtue of poorer performance status," they write. They suggest that electronic medical record systems can be harnessed to meet this goal, which would "build a shared knowledge base beyond the boundaries of the three individual pharmaceutical companies."
Both Dr Gradishar and Dr Sledge indicate that currently there are no data for one drug to claim superiority over the others. Only head-to-head trials can provide conclusive evidence, they noted. "Outside the setting of an NCI [National Cancer Institute]-sponsored trial, this is unlikely to happen," Dr Sledge said.
In his own practice, Dr Winer uses palbociclib and ribociclib, but not in all patients. "Although there is a substantial PFS benefit, we do not know which patients benefit more or less," he said. In the first-line setting, he uses a CDK 4/6 inhibitor with hormonal therapy. In the refractory setting, he uses it only if patients have not received it first line.
The editorialists voice a cautionary note about clinical trial data and cost-effectiveness of therapy. "We remain mindful that efficacy as measured in the context of controlled clinical trials is not equivalent to effectiveness as demonstrated by real-world use of a new agent," they write. They are hopeful that in a free-market setting the availability of three drugs in the same class would result in competitive pricing — "aside from the usual efforts to identify marketing distinctions without a meaningful clinical difference."
Details of the MONARCH 2 Study
Results from the MONARCH 2 study were published online on June 3 in the Journal of Clinical Oncology and were also presented at the American Society of Clinical Oncology 2017 Annual Meeting.
MONARCH 2 was a phase 3 study conducted in women with HR+/HER2– advanced breast cancer to receive abemaciclib plus fulvestrant (446 patients) or placebo plus fulvestrant (223 patients). These patients were resistant to ET; they were required to have disease progression while receiving neoadjuvant or adjuvant ET, 12 or fewer months after adjuvant ET, or while receiving ET for advanced breast cancer.
Abemaciclib was initially given at a dose of 200 mg twice daily. But a review of the safety data and dose reduction rates seen with the first 121 patients led to a protocol amendment. All subsequent patients received abemaciclib 150 mg twice daily. Fulvestrant 500 mg was provided as per label.
At baseline, median age for the total population was about 60 years. Twenty-five percent of patients showed primary resistance to ET, 60% had received neoadjuvant or adjuvant ET; about 82% were postmenopausal, about 56% had visceral disease, about 72% of patients had measureable disease, and about 60% of patients had an Eastern Cooperative Oncology Group performance status of 0. Baseline characteristics were well balanced across the two groups.
Median follow-up was 19.5 months. Median PFS was 16.4 months for patients receiving the abemaciclib/fulvestrant combination and 9.3 months for those receiving fulvestrant (P < .001). With a hazard ratio of 0.553, patients receiving the combination were at a 45% significantly reduced risk for progression. Similar observations were reported for PFS undertaken with central review and in an analysis that included only patients enrolled after dose change.
In the intention-to-treat population, the overall response rate (ORR [complete response plus partial response]) was 35.2% for the abemaciclib combination and 16.1% for fulvestrant alone (P < .001). In women with measurable disease, the ORR was 48.1% with the abemaciclib combination and 21.3% with fulvestrant alone (P < .001).
Patients receiving abemaciclib with fulvestrant (vs fulvestrant alone) had a higher incidence of diarrhea (86.4% vs 24.7%), neutropenia (46.0% vs 4.0%), nausea (45.1% vs 22.9%), and fatigue (39.9% vs 26.9%). Rates of grade 3/4 diarrhea and neutropenia (vs fulvestrant alone) were 13.4% (vs 0.4%) and 26.5% (vs 1.7%), respectively.
Treatment was discontinued in 15.9% of patients receiving the abemaciclib combination and in 3.1% of those receiving fulvestrant. Dose interruptions were higher with the abemaciclib combination — 51.9% vs 11.7% for fulvestrant.