Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are changing the landscape of the treatment of hormone receptor (HR)-positive/HER2-negative breast cancer. Three CDK4/6 inhibitors are approved by the U.S. Food and Drug Administration—ribociclib, palbociclib, and abemaciclib—as first- or second-line therapy for metastatic HR-positive/HER2-negative breast cancer. The data on which approval was based for these drugs were derived from clinical trials, which have a homogeneous patient population and tend to exclude older, sicker patients.
So how do these drugs do in the real world? Does their performance match clinical trial data? How are they being used in the community?
With these questions in mind, one study presented at the 2019 San Antonio Breast Cancer Symposium showed that the magnitude of improvement in progression-free survival with the CDK4/6 inhibitor palbociclib is maintained in real-world practice in patients with metastatic breast cancer. Moreover, there is an overall survival benefit as well when palbociclib is combined with letrozole.1
Another study presented in San Antonio found that abemaciclib is being used as first-, second-, third-line, and later treatment.2
Palbociclib Improves Outcomes
Real-world data suggest that palbociclib added to letrozole significantly prolongs progression-free survival by 45% vs letrozole alone (P < .0001) and significantly improves overall survival by 48% vs letrozole alone (P < .0001), according to a retrospective analysis of electronic health records reported at the San Antonio meeting.1
“Our question was, ‘Do real-world data mirror progression-free survival previously reported in the pivotal PALOMA-2 trial?’ Our study showed that, in the real world, we see almost the same progression-free survival that was reported in PALOMA-2 with palbociclib plus letrozole vs letrozole alone. We also found an overall survival difference with the addition of palbociclib,” said lead author Angela DeMichele, MD, MSCE, Director of the Breast Cancer Clinical Trials Unit at Penn Medicine’s Abramson Cancer Center, Philadelphia.
“A consistent survival benefit of palbociclib plus letrozole vs letrozole alone was observed generally across all studied subgroups except for race.”— Angela DeMichele, MD, MSCE
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The double-blind, phase III PALOMA-2 study included postmenopausal women with estrogen receptor–positive/HER2-negative advanced breast cancer, randomly assigned 2:1 to receive front-line treatment with palbociclib plus letrozole vs placebo plus letrozole. Median progression-free survival in that study was 27.6 months for palbociclib plus letrozole vs 14.5 months with letrozole alone (P < .0001), a 46% improvement.3
In the real-world data presented by Dr. DeMichele, median progression-free survival was 20 months with the addition of palbociclib, compared with 12.1 months with letrozole alone, representing a 45% improvement (P < .0001). “The hazard ratio of 0.55 was just about the same as what it was in PALOMA-2,” she said.
The analysis was based on electronic health records from the Flatiron Health Analytic database, which compiles data from more than 280 cancer clinics in the United States and currently includes more than 2.2 million patients with cancer.
The retrospective study used similar eligibility criteria as in PALOMA-2: women aged 18 years or older with HR-positive/HER2-negative metastatic breast cancer treated with front-line palbociclib plus letrozole or letrozole alone between February 2015 and May 2019. Prior treatment with CDK4/6 inhibitors, aromatase inhibitors, tamoxifen, raloxifene, toremifene, or fulvestrant in the metastatic setting was not allowed.
There were 772 patients treated with front-line palbociclib plus letrozole and 658 patients who received letrozole alone. Patient characteristics were not as well balanced between the cohorts as they are in clinical trials, so propensity score matching was used to adjust for confounding factors.
Using propensity score matching, 464 patients were left in each arm. The median age for the adjusted cohorts was approximately 67 years in each group, with about 25% of patients in each group aged ≥ 75 years. About 55% of patients in each cohort had stage III/IV disease. Most patients who had available Eastern Cooperative Oncology Group performance status data had a score of 0 or 1.
Just over one-third of patients in each arm had visceral disease at diagnosis, and about 40% in each group had bone-only disease. Over 90% of patients in each arm did not have brain metastases. More than 80% of patients in each arm had either one or two metastatic sites.
Median follow-up was 23.1 months in the palbociclib group and 24.4 months in the control arm. Median overall survival was not reached in the palbociclib arm. The 2-year overall survival rate was 80.1% vs 63.9% in the palbociclib vs control arms, respectively.
“These data are the first to suggest that improvement in progression-free survival leads to improved overall survival. A consistent survival benefit of palbociclib plus letrozole vs letrozole alone was observed generally across all studied subgroups except for race,” noted Dr. DeMichele.
She added that these data alone do not have the clout to guide treatment as compared with a clinical trial, but she considers them corroborative. “An oncologist could use these findings in conjunction with clinical trial data to support the drug’s effectiveness, and the findings might encourage a doctor to give the drug in a situation where he or she might not have otherwise,” she told The ASCO Post.
Dr. DeMichele is principal investigator on the phase III PALLAS study in HR-positive/HER2-negative early breast cancer, which is designed to compare palbociclib plus standard adjuvant endocrine therapy with standard adjuvant endocrine therapy alone. Enrollment has been completed for the trial. “Similar trials are ongoing with the other two CDK4/6 inhibitors, ribociclib and abemaciclib,” she said.
Real-World Use of Abemaciclib
A second study presented in San Antonio described real-world use of another CDK4/6 inhibitor, abemaciclib.2 This retrospective observational study found that real-world data show that abemaciclib is being used as first-line, second-line, third-line, and later treatment. Its use has led to a 12-month progression-free survival rate of 61.7%, and median progression-free survival had not been reached at the time of the San Antonio meeting.
This study population was drawn from the Flatiron Health electronic health records database and included 118 female patients with HR-positive/HER2-negative metastatic breast cancer who initiated treatment with abemaciclib between June 30, 2016, and August 31, 2018, and at least 4 months prior to the cutoff date of December 31, 2018. Median follow-up time for this analysis was 6.4 months. Almost all patients (98.3%) were treated in a community oncology practice.
“It’s important to understand how abemaciclib is being used because you want to understand if it’s similar to its indication.”— Gebra Cuyun Carter, PhD
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“It’s important to understand how abemaciclib is being used because you want to understand if it’s similar to its indication,” said lead author Gebra Cuyun Carter, PhD, a research scientist at Eli Lilly and Company, Indianapolis. “Clinical trial patients are often a homogeneous patient population…. Only 3% of patients with cancer participate in clinical trials, [and] it’s important to understand utilization in a more heterogeneous patient population in a clinical practice setting. You’re looking at patients who are often excluded or choose not to participate in clinical trials or don’t have the option to participate.”
Abemaciclib was used in the first-line setting in 34 (28.8%) of the 118 abemaciclib recipients, in the second line in 25 (21.2%), in the third line in 24 (20.3%), and in the fourth or later line in 35 (29.7%). As part of a combination, abemaciclib was most often used with fulvestrant (n = 70), followed by an aromatase inhibitor (n = 27), and the combination of fulvestrant and an aromatase inhibitor (n = 6).
In the first line, abemaciclib was most often used with fulvestrant (n = 18) or an aromatase inhibitor (n = 11). It was used as monotherapy in the first line in two patients. In the 25 patients in whom abemaciclib was used in the second-line setting, use in combination with fulvestrant was the most common (n = 18). Abemaciclib was not used as monotherapy in the second line. In the third line, abemaciclib was again used most often with fulvestrant (n = 17). When used in the fourth line or later, abemaciclib was used most often with fulvestrant (n = 17), followed by abemaciclib monotherapy (n = 12).
About 85% of patients initiated abemaciclib at a starting dosage that is consistent with U.S. Food and Drug Administration–approved labeling. Most patients appeared to tolerate treatment: no dose reduction was required in 93.2%; 62.7% did not have a dose held; and 78.8% of patients did not have a change in dosing schedule.
DISCLOSURE: Dr. DeMichele has received honoraria from Pfizer; has served in a consulting or advisory role for Calithera Biosciences, Context Therapeutics, Novartis, and Pfizer; has received institutional research funding from Bayer, Calithera Biosciences, Genentech, GlaxoSmithKline, Incyte, Millennium, Pfizer, Veridex, and Wyeth; and has been reimbursed for travel, accommodations, or other expenses by Calithera Biosciences, Novartis, and Pfizer. Dr. Carter is employed by Eli Lilly and holds stock or other ownership interests in Eli Lilly.
1. DeMichele A, Cristofanilli M, Brufsky A, et al: Overall survival for first-line palbociclib plus letrozole vs letrozole alone for HR+/HER2- metastatic breast cancer patients in U.S. real-world clinical practice. 2019 San Antonio Breast Cancer Symposium. Abstract P1-19-02. Presented December 11, 2019.
2. Carter GC, Sheffield KM, Gossan A, et al: Initial real world treatment patterns and outcomes of abemaciclib for the treatment of HR+, HER2- metastatic breast cancer. 2019 San Antonio Breast Cancer Symposium. Abstract P2-08-12. Presented December 11, 2019.
3. Rugo HS, Finn RS, Diéras V, et al: Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat 174:719-729, 2019.
Harold J. Burstein, MD, PhD, FASCO
Commenting on Dr. DeMichele’s poster presentation at the 2019 San Antonio Breast Cancer Symposium, Harold J. Burstein, MD, PhD, FASCO, Professor of Medicine at Harvard Medical School and a medical oncologist at Dana-Farber Cancer Institute and Brigham and...