The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are rapidly transforming the care of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2−) advanced breast cancer. Current clinical questions include how to choose among these agents and how to sequence them with other therapies. Areas of active inquiry include identifying predictive biomarkers for CDK4/6 inhibitors, deciding whether to continue CDK4/6 inhibitors after disease progression, creating novel treatment combinations, and expanding use beyond HR+/HER2− advanced breast cancer. Here, we review the current use of and potential next directions for CDK4/6 inhibitors in the treatment of patients with HR+ breast cancer.
Despite the availability of many therapies, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2−) advanced breast cancer is rarely curable. The current treatment paradigm for HR+/HER2− advanced breast cancer involves sequencing endocrine therapy, targeted therapy, and/or chemotherapy to prolong patients’ lives, delay disease progression, and minimize cancer-related symptoms. The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are rapidly transforming this treatment landscape. There are currently three CDK4/6 inhibitors that have been approved by the US Food and Drug Administration: palbociclib, ribociclib, and abemaciclib. How to choose among these agents and how to sequence them with other therapies are currently the most pressing questions. The possibility of using biomarkers to predict response, novel treatment combinations with CDK4/6 inhibitors, and the potential activity of these agents beyond the setting of HR+/HER2− advanced breast cancer are areas of active research. We will review the current role of CDK4/6 inhibitors in the treatment of patients with HR+ breast cancer, as well as promising future applications.
Mechanism of Action of CDK4/6 Inhibitors
The CDK4/6 inhibitors act at the G1-to-S cell cycle checkpoint. This checkpoint is tightly controlled by the D-type cyclins and CDK4 and CDK6. When CDK4 and CDK6 are activated by D-type cyclins, they phosphorylate the retinoblastoma-associated protein (pRb). This suspends pRb’s suppression of the E2F transcription factor family and ultimately allows the cell to proceed through the cell cycle and divide. In HR+ breast cancer, cyclin D overexpression is common and loss of pRb is rare, making the G1-to-S checkpoint an ideal therapeutic target. The CDK4/6 inhibitors prevent progression through this checkpoint, leading to cell cycle arrest.
Approved CDK4/6 Inhibitors for HR+/HER2− Advanced Breast Cancer
Table 1 summarizes the evidence from the pivotal trials that led to the FDA approveals of palbociclib, ribociclib, and abemaciclib.
Palbociclib was approved for use with an aromatase inhibitor (AI) as first-line treatment of HR+/HER2− advanced breast cancer in postmenopausal women, based on the phase II study PALOMA-1/TRIO-18 and the phase III study PALOMA-2. Palbociclib was approved for use with fulvestrant as second- or later-line treatment of HR+/HER2− advanced breast cancer based on the phase III study PALOMA-3.
In PALOMA-1/TRIO-18, 165 women with HR+/HER2− untreated advanced breast cancer were randomized to receive either palbociclib and letrozole or letrozole alone. Previous treatment with an AI more than 12 months before enrollment was allowed. The study’s primary endpoint was median progression-free survival (PFS). Patients who received palbociclib and letrozole had a median PFS of 20.2 months, compared with only 10.2 months with letrozole alone (hazard ratio, 0.488; 95% CI, 0.319–0.748; P = .0004). This study led to accelerated approval of palbociclib in February 2015. Median overall survival (OS) was 37.5 months with palbociclib and letrozole and 34.5 months with letrozole alone (HR, 0.897; 95% CI, 0.623–1.294; P = .281). This difference was not significant, but the study was not powered to show a difference in OS.
In PALOMA-2, 666 treatment-naive patients with HR+/HER2− advanced breast cancer were randomized to receive palbociclib and letrozole or placebo and letrozole. Median PFS was 24.8 months in the patients who received palbociclib and letrozole and 14.5 months in those who received placebo and letrozole (hazard ratio, 0.58; 95% CI, 0.46–0.72; P = .001). This led to regular approval of palbociclib in March 2017. OS data are still maturing.
In PALOMA-3, 521 women of any menopausal status with HR+/HER2− advanced breast cancer whose disease had progressed on prior endocrine therapy or recurred within 12 months of stopping adjuvant endocrine therapy were randomized to receive either palbociclib and fulvestrant or placebo and fulvestrant. Approximately half the patients had received two or more lines of endocrine therapy in the metastatic setting and approximately one-third had received chemotherapy in the metastatic setting. Final analysis demonstrated a median PFS in the palbociclib and fulvestrant group of 9.5 months, compared with 4.6 months in the placebo and fulvestrant group (hazard ratio, 0.46; 95% CI, 0.36–0.59; P < .0001),[5,6] which led to the approval of palbociclib in combination with fulvestrant for use after progression while receiving endocrine therapy.
Ribociclib was approved in March 2017 for first-line treatment of HR+/HER2− advanced breast cancer in postmenopausal women, based on the results of the phase III MONALEESA-2 study. In this study, treatment-naive patients with HR+/HER2− advanced breast cancer received letrozole with ribociclib or placebo. Prior AI therapy was allowed if it had been discontinued 12 months before enrollment. At the 18-month follow-up, median PFS had not been reached in the ribociclib-treated arm, compared with a median PFS of 14.7 months in the placebo group (hazard ratio, 0.56; 95% CI, 0.43–0.72; P < .001). Updated analysis showed a median PFS of 25.3 months in the ribociclib group vs 16.0 months in the placebo group.[7,8] OS data are not available yet.
MONALEESA-3 is a phase III study assessing ribociclib in combination with fulvestrant for both second-line and first-line treatment of HR+/HER2− advanced breast cancer in both postmenopausal women and men. This study has completed recruitment but results are not yet available.
Abemaciclib was approved in February 2018 in combination with an AI for first-line therapy of HR+/HER2− advanced breast cancer in postmenopausal women, based on results from the MONARCH-3 study. Abemaciclib was approved in September 2017 for second- or later-line therapy in combination with fulvestrant, based on the results of MONARCH-2, and as a single agent for third- or later-line therapy for women and men, based on MONARCH-1.
MONARCH-3, a phase III study, compared an AI with abemaciclib or placebo in treatment-naive patients with HR+/HER2− advanced breast cancer. Interim results after 18 months of follow-up demonstrated that median PFS was not reached in the abemaciclib arm, compared with a median PFS of 14.7 months in the placebo arm (hazard ratio, 0.543; 95% CI, 0.409–0.723; P < .001).[9,10]
MONARCH-2 was a phase III study that randomized patients with HR+/HER2− advanced breast cancer whose disease had progressed on prior endocrine therapy to receive either abemaciclib and fulvestrant or placebo and fulvestrant. Patients could enroll if their disease had progressed during adjuvant or neoadjuvant endocrine therapy, ≤ 12 months after completion of adjuvant endocrine therapy, or while receiving endocrine therapy for advanced breast cancer. Patients had received only one prior line of endocrine therapy and no chemotherapy for their advanced breast cancer. Median PFS in the abemaciclib group was significantly improved: 16.4 months, compared with 9.3 months in the placebo group (hazard ratio, 0.553; 95% CI, 0.449–0.681; P < .001). OS data are still maturing.
MONARCH-1 was a phase II single-arm study of abemaciclib as a single agent; it enrolled women of any menopausal status with HR+/HER2− advanced breast cancer that had progressed on prior endocrine therapy and chemotherapy (at least one line of chemotherapy). Patients in this study had received a median of three prior lines of systemic treatment for advanced breast cancer. The majority (90.2%) had visceral disease. The objective response rate (ORR) was 19.7% at 12 months, median PFS was 6.0 months, and median OS was 17.7 months.
Comparative Efficacy of CDK4/6 Inhibitors for HR+/HER2− Advanced Breast Cancer
Palbociclib, ribociclib, and abemaciclib are approved in combination with an AI for first-line therapy of HR+/HER2− advanced breast cancer. These drugs have never been directly compared and are considered equivalent in efficacy. Palbociclib and ribociclib demonstrated similar prolongations of PFS when compared with AI-only therapy in PALOMA-1/PALOMA-2 and MONALEESA-2, respectively. Data regarding abemaciclib with an AI vs an AI only are comparatively immature. Only results from 18 months of follow-up have been reported thus far; however, the hazard ratio is similar to that seen in studies with palbociclib and ribociclib, suggesting similar efficacy. All three agents are appropriate choices in combination with an AI for first-line treatment.
Palbociclib and abemaciclib are both approved in combination with fulvestrant for second- or later-line treatment of HR+/HER2− advanced breast cancer, and either combination is an appropriate choice in this setting. There are no direct comparisons of these two agents and they are likely equivalent in efficacy. Of note, the patients who received abemaciclib-fulvestrant in MONARCH-2 had a much longer PFS (16.4 months) than did patients who received palbociclib-fulvestrant in PALOMA-3 (9.5 months). This likely reflects differences in the characteristics of the patient populations enrolled. The patients in MONARCH-2 had received only one prior line of endocrine therapy, and 59% had received only adjuvant or neoadjuvant endocrine therapy. No patients had received chemotherapy in the metastatic setting. In contrast, about half the patients enrolled in PALOMA-3 had received two or more lines of endocrine therapy in the metastatic setting, and about one-third had received chemotherapy in the metastatic setting, indicating a population that was more endocrine-resistant and possibly more treatment-resistant. Consequently, the median PFS for patients in the control (fulvestrant alone) arm of MONARCH-2 was much longer than for patients in the control arm of PALOMA-3 (9.3 vs 4.6 months). Ribociclib with fulvestrant will likely have activity similar to that of the palbociclib-fulvestrant and abemaciclib-fulvestrant combinations.
CDK4/6 Inhibitors in Premenopausal Women
The combination of palbociclib or ribociclib with an AI is only approved for postmenopausal women. Many providers are treating premenopausal women with a CDK4/6 inhibitor, an AI, and ovarian function suppression with a gonadotropin-releasing hormone agonist, based on studies showing that an AI with ovarian suppression is efficacious for premenopausal women with HR+/HER2− advanced breast cancer. Several ongoing studies specifically include premenopausal women receiving palbociclib or ribociclib and endocrine therapy with ovarian function suppression (eg, FATIMA [ClinicalTrials.gov identifier: NCT02917005], COMPLEEMENT-1 [NCT02941926]).
MONALEESA-7 was the first of these trials that included premenopausal women to be reported. In this phase III study, premenopausal women with HR+/HER2− advanced breast cancer were treated with first-line ribociclib vs placebo, along with goserelin and tamoxifen or a nonsteroidal AI. The improvement in PFS seen in the ribociclib arm (23.8 vs 13.0 months [hazard ratio, 0.553; 95% CI, 0.441–0.694; P < .001]) was similar to that seen in postmenopausal women in MONALEESA-2.
In PALOMA-3, premenopausal women were included and received goserelin. A subgroup analysis of the PALOMA-3 study showed that premenopausal women derived a benefit similar to that seen in the overall study population. The combination of palbociclib and fulvestrant is approved regardless of menopausal status.
None of the first-line studies looked at the activity of CDK4/6 inhibitors in premenopausal women in the absence of ovarian suppression. In MONARCH-1, a single-arm study of abemaciclib as a single agent, women were enrolled regardless of their menopausal status. However, all had demonstrated prior progression on at least one line of chemotherapy for advanced disease, so presumably the premenopausal women had some degree of ovarian failure while enrolled in the study.
Safety of CDK4/6 Inhibitors
The CDK4/6 inhibitors as a class are generally well tolerated. The most common class-wide adverse effects include nausea, diarrhea, fatigue, neutropenia, leukopenia, anemia, and thrombocytopenia. Palbociclib and ribociclib most commonly cause neutropenia, while diarrhea is the most common adverse effect of abemaciclib, perhaps because of its greater affinity for CDK4 over CDK6. The safety profiles of these agents do not absolutely favor one agent over another, and patient-specific concerns related to toxicity should be taken into account. If a patient is intolerant of one agent, it is reasonable to try another.
Palbociclib, administered at a dosage of 125 mg daily for 3 weeks on and 1 week off, was associated with grade 3/4 neutropenia in 55% to 65% of patients across clinical studies. Febrile neutropenia occurred in only 0% to 2% of patients, and permanent discontinuation of therapy was infrequent.[4,17] Complete blood count (CBC) should be monitored frequently early in therapy, and neutropenia should be managed with appropriate dose interruption and/or dose reduction. Palbociclib-induced neutropenia occurs via a unique mechanism, in which cell cycle arrest occurs without apoptosis of hematopoietic precursor cells. This unique mechanism allows rapid reversal with dose interruption and/or dose reduction, unlike with chemotherapy-induced neutropenia. Detailed safety analysis of PALOMA-3 showed that neutropenia occurred early (median time to onset, 16 days), was reversible (median duration, 7 days), and was not cumulative (became increasingly rare with subsequent cycles). Dose reduction did not seem to impact efficacy. Of note, grade 3 anemia, although uncommon, can be a late event, justifying continued hematologic monitoring.
Ribociclib, at a dosage of 600 mg daily for 3 weeks on and 1 week off, was associated with grade 3/4 neutropenia in ~60% of patients in MONALEESA-2; however, febrile neutropenia was rare, as was permanent discontinuation of the study drug. Other important adverse effects that require monitoring include elevated alanine aminotransferase or aspartate aminotransferase levels and prolonged QT interval. CBC should be monitored frequently early in treatment, and neutropenia can be managed in a manner similar to that used for palbociclib-associated neutropenia.
Abemaciclib, at a dosage of 150 mg twice daily with fulvestrant or 200 mg twice daily alone, was associated with diarrhea of any grade in 85% to 90% of patients and with grade 3/4 diarrhea in 15% to 20% of patients across clinical studies. Diarrhea typically occurred early (median time to onset, 6 days in MONARCH-2) and was managed with antidiarrheals, followed by dose interruption and dose reduction if needed. More than 70% of the patients in MONARCH-2 who experienced diarrhea did not need dose reduction. Grade 3/4 neutropenia occurred in approximately 25% of patients across studies; this adverse effect can also be managed with dose interruption/dose reduction.
For all three agents, we recommend initiating the approved dose for most patients and then making adjustments for toxicities. Patients should be counseled that dose adjustments may be necessary but that they can still have benefit on a lower dose. Specific guidance about monitoring parameters is provided in Table 2.
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