Neil Vasan, MD, PhD
Maura N. Dickler, MD
THE BODY OF EVIDENCE supporting the use of cell-cycle inhibitors in combination with endocrine therapy for estrogen receptor–positive metastatic breast cancer now has another agent in the spotlight. The phase III MONARCH 2 trial—reported at the 2017 ASCO Annual Meeting and by Sledge et al in the Journal of Clinical Oncology1—showed that adding abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, to fulvestrant (Faslodex) resulted in an improved progression-free survival in patients whose disease had progressed on prior endocrine therapies. Undoubtedly, patients will benefit by this third addition to the arsenal of therapies in estrogen receptor–positive metastatic breast cancer, but this also unveils new clinical and translational questions into how we best choose and sequence these agents.
Comparing CDK4/6 Inhibitors
ABEMACICLIB, like palbociclib (Ibrance) and ribociclib (Kisqali), which are approved by the U.S. Food and Drug Administration (FDA) in combination with endocrine therapy metastatic breast cancer, is a small-molecule inhibitor of CDK4 and CDK6, which drive the cell cycle. CDK4 and CDK6 phosphorylate the retinoblastoma tumor suppressor protein (Rb), which de-represses the E2F transcription factor, leading to E2F-mediated transcription and cell-cycle progression.2
In preclinical models, abemaciclib had greater affinity for CDK4 than palbociclib and ribociclib,2 which is thought to be more important than CDK6 in breast cancer oncogenesis. Additionally, palbociclib and ribociclib are limited by their pharmacodynamics in their on-target inhibition of CDK6, which is critical for hematopoiesis. As a result, palbociclib and ribociclib require “off weeks” to allow for bone marrow recovery, whereas abemaciclib can be dosed continuously without a break.
This differing dosing schedule may explain response to abemaciclib as a single agent. In the phase II MONARCH 1 trial,3 abemaciclib monotherapy (200 mg orally twice daily) was associated with a 20% response rate, a 42% clinical benefit rate, a 6-month progression-free survival, and an 18-month overall survival, in patients with endocrine-refractory estrogen receptor–positive metastatic breast cancer.
Key Findings of MONARCH 2
THE MONARCH 2 TRIAL built on the success of MONARCH 1 by exploring the combination of abemaciclib with fulvestrant in pre/perimenopausal and postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer whose disease had progressed on prior endocrine therapies. Patients (n = 669) who had either disease progression while receiving adjuvant endocrine therapy, within 12 months of having completed adjuvant endocrine therapy, or while on first-line endocrine therapy for metastatic disease (either de novo or having progressed after adjuvant therapy) were randomized to receive abemaciclib plus fulvestrant vs placebo plus fulvestrant. Of note, no patients received prior chemotherapy, fulvestrant, everolimus, or CDK4/6 inhibitor; and patients with brain metastases were excluded. The dose of abemaciclib was reduced to 150 mg orally twice daily after review of safety data, with an expansion in enrolled patients to ensure statistical power at the lower dose.
The primary endpoint was progression-free survival. The trial met its primary endpoint, with a median progression-free survival of 16.4 months with abemaciclib plus fulvestrant vs 9.3 months with placebo plus fulvestrant (hazard ratio = 0.553, 95% confidence interval = 0.449–0.681, P < .001). All patient subgroups benefited from abemaciclib. Additionally, the response rate with the combination was 48% vs 21%.
The most common side effects were diarrhea, noted in 86% of patients on the combination (grade 3 in 13%), and neutropenia, seen in 45% of patients on the combination (grade 3 or 4 in 27%). Diarrhea was managed with dose reductions and loperamide. The adverse events mirrored what was observed in MONARCH 1, with no new safety signals.
Questions Remain
NOW THAT ABEMACICLIB joins palbociclib and ribociclib in the landscape of estrogen receptor–positive metastatic breast cancer, how will clinicians decide who benefits from CDK4/6 inhibitors and in which line of therapy? Is there a hierarchy within the triumvirate?
One awaited metric will be the overall survival readouts of the respective clinical trials. Indeed the PALOMA 1 trial of palbociclib4 did not report an overall survival benefit; however, this may be due to the small size (N = 165) of this trial. The most salient differences between these drugs remain the side-effect profiles, with abemaciclib causing more diarrhea, and palbociclib and ribociclib causing more neutropenia. Ribociclib is associated with rare liver injury and QTc prolongation, and so liver function tests and serial electrocardiographic monitoring remain important diagnostics for these patients at the present time.
“How will clinicians decide who benefits from CDK4/6 inhibitors and in which line of therapy? Is there a hierarchy within the triumvirate?”— Neil Vasan, MD, PhD, and Maura N. Dickler, MD
Tweet this quote
Currently, palbociclib is approved by the FDA in combination with first-line aromatase inhibitors and with fulvestrant; ribociclib is approved by the FDA in combination with aromatase inhibitors only; and abemaciclib is under FDA priority review as monotherapy and in combination with fulvestrant. Given that palbociclib was the first FDA-approved CDK4/6 inhibitor in breast cancer and that many clinicians are familiar with the drug and its side effects, it will be of great interest to determine whether ribociclib or abemaciclib is effective after disease progression on palbociclib; indeed, there are preclinical data showing non–cross resistance among different CDK4/6 inhibitors,5 and clinical trials in this setting are ongoing.
From a translational point of view, we still do not understand which estrogen receptor–positive patients will benefit from CDK4/6 inhibition, let alone who may benefit from one CDK4/6 inhibitor vs another. Loss of Rb, a rare event in estrogen receptor–positive metastatic breast cancer, is associated with primary or acquired resistance to CDK4/6 inhibitors.6 Many preclinical reports have defined biomarkers of resistance, including CDK6 amplification7 and cyclin E amplification.8 However, in the randomized clinical trials, biomarkers tested to date have not detected any clinically meaningful differences in response to therapy. Given the intimate role of CDK4 and CDK6 in transcription, perhaps “deeper dives” into RNA-expression profiling may discern who ultimately benefits from CDK4/6 inhibition.
Tantalizingly, these three therapies are being combined with other agents in novel ways to take advantage of their activity, including immunotherapy, anti-HER2 agents, mechanistic target of rapamycin inhibitors, and phosphoinositide 3-kinase inhibitors, as well as being evaluated in the adjuvant setting.9 We await the results of these clinical trials to see whether there will be a winner among this triumvirate of therapies. ■
DISCLOSURE: Dr. Dickler is a consultant for Novartis, Pfizer, AstraZeneca, Genentech/Roche, TapImmune, Puma, Syndax, and G1 Therapeutics; she also has received institutional research support from Eli Lilly, Genentech/Roche, and Novartis. Dr. Vasan reported no conflicts of interest.
REFERENCES
1. Sledge GW Jr, Toi M, Neven P, et al: MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2– advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. June 3, 2017 (early release online).
2. Asghar U, Witkiewicz AK, Turner NC, et al: The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 14:130-146, 2015.
3. Dickler MN, Tolaney SM, Rugo HS, et al: MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2– metastatic breast cancer. Clin Cancer Res. May 22, 2017 (early release online).
4. Finn RS, Crown JP, Lang I, et al: The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol 16:25-35, 2015.
5. Lenihan C, Bouchekioua-Bouzaghou K, Abdulghani R, et al: CDK4/6 inhibitor resistant ER-positive cells remain dependent on estrogen signaling and retain sensitivity to endocrine therapy. 2016 San Antonio Breast Cancer Symposium. Abstract P3-03-12.
6. Treré D, Brighenti E, Donati G, et al: High prevalence of retinoblastoma protein loss in triple-negative breast cancers and its association with a good prognosis in patients treated with adjuvant chemotherapy. Ann Oncol 20:1818-1823, 2009.
7. Yang C, Li Z, Bhatt T, et al: Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene 36:2255-2264, 2017.
8. Herrera-Abreu MT, Palafox M, Asghar U, et al: Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res 76:2301-2313, 2016.
9. Vasan N, Dickler MN: State-of-the-art update: CDK4/6 Inhibitors in ER+ metastatic breast cancer. Am J Hematol Oncol 13:16-22, 2017.
