Introduction: CDK4/6 Inhibitors: Moving Beyond the Breast Cancer Setting

Research Initiatives, Early Data, and Clinical Trials


The novel mechanism of action of drugs that inhibit the cyclin D–dependent kinases CDK4 and CDK6 has prompted effective new treatment strategies. Although the bulk of the data supporting the use of selective CDK4/6 inhibitors is currently in breast cancer, patients with other tumor types are expected to benefit as well from this class of agents, which are able to counter growth signaling pathways and restore cell-cycle control within cancer cells.

Next-Generation CDK Inhibitors

CDK4 and CDK6 interact with D-type cyclins to play a critical role in cell-cycle progression. Selective CDK4/6 inhibitors block these targets and thus halt the cell’s progression from G1 to S phase. Although this inhibition was conceived as a rational antitumor strategy, first-generation CDK inhibitors were limited by their relative nonselectivity for CDK family members and by cumbersome administration schedules. The oral, next-generation CDK inhibitors created a better therapeutic window, with their improved selectivity for CDK4 and CDK6—two kinases that are responsible for much of the uncontrolled cancer cell growth. The CDK4/6 inhibitors exert more predictable effects on target proteins and have proved capable of inducing cell-cycle arrest as well as leading to cancer cell senescence. Additionally, apoptotic outcomes have been observed in some hematologic malignancy tumor types.

First Up: Breast Cancer

Two selective CDK4/6 inhibitors—palbociclib (Ibrance) and ribociclib (Kisqali)—have been approved by the U.S. Food and Drug Administration (FDA) for treating hormone receptor–positive breast cancer in combination with hormonal therapy. Abemaciclib and a few other compounds, including trilaciclib, are still in development. Although the drugs produce similar biologic effects in model systems, they each have unique properties, including their side-effect profiles. How they will ultimately be positioned is not yet clear, but as a class, these agents are offering new options for treating cancer.

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Hormone receptor–positive, HER2-negative advanced breast cancer is the tumor type in which two CDK4/6 inhibitors have already proved their worth. Palbociclib was approved based on the phase II PALOMA-1 study, where palbociclib in combination with letrozole in the first-line setting substantially improved median progression-free survival and yielded an absolute 10-month benefit,1 which was confirmed in the phase III PALOMA-2 study.2 In PALOMA-3, palbociclib paired with fulvestrant (Faslodex) in the second line and beyond showed a benefit.3 Next to become FDA-approved was ribociclib, which when combined with letrozole in the MONALEESA-2 trial, led to an 18-month progression-free survival rate of 63%, vs 42.2% for letrozole alone (P = .00000329).4

A third selective CDK4/6 inhibitor is abemaciclib, which has been granted breakthrough designation while still in development. In the phase II MONARCH-1 trial, as updated recently at the 2017 American Association of Cancer Research (AACR) Annual Meeting by Rugo et al, abemaciclib showed antitumor activity as a single agent in heavily pretreated patients with metastatic breast cancer for whom endocrine therapy was no longer effective.5 Responses were observed in 19.7%, and stable disease ≥ 6 months was reported in 22.7% of patients. The median duration of response was 8.9 months, and disease was stable for at least 12 months in one-third of patients. Abemaciclib is currently being evaluated in combination with endocrine therapy in two phase III trials (MONARCH-2 and MONARCH-3) of patients with hormone receptor–positive, HER2-negative locoregionally advanced or metastatic breast cancer.

Ongoing clinical trials are expanding the potential application of these agents outside the hormone receptor–positive, HER2-negative advanced breast cancer setting, including as adjuvant and neoadjuvant treatments and in combination with chemotherapy and targeted agents. The CDK4/6 inhibitors are also being evaluated in HER2-positive subsets of breast cancer as well as in women with triple-negative breast cancers that retain expression of the retinoblastoma protein (Rb). The significant activity of the CDK4/6 inhibitors, along with their safety and favorable toxicity profile, has made this class of novel agents an important step forward in the treatment of breast cancer.

CDK4/6 Inhibitors in Other Tumor Types

Based on the power of the CDK4/6 inhibitors to restore cell-cycle control and halt tumor growth, this class of agents is expected to be efficacious in a number of tumor types beyond breast cancer. Studies are underway in unselected patients and, more selectively, in patients with malignancies that demonstrate Rb expression and pathway aberrations, suggesting they may be molecularly susceptible to these drugs. To date, these agents have demonstrated clinical benefit among patients with liposarcoma (which harbors CDK4 amplification),6,7 mantle cell lymphoma (which harbors CCND1 translocation),8 and non–small cell lung cancer (particularly among tumors harboring KRAS mutation).9 Current research questions seek to further define these and other molecular characteristics that may predict the greatest sensitivity to these drugs as well as to define the determinants that predict induction of senescence and/or apotosis—biologic outcomes that may be associated with the most favorable and prolonged clinical outcome.

Ongoing Clinical Trials

The list of clinical trials evaluating selective CDK4/6 inhibitors in the pipeline now number in the hundreds, and approximately half of these trials are in cancers other than breast cancer. Some of these trials are mentioned in this supplement (see page 12). In addition to the tumors listed here, cancers of special interest include glioblastoma (including in children), pancreatic adenocarcinoma, urothelial cancer, squamous cell carcinoma of the head and neck, metastatic castrate-resistant prostate cancer, as well as ovarian and endometrial cancers. Additionally, because abemaciclib crosses the blood-brain barrier, it is being evaluated as a treatment for brain metastases. Trials of high priority are combining these agents with other inhibitors of growth signaling pathways, including phosphatidylinositol 3-kinase (PI3K),10 MAP kinase,11 and B-cell receptor–signaling pathways.12,13 Trials are also underway in which these agents are combined with chemotherapy agents in sequential schedules that do not antagonize cell-cycle–specific activities of the agents involved. Additionally, CDK4/6 inhibition may result in favorable modulation of the immune microenvironment, so combination trials with immune checkpoint blockers have also been initiated.

Challenges in pursuing CDK4/6 inhibition will be the same as for virtually all cancer drugs—the emergence of drug resistance and the identification of rational and effective combinations in molecularly selected groups of patients. The identification of novel predictive biomarkers of response or resistance to monotherapy or combination treatment could propel the CDK4/6 inhibitors toward their full potential in the treatment of cancer. ■

—Geoffrey I. Shapiro, MD, PhD
Guest Editor

References

1. 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.

2. Finn RS, Martin M, Rugo HS, et al: Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925-1936, 2016.

3. Cristofanilli M, Turner NC, Bondarenko I, et al: Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 17:425-439, 2016.

4. Hortobagyi GN, Stemmer SM, Burris HA, et al: Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375:1738-1748, 2016.

5. Rugo HS, Tolaney SM, Cortés J, et al: MONARCH 1: Final overall survival analysis of a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. 2017 American Association of Cancer Research. Abstract CT044. Presented April 3, 2017.

6. Dickson MA, Tap WD, Keohan ML, et al: Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol 31:2024-2028, 2013.

7. Dickson MA, Schwartz GK, Keohan ML, et al: Progression-free survival among patients with well-differentiated or dedifferentiated liposarcoma treated with CDK4 inhibitor palbociclib: A phase 2 clinical trial. JAMA Oncol 2:937-940, 2016.

8. Leonard JP, LaCasce AS, Smith MR, et al: Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119:4597-4607, 2012.

9. Patnaik A, Rosen LS, Tolaney SM, et al: Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 6:740-753, 2016.

10. Vora SR, Juric D, Kim N, et al: CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26:136-149, 2014.

11. Shapiro GI, Hilton J, Gandi L, et al: Phase I dose escalation study of the CDK4/6 inhibitor palbociclib in combination with the MEK inhibitor PD-0325901 in patients with RAS mutant solid tumors. 2017 AACR Annual Meeting. Abstract CT046.

12. Martin P, Blum K, Bartlett NL, et al: A phase I trial of ibrutinib plus palbociclib in patients with previously treated mantle cell lymphoma. 2016 ASH Annual Meeting. Abstract 150.

13. Clark AS, O’Dwyer PJ, Heitjan D, et al: A phase I trial of palbociclib and paclitaxel in metastatic breast cancer. 2014 ASCO Annual Meeting. Abstract 527.