Novel Treatment Targets: Cyclin-Dependent Kinases

The concept of individualized or personalized medicine in oncology has evolved from the use of imatinib (Gleevec) to target the breakpoint cluster region-Abelson protein (BCR-ABL) in chronic myelogenous leukemia, to next generation sequencing panels able to provide more complete genetic analysis of a given tumor or malignant cell. These types of multiplex sequencing assay results are what I attempt to translate into clinical recommendations as part of the Personalized Medicine Consult Service at Moffitt Cancer Center. 

Approximately 25% of my patient cases are from the sarcoma service.  These are often young patients with a good performance status who have been diagnosed with a variety of sarcoma histologies, but are similar in that they have poor responses to traditional chemotherapy.  The rare nature of many of these malignancies also makes finding patient data for different novel therapies a challenge.  Genetic tumor profiling potentially allows for a greater understanding of possible oncogenic driver pathways that could provide rationale targeted treatment options based on cancer biology.  The clinical translation of these interpretations depends upon available treatment options, either using FDA-approved therapies for off-label indications or identifying potential clinical trial options. 

One of the more commonly altered pathways in sarcoma is the cyclin-dependent kinase (CDK) pathway, which can occur through loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) and B.  The CDKN2A gene encodes the tumor suppressor proteins p16INK4a and p14ARF, and the CDKN2B gene encodes the tumor suppressor protein p15INK4b.  Both p16INK4a and p15INK4b inhibit CDK4/6, which maintains the ability of the retinoblastoma gene (RB) to suppress cell growth.  Additionally, p14ARF is involved in the stabilization and activation of tumor protein (p53) through inhibiting the mouse double minute 2 homolog (MDM2).¹

CDKN2A and B are deleted in approximately 13% of the unselected sarcoma population. The CDK pathway can also be altered through amplifications.  CDK4 amplification is seen in approximately 23% of the unselected sarcoma population.  Liposarcoma specifically, is characterized by this CDK4 amplification, along with amplification in MDM2.   The loss of the tumor suppressors CDKN2A/B, and/or amplification of CDK4 and MDM2, can result in unchecked activation of CDK 4/6, ultimately leading to loss of the p53 function along with dysregulation of the Rb pathway-- resulting in loss of cell cycle control.  This is similar to the loss of brake function on a car.

There are currently no FDA-approved therapies to target CDK4; however, there are CDK4 inhibitors in clinical trials.  PD-0332991 (palbociclib), a CDK4 inhibitor, was assessed in a phase II trial of 30 patients with dedifferentiated liposarcoma dosed at 200 mg (oral) daily for 14 days, repeated every 21 days.  All patients had CDK4 amplification by FISH and Rb expression by IHC.  The 12-week progression-free survival (PFS) was 66%, and the median PFS was 18 weeks; one patient had a partial response (PR).  In general, the drug was relatively well tolerated with most toxicities being hematologic in nature (grade 2 to 4 anemia was seen in 17%, neutropenia in 50%, and thrombocytopenia in 30%).²

A phase II study using different dosing with 125 mg (oral) daily for 21 days, repeated every 28 days, has completed enrollment, but data collection is ongoing--though preliminary data of 29 patients at ASCO 2013 indicated 12-week PFS was 56% and median PFS was 23.6 weeks, with one PR lasting greater than 1 year.  This schedule was better tolerated than the previous study, and a phase III trial is planned, but not enrolling yet.³

Given the limited activity of palbociclib as a single agent, combination therapies are also being assessed as part of the 26 ongoing clinical trials with the drug across a variety of malignancies.  The use of palbociclib has also been assessed in the estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer population.  Combination trials with letrozole have demonstrated encouraging clinical benefit rates and median progression-free survival of 20.2 months.⁴  Based on these encouraging results, Pfizer just recently submitted a New Drug Application (NDA) to the FDA for palbociclib--in combination with letrozole--for the treatment of postmenopausal ER-positive, HER2-negative, previously untreated advanced breast cancer. 

LEE011 is also an inhibitor of CDK4/6 currently in clinical trials.  Twenty different trials in a variety of malignancies and combinations are underway.  One of these trials includes an arm of the signature “basket trial,” specifically targeting patients diagnosed with advanced solid tumors or hematologic malignancies that harbor genetic alterations which activate the CDK4/6 pathway (NCT02187783). This trial will hopefully provide insight into possible predictive biomarkers in the CDK pathway that may predict benefit from LEE011.

Personally, I am excited to have open trials with CDK 4/6 inhibitors available for patients, especially those with alterations in the CDK pathway that may have a better chance of benefiting from these agents compared to others.  I anxiously await final results and biomarker studies as well. This will hopefully provide insight towards better matching of patients to therapies based on their somatic profiles.

References:

• Musgrove EA, et al.  (2011). Cyclin D as a therapeutic target in cancer.  Nature Rev Cancer. Jul 7; 11(8):558-72.
• Dickson MA, et al.  (2013). Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma.  J Clin Oncol. Jun 1; 31(16):2024-8.
• Dickson MA, et al.  (2013). Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified liposarcoma.  J Clin Oncol. Abstract 10512.
• Finn RS, et al. (2014). PALOMA-1; TRIO-18 Clinical Trial Presentation. AACR Annual Meeting. Apr 6, San Diego, CA.