Monday, October 14, 2013
For surgical, medical, and radiation oncologists, the management of chordomas can be daunting. Only a handful of studies have prospectively evaluated systemic therapies, and cytotoxic chemotherapies are widely considered ineffective.
With the exception of dedifferentiated chordoma (which has been reported to have modest response to cytotoxic chemotherapies) there is no accepted standard of care with systemic therapies. Most chordomas are of conventional histology and considered resistant to chemotherapy. In fact, optimal supportive care remains the only option in a majority of patients with advanced chordomas.
The need for novel therapies in chordoma is unmet.
The Biology of Chordomas
Over the past decade, significant efforts to understand the biology of chordomas have yielded valuable knowledge in identifying a mechanism-based drug therapy. Recurrent chromosomal abnormalities have been found across the genome of these tumors. But in spite of these efforts, no specific oncogenic driver mutation has been found.
Perhaps the biggest leap in understanding chordoma biology came from the discovery of brachyury, a transcription factor critical in chordoma. Currently, the National Institutes of Health is conducting a phase I vaccine study of GI-6301, a heat-inactivated S. cerevisiae yeast that expresses human brachyury protein.
Platelet-derived growth factor-B (PDGFRB) is a receptor tyrosine kinase that plays an important role in cell growth, differentiation, and angiogenesis. Most chordomas over-express PDGFRB. This finding prompted a small case series in which six patients with advanced chordoma were treated with imatinib (Gleevec®). No objective tumor shrinkage was seen, but growth inhibition was observed — along with a decrease in tumor density/cellularity and decreased uptake by FDG/PET.Back to top
A Landmark Study
This promising result led to a large, multicenter prospective trial of imatinib in advanced chordoma. This has proved to be a landmark study, ushering in the promise of novel targeted agents in chordoma and accelerating the field in terms of identifying new targets.
As part of the study, which enrolled 50 subjects:
- one patient had an objective response (decrease of more than 30 percent in tumor dimension)
- nine patients had a minor response (less than 30 percent)
- more than 70 percent of patients had stabilization of tumor growth at 9 months and a median overall survival of 34 months
- decreases in SUV uptake were noted in 13 of 26 patients who were followed with a PET scan.
Patients reported improvement in pain and other symptoms.
Work in chordoma cell lines demonstrated the role of dual inhibition of the P13K and mTOR signaling pathways.Back to top
These findings led to a small case series in which ten patients who progressed on single agent imatinib or combination with cisplatin were treated with imatinib and sirolimus. Of the nine evaluable patients, one patient had a response, seven had stable disease, and one progressed. Decrease in FDG/PET signal was seen in several patients.
Currently, a large phase II trial is underway in Europe to evaluate imatinib and everolimus (Afinitor®). Since the majority of chrodomas express EGFR, the receptor is an attractive target.
As with PDGFRB, no oncogenic mutations in EGFR have been identified and the oncogenic role of HER2 and HER4 remains unknown. Recently, investigators reported the first case of a patient treated with a combination of cetuximab and gefitinib that showed tumor regression for more than nine months. Cetuximab is a monoclonal antibody that prevents the ligand from binding to EGFR. Gefitiinib is a tyrosine kinase involved in downstream cell signaling. However, a large prospective phase II study of lapatinib (Tykerb®), an oral drug targeting HER2, concluded that lapatinib as a single agent was not a promising therapy.
Other receptor tyrosine kinases (RTK)s such as MET, an insulin-like growth factor receptor, have been shown to be potential targets in pre-clinical studies. To date there are no reported studies in patients.
Recently, investigators showed that combining imatinib with low-dose weekly cisplatin induced some responses. Similarly, trabectedin (Yondelis®) binds to DNA minor groove and induces apoptosis. The mechanism is not known, but it is thought to inhibit transcription regulators such as brachyury. Clinical trials are underway. Hedgehog is a family of embryonic proteins that plays a critical role in skeletal development. High levels of hedgehog expression are seen in chordoma, thus making it an attractive target.Back to top
Clinical Trials at Memorial Sloan Kettering
Several other clinical trials that could potentially benefit chordoma patients are underway.
- CDK4, a cell cycle dependent kinase, is known to be upregulated in chordoma. A phase I trial designed to determine the maximum tolerated dose of the drug is enrolling patients with CDK4 inhibitors.
- A phase II study of a novel HER2 inhibitor is underway and might be considered for patients with chordoma, given the high expression of HER2 and EGFR with this neoplasm. (Please note that this trial is closed to accrual.)
- A phase I trial of a compound targeting two pathways is currently underway in all solid tumors and might represent an excellent choice for chordoma patients given the upregulation of the P13 kinase and mTOR pathway in people with this neoplasm. Chordomas are thought to be hypoxic tumors. Because clostridium spores germinate only in hypoxic areas, chordoma would be an ideal tumor candidate to induce immunogenic and nonimmunogenic antitumor response. Pre-clinical studies have demonstrated the role of immunotherapy in chordoma. A novel clinical trial using spores from clostridium is currently underway.
- A phase I/II study is currently evaluating dasatinib (Sprycel®), an oral tyrosine kinase inhibitor, and ipilimumab (Yervoy™), an immune therapy approved in melanoma, in patients with advanced sarcomas including chordomas.
For additional details please, contact Dr. Gounder at 646-888-4167.Back to top