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The investigational compound cabozantinib (formerly known as XL184) has generated much excitement in recent years for its ability to target multiple pathways involved in the development of cancer.
Although Exelixis has a number of anticancer compounds in its product pipeline, the San Francisco-based biotechnology company has 1 compound in particular that defines its genomics-based research program. The investigational compound cabozantinib (formerly known as XL184) has generated much excitement in recent years for its ability to target multiple pathways involved in the development of cancer, thus allowing it to be used against more than 1 tumor type.
“Our goal is to bring active compounds to patients who have an unmet medical need,” said Gisela M. Schwab, MD, Exelixis’s executive vice president and chief medical officer. “We set out to really create a compound that was broadly effective.”
Cabozantinib is such a compound. The drug is currently in a phase III trial for medullary thyroid cancer, and phase II trials are underway to explore its efficacy in patients with a wide range of cancers, including breast, ovarian, melanoma, pancreatic, and small cell lung cancers.
Schwab said that the company is confident that the drug is capable of treating different tumors because it targets 2 separate pathways that are both involved in the proliferation of these tumors. Cabozantinib inhibits the MET pathway. In cancer, the dysregulation of the MET pathway leads to cell proliferation, protection from apoptosis, angiogenesis, invasion, and an increased risk of metastasis. The drug also inhibits the VEGF pathway, which is closely associated with angiogenesis and the ability of tumors to grow blood vessels.
Exelixis is farthest along in studying cabozantinib’s effects on patients with medullary thyroid cancer. This is the third most common form of thyroid cancer, and it affects about 3% to 8% of patients who have the disease. The disease originates from the parafollicular cells, which are responsible for producing calcitonin, a hormone with a poorly understood role in humans. The cure rates for this particular form of cancer are not as high as for other forms. While patients with stage I disease typically survive after a thyroidectomy, only 28% of patients with stage IV metastatic disease are alive after 5 years, compared with 51% of patients with papillary thyroid cancer and 50% of patients with follicular thyroid cancer.
In October, the results of the company’s ongoing EXAM trial, a randomized, double-blind, placebo-controlled phase III study, showed that cabozantinib improved median progression-free survival by 7.2 months (11.2 mo) compared to placebo (4.0 mo) in patients with advanced medullary thyroid cancer (hazard ratio, 0.28; 95% CI 0.19-0.40; P <.0001).
The company has recently run into a few regulatory hurdles in its effort to get cabozantinib approved for patients with metastatic castration-resistant prostate cancer. Exelixis sought FDA approval to measure the drug’s effects on patients with bone pain, since prostate cancer metastasizes to the bone in approximately 90% of cases of advanced-stage disease. Exelixis designed the study to measure pain reduction as a primary endpoint because many of these patients rely heavily on narcotic drugs to manage their pain symptoms. The FDA contested the study on the grounds that many cancer drug studies tend to use survival as a primary endpoint. However, Schwab said that bone pain was 1 part of the study, and the company is designing a trial that measures overall survival (OS) as the primary endpoint.
“We were of course disappointed with the FDA’s decision regarding our study design,” Schwab said. “But we worked very closely with them and have a lot of valuable input that we’re going to implement in our studies going forward.”
Schwab explained that the bone pain and OS studies will be done in parallel, and they plan to enroll patients from the United States, Canada, and the United Kingdom in multicenter studies.
Schwab said that it was impossible to predict exactly how the next year is going to play out in terms of approvals and marketing for cabozantinib. She noted, however, that Exelixis presented results of the drug at the recent San Antonio Breast Cancer Symposium in December, and will present additional data at next year’s American Society of Clinical Oncology meeting.
In the meantime, the final analysis of the phase III EXAM trial data evaluating cabozantinib’s ability to treat medullary thyroid cancer is currently underway, and the much-anticipated results will be available shortly.