Why is cabozantinib (XL184) so interesting in cancer?

As reported by Sally Church, PhD on Pharma Strategy Blog yesterday, Exelixis announced positive phase 3 trial data for cabozantinib in medullary thyroid cancer (MTC).

There are four main types of thyroid cancer:

  • papillary
  • follicular
  • medullary
  • anaplastic.

According to the NCI there are 48,000 new thyroid cancer cases a year in the United States and 1700 deaths.  Medullary thyroid cancer is estimated to be only 5-8% of cases, and thyroidectomy is curative in a high percentage of cases.  This low incidence, therefore, makes this a small target market.

As noted on Pharma Strategy Blog, the topline data for cabozantinib in MTC showed an increase in progression free survival  (PFS) of 7.2 months.

This is good news for MTC patients. Earlier this year AstraZeneca’s vandentanib (Caprelsa®) was approved by the FDA in medullary thyroid cancer, but as Pharma Strategy Blog mentioned, it has a number of challenges:

“namely prolongation of QT, causing irregular heart beat and thus it was made available under a Risk Evaluation and Mitigation Strategy (REMS).”

Cabozantinib-XL184-Exelixis-bannerWhat makes cabozantinib (XL184) so interesting in cancer drug development?

As Sally noted in her insightful blog post, cabozantinib “targets MET, RET and VEGFR2.

It is a targeted therapy that inhibits both MET and VEGFR.  MET and its ligand HGF drive tumor cell invasion and metastasis.  MET and VEGFR2 synergize to promote angiogenesis.

In approximately half of the patients with sporadic MTC, there are germline mutations of RET (Rearranged during Transfection) gene. MTC mutations activate the RET kinase, and several signaling pathways including the RAS/MEK/ERK/PI3K pathway. This in turn promotes cell proliferation, invasion and survival.

At the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago earlier this year, phase 2 data for cabozantinib in metastatic castration resistant prostate cancer was presented. The preliminary results showed a dramatic effect on bone pain and narcotic use. Validation of these results that may have a big impact on the quality of life for advanced prostate cancer patients is awaited in a more formal pain study.

Cabozantinib is an interesting broad-acting product to watch out for and further data in ovarian and prostate cancer is expected. You can follow its development on Pharma Strategy Blog.

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