Pazopanib and Cabozantinib Explored in Thyroid Cancer

Eric J. Sherman, MD

Associate Professor, Department of Head and Neck Oncology

Memorial Sloan-Kettering Cancer Center, New York, NY

Two targeted agents, pazopanib (Votrient) and cabozantinib, are under investigation for different types of thyroid cancer, and while the therapies have not yet been approved for these indications, researchers are already trying to determine the best way to integrate them into existing treatment regimens.

Several clinical trials are investigating pazopanib, a small-molecule multikinase inhibitor that is already approved to treat advanced renal cell carcinoma and soft-tissue sarcoma, for use in advanced thyroid cancer. A phase II trial is under way to assess pazopanib in combination with the chemotherapy agent paclitaxel and radiation therapy in patients with anaplastic thyroid cancer, a very rare and aggressive form that accounts for about 1% of all cases of thyroid cancer.

“Survival is horrible in these patients,” said Eric J. Sherman, MD, one of the investigators in the trial. “We’re already interested in paclitaxel and radiation therapy and trying to figure out better ways to improve treatment for anaplastic thyroid cancer, and we know from previous data that when you add paclitaxel and pazopanib together, there seems to be some synergy between the two agents. So the combination made sense to put together.”

Sherman said that responses observed in the clinical trial so far have been better than what has been seen in patients who received pazopanib alone.

Another agent, cabozantinib, is being explored for use in medullary thyroid cancer (MTC) patients. Like pazopanib, cabozantinib is a multikinase inhibitor. The results of the phase III EXAM trial, presented at the 2012 Annual Meeting of the American Society of Clinical Oncology, showed that cabozantinib improved progression-free survival by more than seven months in patients with advanced MTC compared with patients who received a placebo (11.2 months vs 4.0 months; HR = 0.28; 95% CI, 0.19—0.40; P < .0001).¹

The FDA granted priority review status to cabozantinib for use in advanced MTC and has set an action date of November 29. Because of the promising data from the EXAM trial, researchers are already looking at the best ways to give cabozantinib to patients.

One consideration will be how best to sequence cabozantinib and vandetanib (Caprelsa), a multikinase inhibitor approved by the FDA for the treatment of MTC in patients with unresectable, locally advanced, or metastatic disease. Sherman said there is not enough information to know what the optimal sequencing will be, but that evidence from clinical trials suggests there is at least one appropriate way to sequence the two agents.

“The one thing we do know is that in the phase III study, as well as the phase I expansion core, when they use cabozantinib in patients whose tumor has already progressed on vandetanib, they’re still seeing responses,” Sherman said. “This suggests that cabozantinib can definitely be used after vandetanib. What we don’t know is what happens if you do the reverse—try cabozantinib and then go to vandetanib.”

Sherman said that since vandetanib is the only approved agent for MTC, the only option now for a patient whose disease progresses is to enroll in a clinical trial. If cabozantinib is approved, Sherman said, those advanced patients would have another option for treating their disease.

Selected Clinical Trials in Thyroid Cancers

Agent

Description

Sponsors

Status

Cabozantinib

Efficacy vs placebo in advanced medullary thyroid cancer (EXAM) (NCT00704730)

Exelixis

Phase III

Drug-drug interaction with rosiglitazone in papillary, follicular, or Huerthle cell thyroid cancers (NCT01100619)

Exelixis

Phase I

Drug-drug interaction with rosiglitazone in papillary, follicular, or Huerthle cell thyroid cancers (NCT01100619)

Exelixis

Phase I

Pazopanib

Safety and efficacy of pazopanib in advanced thyroid cancer (NCT00625846)

Mayo Clinic/ National Cancer Institute

Phase II

Safety and tolerability of combination therapy with pazopanib and trametinib (GSK1120212) in advanced differentiated thyroid cancer (NCT01438554)

Sidney Kimmel Comprehensive Cancer Center/ National Comprehensive Cancer Network/ GlaxoSmithKline

Phase I

Intensity-modulated radiation therapy and paclitaxel with or without pazopanib in anaplastic thyroid cancer (NCT01236547)

Radiation Therapy Oncology Group/ National Cancer Institute

Phase II

Source: US National Institutes of Health. ClinicalTrials.gov website.

Reference

1. Schöffski P, Elisei R, Müller S, et al. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin Oncol. 2012;30(suppl; abstr 5508).