Cabozantinib Shows Promise as Potent RET Inhibitor in MTC

Ezra E.W. Cohen, MD

Associate Professor, Section of Hematology/Oncology, Department of Medicine, Co-Director, Head and Neck Cancer Program, Director, Hematology/Oncology Fellowship Program, University of Chicago Medical Center, Chicago, IL

The ability of cabozantinib (XL184) to inhibit the RET pathway contributed to the pivotal clinical trial findings demonstrating that the novel oral agent significantly improved progression-free survival (PFS) in patients with advanced medullary thyroid cancer (MTC), according to Ezra E.W. Cohen, MD.

Cohen was a coauthor on the phase III EXAM trial, in which patients randomized to receive cabozantinib experienced a one-year progression-free survival (PFS) rate of 47.3% compared with 7.2% for patients on placebo.¹ Trial results were presented at the American Society of Clinical Oncology annual meeting in Chicago, Illinois, in June.

Cabozantinib inhibits the receptor tyrosine kinase for the RET (rearranged during transfection) protooncogene, as well as the kinases for MET and VEGFR2.

In MTC, about 75% of cases occur sporadically, and of those cases, as many as 65% of patients have somatic RET mutations. In the 25% of cases of MTC that are hereditary, more than 95% of those patients have germline RET mutations. In all, MTC accounts for between 5% and 8% of all thyroid cancers.

“For this disease, you’re talking about the majority of patients having a single genomic alteration that drives the entire process,” said Cohen. “We’ve known a lot about its biology before we had any therapeutic avenues to explore or any drugs that we could use in patients.”

Cohen said the RET pathway is the main driver of MTC, and that he had hypothesized that cabozantinib could have a potent effect on the tumors.

“In other diseases where that is true—chronic myelogenous leukemia, certain subsets of non-small cell lung cancer, etc—targeted therapy has been extremely successful, so we had hoped we would see the same for medullary thyroid cancer when RET inhibitors began to emerge from the different laboratories,” Cohen said. “And indeed we did.”

Vandetanib (Caprelsa), which inhibits the RET pathway along with several angiogenic avenues, was approved in 2011 for the treatment of patients with symptomatic or progressive MTC with unresectable locally advanced or metastatic disease. Other RET inhibitors that have been used to treat patients with MTC include sorafenib (Nexavar) and sunitinib (Sutent).²

In the EXAM trial, the median PFS for patients who received cabozantinib was 11.2 months compared with 4.0 months in patients who received the placebo (HR = 0.28; 95% CI, 0.19-0.40; P < .0001). The objective response rate was 28% for the cabozantinib group compared with 0% for the control group (P < .0001), with a median duration of response of 14.6 months for those who received the study drug.

The researchers noted that the PFS results favored the cabozantinib cohort across patient subset analyses, including groups with the RET mutation and prior tyrosine kinase inhibitor treatment.

While the PFS data are very promising, an interim analysis of overall survival (OS) did not show a difference between the cabozantinib and placebo arms of the study. Cohen said that the OS data are premature, and that cabozantinib may not be the first RET inhibitor that patients who were enrolled in the trial received, thereby making overall survival a difficult endpoint to measure.

“There are other agents on the market, such as vandetanib and sunitinib, that people can use to treat patients with medullary thyroid cancer, and so although there was no crossover for XL184 per se, there are other RET inhibitors that patients could have been exposed to,” Cohen said.

On July 30, Exelixis, Inc, the California-based company developing the drug, announced that the FDA has accepted its New Drug Application for cabozantinib under its priority review program. The requested indication is for patients with progressive, unresectable, locally advanced, or metastatic MTC.

References

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).
2. Gómez K, Varghese J, Jiménez C. Medullary thyroid carcinoma: molecular signaling pathways and emerging therapies. J Thyroid Res. 2011:815826. Published May 16, 2011. Accessed August 3, 2012. doi:10.4061/2011/815826.