Cabozantinib Benefit Greater in MTC Patients With RET and RAS Mutations

Steven I. Sherman, MD

A detailed analysis of previously reported data on the multikinase inhibitor cabozantinib (Cometriq) in medullary thyroid cancer (MTC) found that patients with mutations of RET and RAS experienced a significantly higher benefit than patients without those mutations, according to findings presented at the 2013 ASCO Annual Meeting.¹

Cabozantinib, which was approved by the FDA for the treatment of MTC in November 2012, inhibits the receptor tyrosine kinase for the RET (rearranged during transfection) proto-oncogene, as well as the kinases for MET and VEGFR2.

Approximately 75% of all cases of MTC occur sporadically, and of those cases, as many as 65% of patients have somatic RET mutations. Approximately 25% of cases of MTC are hereditary, and of those, more than 95% of patients have germline RET mutations. Between 5% and 8% of all cases of thyroid cancer are MTC.

In the phase III EXAM trial, patients were randomized to receive 140 mg of cabozantinib once daily or a placebo until disease progression. In survival data presented at last year’s ASCO annual meeting, patients who received cabozantinib had a median progression-free survival (PFS) of 11.2 months compared with 4 months in the placebo arm (hazard ratio [HR] = 0.28; P <.001).²

To determine how patients with RET mutations may have benefited with cabozantinib, next-generation sequencing methods were used on blood and tumor samples to sequence for RET exons 10, 11, and 13-16, with patients being considered positive if mutations in those exons were identified in either a blood or a tumor sample. Only mutations identified in the 2009 American Thyroid Association guidelines were considered.

“These [mutations] are associated with hereditary disease and are clearly pathogenetic,” said Steven I. Sherman, MD, chair of the Department of Endocrine Neoplasia and Hormonal Disorders in the Division of Internal Medicine at the University of Texas MD Anderson Cancer Center in Houston, and lead author of the study.

The analysis found that 169 patients were RET-positive, 46 patients were RET-negative, and 115 patients had an unknown RET status. In patients who were RET-positive, the median PFS was 60 weeks with cabozantinib compared with 20 weeks in patients receiving a placebo (HR = 0.23; 95% CI, 0.14-0.38).

The PFS benefit was slightly more pronounced in patients with RET M918T, the most common RET mutation. Patients with this mutation who received cabozantinib experienced a median PFS of 61 weeks compared with 17 weeks in the placebo arm (HR = 0.15; 95% CI, 0.08-0.28).

In RET-negative patients, there was no significant difference in survival based on whether patients received cabozantinib or placebo (26 weeks vs 23 weeks, respectively), although Sherman said there was a substantial difference at the end of the survival curves that may have been caused by heterogeneity within the RET-negative group.

In patients with unknown RET mutation status, a benefit in PFS was also observed, with patients in the cabozantinib arm of this subgroup achieving a median PFS of 48 weeks compared with 13 weeks in the placebo arm (HR = 0.30; 95% CI, 0.16-0.57).

Since RAS mutations have been identified in patients who lack a mutation of RET, the investigators decided to look for potential RAS mutations in the RET status unknown arm. A total of 85 patients in the RET-negative and RET-mutation-unknown groups were analyzed for mutations of RAS, and 16 patients tested positive for this mutation. The researchers concluded that the benefit observed in patients with an unknown-RET-mutation status might have been due to undetected RET mutations or RAS mutations.

The results showed that patients with RAS mutations also experienced a significant benefit in PFS with cabozantinib, with patients in the experimental arm achieving a median PFS of 47 weeks compared with 8 weeks in the placebo arm (HR = 0.15; 95% CI, 0.02-1.10; P = .0317).

The standard of care for MTC does not involve testing for these mutations in tumors even though germline testing for the mutations is standard. Sherman explained that it might be some time before this becomes routine practice.

“Looking for other codons and other RET abnormalities actually requires a very extensive sequencing procedure that’s probably not amendable right now to routine clinical use,” Sherman said.

1. Sherman SI, Cohen EEW, Schöffski P, et al. Efficacy of cabozantinib (Cabo) in medullary thyroid cancer (MTC) in patients with RAS or RET mutations: results from a phase III study. J Clin Oncol. 2013;31(suppl; abstr 6000).
2. 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).