RET, RAS mutations affected cabozantinib response in medullary thyroid cancer

SAN JUAN, Puerto Rico — In patients with medullary thyroid cancer, progression-free survival was significantly greater after treatment with cabozantinib in those with RET or RAS mutations vs. their counterparts without mutations, according to phase 3 trial results presented here at the American Thyroid Association Annual Meeting.

“When we see the response across all of the mutation subgroups, what is clear is the patients who had the best response correlated with the same groups who had the best progression-free survival (PFS), with the best response being observed in patients who harbored either at M918T RET mutation or those who were RAS-positive,” said Marcia S. Brose, MD, PhD, director of the thyroid cancer therapeutics program at the University of Pennsylvania Health System.

Marcia S. Brose

Previous studies have shown cabozantinib (Cometriq, Exelixis) to be effective in extending PFS across all subgroups of patients with medullary thyroid cancer, but Brose and colleagues further examined 330 tissue samples to determine mutation-specific response.

A total of 169 patients were RET-mutation positive, with 126 carrying the M918T mutation, and 46 were RET mutation-negative. Mutation was unknown in 115 patients due to insufficient samples, assay failure, sample discrepancies or mutations of unknown significance such as small deletions (n=16) or point mutations (n=5).

PFS was 60 weeks in patients with RET mutations who were randomly assigned treatment with cabozantinib, as compared with 20 weeks in patients assigned placebo (HR=0.23; 95% CI, 0.14-0.38). In contrast, median PFS in patients who were RET mutation-negative was 25 weeks in the cabozantinib group and 23 weeks in the placebo group (P=.2142).

Specifically in carriers of the RET mutation M918T, researchers found that median PFS was 61 weeks in the cabozantinib group vs. 17 weeks in the placebo group (HR=0.15; 95% CI, 0.08-0.28). Other RET mutation carriers demonstrated median PFS of 36 weeks with cabozantinib vs. 24 weeks with placebo (HR=0.7; 95% CI, 0.26-1.87).

In those with uncharacterized RET mutations or no RET data, PFS was 24 weeks in the cabozantinib group vs. 13 weeks in the placebo group (HR=0.47; 95% CI, 0.14-1.5), whereas median PFS was 49 weeks with cabozantinib vs. 15 weeks with placebo in patients with no RET data (HR=0.26; 95% CI, 0.12-0.55).

Lastly, Brose presented data on patients in the RET mutation-negative subgroup who tested positive for RAS mutations (n=16) as compared with those with no RAS mutations (n=69). Median PFS was 47 weeks in patients with a RAS mutation vs. 8 weeks in those without a RAS mutation (HR=0.15; 95% CI, 0.02-1.1).

Residual clinical activity in patients lacking both RET and RAS mutations showed less than 2 weeks difference in their median PFS when treated with cabozantinib or placebo. – by Katrina Altersitz

For more information:

Brose MS. Highlighted Oral 4. Presented at: the 83rd Annual Meeting of the American Thyroid Association; Oct. 16-20, 2013; San Juan, Puerto Rico.

Disclosure: Brose reports no relevant financial relationships.