Mutations Linked to Drug Response in Medullary Thyroid Cancer
Metastatic medullary thyroid cancers with certain genetic mutations respond better to treatment with Cometriq™ (cabozantinib) than tumors without those mutations, according to the results of a study presented at the 83rd Annual Meeting of the American Thyroid Association, October 16- 20, 2013, in San Juan, Puerto Rico.
The thyroid is a gland in the throat that produces hormones mostly related to metabolic processes in the body. Medullary thyroid cancers account for approximately 2-3% of all thyroid cancers. These cancers tend to have a somewhat worse prognosis than more common types of thyroid cancer, and up to 25% of cases are thought to be hereditary. When possible, treatment involves surgery to remove the thyroid gland. Conventional chemotherapy has limited effectiveness against medullary thyroid cancer, and there is growing interest in newer, targeted drugs.
Cometriq is a targeted agent known as a tyrosine kinase inhibitor. It targets specific biological pathways that contribute to the growth of several types of cancer, including the receptor tyrosine kinase RET as well as MET and VEGFR2. The drug is approved for the treatment of metastatic medullary thyroid cancer.
Researchers conducted a retrospective subgroup analysis of data from a phase III trial to determine whether mutation status affected outcomes. They examined outcomes by RET mutations, and patients without RET mutations were examined for RAS mutations. Overall, 79% of the cohort had an RET mutation, and among those without RET, about 20% had an RAS mutation.
The results indicated that patients with an RET mutation, particularly the M918T polymorphism, and those with RAS mutations had significant advantages in progression-free survival. Patients with mutation experienced a median progression-free survival of 60 weeks with the drug, compared to 25 weeks for those without the mutation. What’s more, patients with the mutation who received the drug did significantly better than patients with the mutation who received placebo.
In terms of the M918T polymorphism of RET, the median progression-free survival with Cometriq was 61 weeks for patients with the mutation compared to 36 weeks for those without.
In patients without an RET mutation but with an RAS mutation, Cometriq provided a significantly greater benefit for progression-free survival compared with placebo (47 weeks versus 8 weeks).
Patients who did not have either mutation did not experience much improvement to progression-free survival with the drug.
The researchers concluded that patients with RET, particularly the M918T polymorphism, or RAS mutations had significant advantages in progression-free survival over those without any genetic mutations when receiving Cometriq for the treatment of metastatic medullary thyroid cancer. They suggest that mutation status might be valuable in selecting patients for Cometriq treatment.
Brose MS, Sherman SI, Schöffski P, et al. Correlative analyses of RET and RAS mutations in a phase III study of cabozantinib in patients with progressive, metastatic medullary thyroid cancer. Presented at the 83rd Annual Meeting of the American Thyroid Association, October 16- 20, 2013, in San Juan, Puerto Rico. Thyroid. October 2013, 23(S1): A-1-A-114. Abstract 4.
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