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Cabozantinib significantly prolongs OS in patients with RET-mutated medullary thyroid cancer
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LAKE BUENA VISTA, Fla. — Treatment with cabozantinib significantly improved OS and exhibited a favorable safety profile in patients with progressive, metastatic medullary thyroid cancer who harbored RET M918T mutations, according to the results of a phase 3 study presented at the International Thyroid Congress.
Although patients who harbored a RET M918T mutation achieved more than a 2-year improvement in OS with cabozantinib (Cometriq, Exelixis), patients without this mutation in the overall population achieved a 5.5-month nonsignificant improvement in OS.
A previous analysis of the EXAM study showed cabozantinib significantly extended PFS in patients with progressive locally advanced or metastatic medullary thyroid cancer. The researchers reported on the secondary endpoint of OS in the current analysis.
Steven I. Sherman
“Patients in this study who progressed on placebo were not unblinded and not allowed to cross over to cabozantinib,” Steven I. Sherman, MD, FACE, professor and chair of the department of endocrine neoplasia and hormonal disorders and vice provost for clinical research at The University of Texas MD Anderson Cancer Center, said during a presentation. “As such, this study was designed to allow assessment of long-term outcomes beyond PFS.”
The researchers randomly assigned 330 patients to 140 mg daily cabozantinib or placebo. They used tumor and blood samples to detect the presence of RET and RAS mutations to determine the influence of genetic subtypes on median duration of OS.
For the entire study cohort, patients assigned cabozantinib had an estimated median OS of 26.6 months, compared with 21.1 months for patients assigned placebo (HR = 0.85; 95% CI, 0.64-1.12).
Sixty-five percent of patients in the overall cohort had available data on RET mutational status. Of those patients, 79% harbored a RET mutation and 21% did not. RET M918T comprised 75% of mutations observed.
Among patients with RET mutations, those assigned cabozantinib achieved a median OS of 31.6 months, compared with 24.8 months in the placebo arm (HR = 0.79; 95% CI, 0.54-1.17). However, patients with RET M918T assigned to cabozantinib achieved a median OS increase of 25.4 months compared with patients assigned placebo (44.3 months vs. 18.9 months; HR = 0.6; 95% CI, 0.38-0.94).
Subgroups of patients lacking RET mutations or RET M918T did not achieve significantly increased OS, although the researchers had observed improvements in PFS and objective response rate.
Further, 16 patients harbored RAS mutations. This subgroup demonstrated a trend toward improved OS with cabozantinib (HR = 0.37; 95% CI, 0.1-1.42).
Patients assigned cabozantinib had a median duration of treatment of 10.8 months, compared with 3.5 months for placebo.
The most common serious adverse events in the cabozantinib arm included pneumonia (4.2%), pulmonary embolism (3.3%), mucosal inflammation (2.8%), hypocalcemia (2.8%), hypertension (2.3%) and lung abscess (2.3%).
“These data support the value of somatic mutation profiles in the selection of patients for treatment with systemic therapies,” Sherman said. – by Cameron Kelsall
Reference:
Sherman SI, et al. Short Oral Communication 51. Presented at: International Thyroid Congress; Oct. 18-23, 2015; Lake Buena Vista, Fla.
Disclosure: Exelixis provided funding for this study. Sherman reports a consultant role with Exelixis. Other researchers report employment roles with Exelixis.
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