Dr. Kunadharaju and Dr. Goyal are house officers in the Department of Internal Medicine, and Dr. Silberstein is a professor and chief of hematology/oncology, all at CHI Creighton University Medical Center in Omaha,Nebraska. Dr. Rudraraju is a house officer at MacNeal Hospital in Berwyn, Illinois. Dr. Silberstein is also chief of oncology at the VA Nebraska-Western Iowa Healthcare System in Omaha.
References
sporadic or hereditary MTC. 48 In a ZETA trial study by Wells Jr and colleagues, patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. After objective disease progression, patients could elect to receive openlabel vandetanib. The primary endpoint was PFS, determined by independent central Response Evaluation Criteria in Solid Tumors assessments.
A total of 331 patients were randomly assigned to receive vandetanib (231 patients) or placebo (100 patients). At data cutoff, with median follow-up of 24 months, PFS was significantly prolonged in patients randomly assigned to vandetanib vs placebo (30.5 mo vs 19.3 mo; HR, 0.46; 95% CI, 0.31-0.69). The objective RR was significantly higher in the vandetanib group (45% vs 13%). The presence of a somatic RET M918T mutation predicted an improved PFS.
Common AEs (any grade) noted with vandetanib vs placebo include diarrhea (56% vs 26%), rash (45% vs 11%), nausea (33% vs 16%), hypertension (32% vs 5%), and headache (26% vs 9%). Torsades de pointes and sudden death were reported in patients receiving vandetanib. Data on OS were immature at data cutoff (HR, 0.89; 95% CI, 0.48-1.65). A final survival analysis will take place when 50% of the patients have died. 48
Vandetanib is currently approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals about serious heart-related risks. Electrocardiograms and serum potassium, calcium, magnesium, and TSH should be taken at 2 to 4 weeks and 8 to 12 weeks after starting treatment and every 3 months after that. Patients with diarrhea may require more frequent monitoring.
Cabozantinib
In 2012, the FDA approved cabozantinib for the treatment of progressive, metastatic MTC. 49 It is an oral, small molecule TKI that targets VEGFRs 1 and 2, MET, and RET. The inhibitory activity against MET, the cognate receptor for the hepatocyte growth factor, may provide additional synergistic benefit in MTC. 50 The daily recommended dose is 140 mg/d. A phase 3 randomized EXAM trial in patients with progressive, metastatic, or unresectable locally advanced MTC. 51 Three hundred thirty patients were randomly assigned to receive either cabozantinib 140 mg or placebo once daily. Progressionfree survival was improved with cabozantinib compared with that of placebo (11.2 vs 4.0 mo; HR, 0.28; 95% CI, 0.19-0.40). Partial responses were observed in 27% vs 0% in placebo. A planned interim analysis of OS was conducted, including 96 (44%) of the 217 patient deaths required for the final analysis, with no statistically significant difference observed between the treatment arms (HR, 0.98; 95% CI, 0.63-1.52). Survival follow-up is planned to continue until at least 217 deaths have been observed.
There was markedly improved PFS in the subset of patients treated with cabozantinib compared with placebo whose tumors contained RET M918T mutations (61 vs 17 wk; HR, 0.15; 95% CI, 0.08-0.28) or RAS mutations (47 vs 8 wk; HR, 0.15; 95% CI, 0.02-1.10). 51
The most common AEs, occurring in ≥ 25% of patients,
