Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib

Abstract

Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously.Experimental Design: We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression.Results: Seventeen patients [8 male, age 13 (9-17)* years] enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1-9.7+)* years with treatment ongoing in 9 patients. Best response was partial response in 10, stable disease in 6, and progressive disease in one patient. Duration of response was 7.4 (0.6-8.7+)* and 4.9 (0.6-7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4-5.7)* years after progression. Median progression-free survival (PFS) was 6.7 years [95% confidence interval (CI): 2.3 years-undefined] and 5-year overall survival (OS) was 88.2% (95% CI: 60.6%-96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression-free survival was 6.7 years (95% CI: 3.1-undefined) and 5-year overall survival was 93.8% (95% CI: 63.2%-99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n = 11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance [*median (range)].Conclusions: This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib. Clin Cancer Res; 24(4); 753-65. ©2017 AACR.

Conflict of interest statement

DECLARATION OF INTERESTS

AstraZeneca provided vandetanib for the phase I/II trial, Sanofi/Genzyme supports the ongoing trial. All authors report no financial or other competing interests.

©2017 American Association for Cancer Research.

Figures

Figure 1. Response and survival analysis of patients on vandetanib

A) Waterfall plot of best percent change in target lesions from baseline for 17 patients. Colors correspond to patient response at data cutoff and symbols indicate criteria for progression. B) Duration of initial response or stable disease and of ongoing vandetanib treatment in patients. Arrows indicate continued follow up at data cutoff. C) Kaplan-Meier plot of progression-free survival of 16 patients harboring the p.Met918Thr RET mutation. 8 patients were censored, 6 of whom remain in follow-up for progression-free survival. D) Kaplan-Meier plot of overall survival of 16 patients harboring the p.Met918Thr RET mutation. 11 patients were censored and remain in follow up on a natural history protocol. E) Kaplan-Meier landmark analysis from median time to PR of 16 patients harboring the p.Met918Thr RET mutation.

Figure 2. Radiographic responses and progression in children and adolescents with MEN2B and MTC

A–C) Computed tomography (CT) of the pelvis of patient #7, a male who achieved SD and subsequently experienced PD in a new lesion. D–F) CT of the prostate of patient #8, a male who achieved SD and subsequently experienced PD in a previously unrecognized lesion. G–I) T2-weighted MRI of the neck of patient #14, a female whom achieved PR and subsequently experienced PD in the thyroid bed.

Figure 3. Biomarker Response

The percent change from baseline in calcitonin (A–C) and CEA (D–F) per RECIST at data cutoff.

Figure 4. Sequencing of DNA from biopsies of patients with MEN2B and MTC

A) Somatic genomic alterations found in a 241-gene panel in biopsy samples from unique patients before-vandetanib and after experiencing progressive disease on therapy. B) Percent change in genome from copy number (CN) alterations predicted by comparing DNA extracted from tumor lesions and germline tissue in unique patients before starting vandetanib and after experiencing progressive disease. Patient #8 and #24 had multiple tumor sample analyzed. C–D) CN gains and loss (C) and % genome and loss of heterozygosity (D) predicted in patient #8 before and after vandetanib, and after cabozantinib by whole exome sequencing. Representative H&E stains and genome-wide CN alterations from patient #8 are shown, and include lymph node (germline) (E), primary MTC (F), prostate metastasis (G), and skin metastasis (H).

Figure 5. Gene expression changes across longitudinal biopsy specimens

A) Gene expression heat map of the 54 most differentially expressed transcripts. Expression levels are colored based on Z-scores across individual genes. Genes are grouped by unsupervised k-means clustering. B) Normalized expression of RET-family genes by RNA-seq. C) Correlation of RET-family genes between RNA-seq and DNA CN across longitudinal biopsies. D) Model of disease progression in patient #8 (male, best response SD) despite vandetanib and cabozantinib therapy.