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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. We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression. Seventeen patients [8 male, age 13 (9-17)* years] enrolled; 16 had a 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 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 ( = 11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance [*median (range)]. 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. .

Background Selumetinib was recently approved for the treatment of inoperable symptomatic plexiform neurofibromas (PNs) in children with neurofibromatosis type 1 (NF1). This parallel phase II study determined the response rate to selumetinib in children with NF1 PN without clinically significant morbidity. Methods Children with NF1 and inoperable PNs, which were not yet causing clinically significant morbidity but had the potential to cause symptoms, received selumetinib at 25 mg/m2 orally twice daily (1 cycle = 28 days). Volumetric magnetic resonance imaging analysis and outcome assessments, including patient-reported (PRO), observer-reported, and functional outcome measures were performed every 4 cycles for 2 years, with changes assessed over time. A confirmed partial response (cPR) was defined as PN volume decrease of ≥20% on at least 2 consecutive scans ≥3 months apart. Results 72% of subjects experienced a cPR on selumetinib. Participants received selumetinib for a median of 41 cycles (min 2, max 67) at data cutoff. Approximately half of the children rated having some target tumor pain at baseline, which significantly decreased by pre-cycle 13. Most objectively measured baseline functions, including visual, motor, bowel/bladder, or airway function were within normal limits and did not clinically or statistically worsen during treatment. Conclusions Selumetinib resulted in PN shrinkage in most subjects with NF1 PN without clinically significant morbidity. No new PN-related symptoms developed while on selumetinib, and PRO measures indicated declines in tumor-related pain intensity. This supports that selumetinib treatment may prevent the development of PN-related morbidities, though future prospective studies are needed to confirm these results. Clinical Trial registration ClinicalTrials.gov NCT01362803.

10540 Background: Vandetanib is well tolerated and active in children with advanced or metastatic hereditary MTC (NCT00514046) [data cutoff 7/2011; Clin Cancer Res. 2013 Aug 1;19(15):4239-48]. We report outcomes as of 1/2017. Methods: We monitored toxicities, RECISTv1.0, carcinoembryonic antigen (CEA), and calcitonin (CT) response. Patients (pts) removed from the vandetanib trial were followed on a natural history study (NCT01660984). Results: Of 17 pts (8 male, age 13 years (9-17)*) enrolled, 1 was lost to follow-up. Of the 16 pts analyzed, 15 had a RET p.M918T germline mutation. The duration of vandetanib therapy was 5.6 years (0.1-9.2+) with treatment ongoing in 8 pts. Best response was partial response (PR) in 10, stable disease (SD) in 5, and progressive disease (PD) in 1 pt. Time to achieve PR (n = 10) was 0.6 years (0.4-2.4). Time to best response (n = 16) was 1.5 years (0.1-4.1). Duration of response was 5.1 years (1.3-8.6+) in pts with PR and 4.8 years (0.6-7.3+) in pts with SD. Seven of 8 pts with PD subsequently received sunitinib, sorafenib, and/or cabozantinib. Disease progression occurred as increase in target (n = 2), non-target/new lesions (n = 5), or CT/CEA (n = 1). Six pts died from disease 2.1 years (0.4-4.3) after stopping vandetanib. Progression free survival was 6.2 years (95% CI 3.0-na) and overall survival was 7.9 years (95% CI 5.9-na).Pts had no difference in enrollment age, baseline CT/CEA, or tumor size per response categories (n = 16). Rate of CEA/CT decrease during initial 4 months of treatment was not associated with PR/SD compared to PD (n = 16). While on vandetanib, 6 pts with PD had CEA or CT doubling time (DT) of < 2 years within 1 year prior to PD. All pts with ongoing PR/SD had CEA and CT DT > 2 years while on vandetanib. No pts came off treatment for toxicity. Dose reductions occurred in 8 pts for grade (gr) 2 weight loss (n = 2), palpitations (n = 1), arrhythmia (n = 1), elevated creatinine (n = 1), diarrhea (n = 2), and gr 3 constipation (n = 1). Conclusions: Many children with hereditary MTC sustained PR/SD on vandetanib. However, half ultimately developed PD and died from disease despite treatment with other targeted therapies. CEA/CT DT < 2 years within 1 year of progression on vandetanib may be associated with PD. *Median (range)