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The only other oncogene found to be altered at somatic level in MTC is RAS gene. Mutations in K- and
HRAS genes have been identified in 20% of sporadic MTC and have been demonstrated to be mutually
exclusive events with RET mutations. Moreover, RAS mutated MTC cases are apparently less aggressive that
RET mutated ones. Thus far, about 20% of sporadic MTC are still orphan of a driver oncogene
alteration [20,56] .

TKIs in clinical practice
Several TKIs have been tested for the treatment of advanced progressive MTC, including imatinib ,
[57]
[65]
[59]
[63]
[64]
[58]
axitinib , motesanib , sorafenib , sunitinib , pazopanib , ponatinib , lenvatinib , and anlotinib .
[62]
[60]
[61]
However, only two of them, vandetanib and cabozantinib, have been approved by the Food and Drug
Administration (FDA) and the European Medicine Agency (EMA), after the phase III studies, ZETA and
EXAM trials [66,67] .
Vandetanib
Vandetanib (also known as ZD6474) is an inhibitor of VEGFR2 and -3, RET, and EGFR kinases [36,68,69]
[Figure 2].
In 2012, the results of the international randomized phase III ZETA trial (ClinicalTrials.gov, number
NCT00410761) demonstrated an efficacy of vandetanib, at dosage of 300 mg/daily, in prolonging
progression free survival (PFS) in 331 patients with advanced progressive MTC, compared to placebo (30.5
months vs. 19.3 months; HR = 0.46; 95%CI: 0.31-0.69). However, no differences in the overall survival (OS)
[66]
between the two groups was shown . The clinical benefit of vandetanib treatment was also confirmed in a
recent post-hoc analysis, when patients were divided into four disease severity subgroups: patients with both
progression and symptoms at baseline, those with symptoms only, those with progression only, and those
with no progression or symptoms at baseline . In 2014, Massicotte et al. , in a retrospective study on a
[70]
[71]
small subgroup of advanced MTC (n = 11), confirmed that a partial response was obtained in 36% of the
study group.

In addition, outside of clinical trial, vandetanib treatment showed its efficacy. In a multicentric French
study, 60 patients with advanced MTC and diffuse metastatic involvement were treated with this drug and
the data were analyzed. After a median follow-up of 20 months and a median duration of treatment of 9.7
months, median PFS was 16.1 months. Moreover, a clinical benefit defined as best tumor response was
observed in most of the patients (75%) . Interestingly, in this study, one patient showed a complete
[72]
response, while, conversely, one patient died because of vandetanib-induced cardiac toxicity.

Recently, clinical experiences in real-life settings have been reported [73,74] . Valerio et al. evaluated 79 MTC
[74]
patients, treated with vandetanib and followed at a tertiary care center. Patients were divided according to
the time of treatment into short- (< 1 year) and long-term (> 1 year) responders. Median PFS of the entire
study group was 47 months, longer than in ZETA trial (30.5 months), and, when considering only the long-
term responders, PFS was even longer (54.5 months). Similar results were reported in a following study by
Ramos et al . showing that that PFS of those patients who continued vandetanib treatment for more than 4
[73]
years was significantly longer (73.2 months) than that of ZETA trial. Interestingly, in both studies, a better
and durable clinical response was experienced in younger patients and in those in whom vandetanib
treatment was started without evidence of tumor progression but just for severe symptoms.