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Matrone et al. J Cancer Metastasis Treat 2021;7:23 https://dx.doi.org/10.20517/2394-4722.2021.47 Page 9 of 19

However, if both were available, the choice should consider both drug characteristics and patient features.
According to the results of the studies, cabozantinib seems to be more rapid in inducing the shrinkage of
the tumor tissue and could be useful when there is the need to rapidly control the tumor burden (e.g.,
vertebral lesion compressing spinal cord). Conversely, vandetanib showed a better safety profile and an
easier manageability of its specific AE.

When choosing the drug, it should also be considered that cabozantinib has been tested as second line
treatment after other TKIs and showed advantages in prolongation of PFS, while this information is
unavailable for vandetanib. Conversely, vandetanib is contraindicated in patients who have a prolonged
QTc (> 450 ms in men and > 470 ms in females) [89-91] , while cabozantinib should not be used in patients with
[67]
a history of diverticulitis , and renal function should be carefully monitored during treatment because of
[92]
the potential onset of renal damage with proteinuria . Moreover, both treatments could modify thyroid
function, in patients with thyroid gland in situ and thyroid hormone metabolism; thus, the evaluation of
[93]
thyroid function tests is mandatory for all patients undergoing TKI treatment . Furthermore, for both
treatments, particular caution should be taken in evaluating the medical history of hemoptysis and
hemorrhages. If the tumor invades the vital structures of the neck and if patients experienced radiation
treatment of the neck or mediastinum, they carry a higher risk for hemorrhages and fistula formation,
which is a life-threatening AE . Moreover, as mentioned above, vandetanib has been approved for the
[94]
treatment of children with MTC, mainly MENII patients, while this is not the case for cabozantinib.
Similarly, no data have been reported on the benefit that cabozantinib has in the treatment of ACTH ectopic
syndrome. Thus, it is intuitive that, in either children or patients with ectopic ACTH, vandetanib should be
preferred if no other elements contraindicate its use.

Furthermore, in vitro studies showed the V804 RET mutation confers resistance to vandetanib , but this
[95]
seems to not be a limitation for cabozantinib. Therefore, in patients with V804M, cabozantinib should be
preferred.

Lastly, AEs are common and similar for both drugs, particularly those of mild intensity (CTCAE Grades 1
and 2), but their prevalence is different according to the drug used [Table 1].

Vandetanib and cabozantinib are two cytostatic drugs, therefore they inhibit cellular growth but do not kill
the neoplastic cells. For this reason, the treatment should be continued as long as there is evidence of
clinical benefit.

To date, no advantages in OS were shown in the exploratory analysis of both phase III studies [70,87] when
comparing vandetanib or cabozantinib to placebo. Moreover, several clinical data indicate that patients on
TKIs treatment will eventually develop a mechanism of resistance to the drug, associated with progression
of the disease. This mechanism, highlighted in all TKIs treatment, seems to be independent of the TKI
used and could be related to secondary mutations in the kinase domains that block the TKIs binding in
[96]
the target genes . For these reasons, in the last years, further studies have been performed to evaluate new
[97]
drugs able to implement the therapeutic landscape of systemic treatment of advanced MTC.

RET SELECTIVE INHIBITORS
Rationale of treatment
RET mutations are found in more than 40% of sporadic and virtually 100% of hereditary cases [15,20,98] .
Moreover, about 85% of advanced metastatic MTC cases carried RET mutations, which are able to induce
higher risk of lymph nodes metastases, disease recurrence/persistence after surgery, and worst survival