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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 11 of 19

[77]
NCT03037385) .

Although the ARROW trial is not completed yet, recently, the ad interim results were presented, and
[77]
efficacy and safety were assessed at the data cut-off of 13 February 2020 . Since March 2017, 79 patients
with RET positive MTC were enrolled, either previously treated with vandetanib and/or cabozantinib or
treatment naïve. Overall OR rate was evaluated on 51 patients and was 65%. In patients previously treated
with vandetanib and/or cabozantinib, OR was 60%, while, in naive patients, it was 74% (14/19). PFS after 18
months was 71% in patients previously treated with other TKIs and 85% in treatment naïve patients. The
authors did not find any influence due to different RET genotype on clinical response. Although the data
about safety are not completed, the AEs were mainly of lower intensity (CTCAE Grade 1 or 2), and only 4%
of patients discontinued the drug because of AEs.

Mechanisms of resistance
Despite the very interesting profile of these new drugs, several emerging reports also observed a potential
resistance to these RET inhibitors. Recently, a patient with KIF5B-RET non-small cells lung carcinoma
[104]
(NSCLC) developed progression after an initial partial response on selpercatinib treatment . Circulating
tumor DNA and post-mortem biopsy analysis showed the appearance of a wide spectrum of RET mutations
on G810 residue, which could be considered a key spot for drug resistance. The appearance of these
mutations was further confirmed in other progressing NSCLC and MTC cases and in vivo and in vitro
models . Structural analysis showed that mutations occurring at 810 residue can sterically alter
[104]
selpercatinib binding. Subbiah et al. , using X-ray crystal analysis, revealed that selpercatinib and
[105]
pralsetinib showed a peculiar binding with RET protein, compared to previous TKIs. This binding permits
avoiding the resistance to 804 mutation, but it can be susceptible to mutations occurring at 738, 806, and
810 residues. In addition, RET-dependent resistance mechanisms, other RET-independent mechanisms
have been described such as KRAS and MET amplification, which have recently been showed in progressing
NSCLC patients [106,107] .

Clinical point of view
Selpercatinib and pralsetinib are two promising drugs which showed a relevant clinical response in MTC
patients, regardless of both previous TKI treatment experienced and different types of RET mutations.
Moreover, their safety profile seems to be very encouraging, compared to previous TKIs. However, they can
only be used in MTC patients harboring RET mutation, which represent the majority, but not all cases .
[20]
Furthermore, these drugs are susceptible to induce peculiar resistance mechanisms, and further studies are
needed to completely understand the ideal clinical and molecular scenario to use these drugs.

At the same time, a third generation of TKIs, RET mutation selective ones, is under evaluation and could
represent the future of the treatment of advanced MTC .
[108]
IMMUNOTHERAPY
Rationale of treatment
In the last decades, many promising results in the treatment of several human cancers derived from the
development of immunotherapy, and in particular of drugs called immune checkpoints inhibitors (ICIs).
The rationale for the use of immunotherapy is the close linkage among immune system, tumors, and tumor
microenvironment (fibroblasts, pericytes, adipocytes, and other stromal cells) [109-111] . The immune system
acts as a mediator of “immune surveillance”, recognizing and removing cancer cells, which try to escape the
[112]
immune control through several mechanisms .