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Page 10 of 19 Matrone et al. J Cancer Metastasis Treat 2021;7:23 https://dx.doi.org/10.20517/2394-4722.2021.47

compared to other mutations [20,55,99] .

In addition to MTC, RET is a driver gene in other tumors such as papillary thyroid, lung, breast, and colon
[100]
cancers. The group of cancers characterized by these driver mutations can be defined as REToma .
According to its role in REToma carcinogenesis, RET protein has been considered an ideal target for highly
selective drugs.

Thus, a second generation of highly selective RET inhibitors have been developed both to maintain a
significant anti-tumor efficacy, similar to vandetanib and cabozantinib, and to improve the safety profile. In
2018, two molecules, selpercatinib and pralsetinib [101,102] , were proposed. These drugs showed a stronger
inhibition of RET and a weaker activity against other targets, such as VEGFR, compared to vandetanib and
[103]
cabozantinib [Figure 2]. Moreover, selpercatinib and pralsetinib inhibited the proliferation of cells
harboring many kinds of RET mutations, both gene fusions and point mutations, including the V804M
mutation which, as mentioned above, showed in vitro resistance to vandetanib . These results were further
[95]
confirmed in animal models and clinical studies [101,102] , in which a relevant tumor shrinkage was shown.
Interestingly, in mouse models, selpercatinib showed anti-neoplastic activity against brain metastasis,
[101]
too .

According to their highly selective activity against RET protein, regardless of tumor type, both drugs were
involved in basket clinical trials with many cancers of the REToma network [76,77] .

Selpercatinib
Between May 2017 and June 2019, 162 patients were enrolled in the phase I/II LIBRETTO-001 trial
(ClinicalTrials.gov, number NCT03157128) to evaluate the OR rate in different histological types of thyroid
cancers harboring RET mutations. Patients enrolled in phase I trial received selpercatinib with different
starting doses (from 20 mg once daily to 240 mg twice daily) and progressive decreases to the highest safe
dose were performed. Conversely, all patients in phase II study started with the same dose of 160 mg twice
daily.

Most patients (143/162, 88.3%) had MTC, and 55 (38.5%) of them were already treated with vandetanib
and/or cabozantinb while 88 (61.5%) were treatment naïve. The remaining patients (19/162, 11.7%) showed
a RET fusion-positive thyroid cancer (PTC, poorly differentiated thyroid carcinoma, Huerthle cell
carcinoma, and anaplastic carcinoma). OR rate was 69% in patients already treated with vandetanib and/or
cabozantinib and 73% in treatment naïve patients. In the remaining patients with RET mutated thyroid
cancers, OR rate was similar (79%). This result was confirmed for all RET mutation profiles, including
V804M. After 1 year, 82% of MTC patients previously treated with vandetanib and/or cabozantinib, 92% of
treatment naïve patients, and 64% of other thyroid cancer patients continued to be free of progression.
However, longer follow-up data are needed to evaluate the duration of the clinical response.

Several AEs were experienced by most of the patients; however, the prevalence of AEs for single patient was
lower and most of them were of lesser intensity (CTCAE Grade 1 or 2), compared with vandetanib and
[66]
cabozantinib [Table 1]. Moreover, the safety profile was the same across all cancers treated in
[67]
[76]
LIBRETTO-001 .
Pralsetinib
ARROW is a phase I dose escalation trial to establish the recommended phase II dose (400 mg once daily)
and phase II expansion cohorts defined by tumor type and/or RET alteration (ClinicalTrials.gov, number