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Page 8 of 19 Matrone et al. J Cancer Metastasis Treat 2021;7:23 https://dx.doi.org/10.20517/2394-4722.2021.47

Cabozantinib
Cabozantinib (also known as XL184) is an inhibitor of VEGFR1 and -2, RET, c-KIT, MET, and KIF 5B
[85]
[84]
rearrangements [Figure 2]. The efficacy of cabozantinib was demonstrated in a phase I study . In 2013,
after the results of the double-blinded, phase III trial EXAM study (ClinicalTrials.gov, number
NCT00704730), cabozantinib was approved by FDA and EMA. In this study, a significant improvement in
PFS was demonstrated in patients with progressive MTC, compared to placebo . Patients (n = 330) with
[67]
progressive MTC were enrolled and treated with cabozantinib (140 mg/daily), at 2:1 compared to placebo.
The estimated median PFS was 11.2 months for cabozantinib group vs. 4.0 months for placebo (HR = 0.28;
95%CI: 0.19-0.40; P < 0.001). The analysis of specific subgroups of patients according to age, previous TKIs
treatment, and hereditary or sporadic cases showed an improved PFS in treated patients compared to
placebo. In addition, response rate (28% vs. 0%) and estimation of progression-free at 1 year (47.3% vs. 7.2%)
were higher in patients treated with cabozantinib.

AEs were commonly described and included diarrhea, palmar-plantar erythrodysesthesia, decreased weight
and appetite, nausea, and fatigue. To manage these AEs, most patients (79%) experienced a dose reduction
and some of them (16%) a treatment discontinuation. Some severe AEs, e.g., hemorrhages and intestinal
perforation, related to the high activity of cabozantinib against VEGFR, were reported during the EXAM
clinical trial.

In 2016, an exploratory analysis in patients of a phase III study was performed to evaluate the clinical
[86]
response to cabozantinib, according to RET or RAS (HRAS, KRAS, and NRAS) mutations . Half of the
patients (51.2%) harbored RET mutation, prevalently M918T (38.2%), while the remaining were RET
negative (13.9%) or RET unknown (34.8%). Only 16 patients (4.8%) showed RAS mutation. PFS was longer
in cabozantinib group compared to placebo in three out of four subgroups of patients: those who harbored
RET mutations (60 weeks vs. 20 weeks; HR = 0.23; 95%CI: 0.14-0.38; P < 0.0001), those with RET unknown
(HR = 0.30; 95%CI: 0.16-0.57; P = 0.0001), and those with RAS mutations (HR = 0.15; 95%CI: 0.02-1.10; P =
0.0317). Interestingly, in the RET-mutated patients, those harboring the M918T mutation showed the
greatest benefit in PFS from cabozantinib therapy compared to placebo (61 weeks vs. 17 weeks; HR = 0.15;
95%CI: 0.08-0.28; P < 0.0001). In patients without RET or RAS mutation, no benefit in PFS was observed. All
subgroups showed similar safety profile.

Overall survival was evaluated in another exploratory analysis assessing the data of patients included in a
[87]
phase III study, after long-term follow up . After a minimum follow-up of 42 months, a 5.5-month
increase in median OS was observed in cabozantinib vs. placebo group (26.6 months vs. 21.1 months; HR =
0.85; 95%CI: 0.64-1.12; P = 0.24), although not statistically significant. However, in this analysis,
cabozantinib treated patients also experienced longer OS if harboring RET M918T mutation, compared to
placebo (44.3 months vs. 18.9 months; HR = 0.60; 95%CI: 0.38-0.94; P = 0.03). The safety profile for
cabozantinib patients remained similar to the data of the primary analysis. The authors concluded that,
although the OS was not significantly longer in the cabozantinib group, patients with RET M918T mutation
could greatly benefit from cabozantinib treatment.

Clinical point of view
At present, vandetanib and cabozantinib are both valid options in the treatment of advanced metastatic
[88]
MTC. Both should be started when a progression of the structural disease according to the RECIST is
documented or according to clinical judgement in peculiar cases. The choice of the drug is dependent on
the drug availability in different countries, because not in all countries are approved and reimbursed.