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Giovanis et al. Hepatoma Res 2018;4:10  I  http://dx.doi.org/10.20517/2394-5079.2018.21                                           Page 7 of 13


               Favorable outcomes were achieved in a phase 2 single-arm study on 46 patients with advanced HCC treated
                                                                  [54]
               with 12 mg of lenvatinib daily until progression or toxicity . An independent review committee referred
               that the median in TTP was 7.4 months, the overall response rate evaluated by modified RECIST criteria
               (mRECIST) was 37%, and the median OS was 18.7 months. The most common toxicities were hypertension,
               palmar-plantar dysesthesia, thrombocytopenia, anorexia and proteinuria. These adverse events leaded to
                                                                        [54]
               dose reductions in 74% of the cases and drug discontinuation in 22% .
               Basing on this phase 2 data, the following phase 3 trial (REFLECT) assumed that lenvatinib exposure was
               influenced by body weight. Consequently, the doses used in the REFLECT trial were 8 mg for patients
               with weight < 60 kg and 12 mg for others. In this phase 3 study, a total of 954 patients with unresectable
               HCC were randomized 1:1 according to an open-label, randomized, parallel-assignment, active-controlled
               protocol, to compare the efficacy of lenvatinib versus sorafenib as a first-line systemic treatment according to
                                   [55]
               a non-inferiority design . The primary endpoint of OS was initially evaluated for non-inferiority and then
               for superiority. The study excluded patients with 50% or higher liver occupation, obvious invasion of the bile
               duct, or invasion at the main portal vein.


               The primary endpoint of non-inferiority of lenvatinib in terms of OS compared with sorafenib was
               met: lenvatinib resulted not-inferior in mOS (13.6 months with lenvatinib and 12.3 months with
               sorafenib). Differently, the OS of lenvatinib over sorafenib was not achieved. Additionally, lenvatinib
               achieved significant and clinically meaningful improvement in PFS (7.4 vs. 3.7 months), TTP (8.9 vs.
               3.7 months) and overall response rate (24% vs. 9% by mRECIST). The median duration of treatment with
                                                       [55]
               lenvatinib was 5.7 vs. 3.7 months with sorafenib .
               Investigators detected that the treatment duration for lenvatinib arm was shorter than time to progression
               (5.7 vs. 8.9 months) and that this datum was not observed in the sorafenib arm (both 3.7 months). This could
               be related to a major incidence of lenvatinib definitive interruption before tumor progression probably due
               to a greather incidence of serious treatment emergent adverse events in the lenvatinib arm and not in the
               sorafenib arm.


               In the two arms of the study, a similar level of treatment-emergent adverse events was observed for dose
               reductions (37% of patients in the lenvatinib arm versus 38% in the sorafenib) and drug discontinuations (9%
               vs. 7% respectively).

               Lenvatinib showed an higher incidence of grade ≥ 3 treatment-emergent adverse events (57% vs. 49%), and
               the most common grade 3/4 treatment-emergent adverse events resulted hypertension (23% in lenvatinib
               arm vs. 14% of sorafenib), decreased weight (8% vs. 3%), decreased platelet count (6% vs. 3%), elevated
               aspartate aminotransferase (5% vs. 8%), decreased appetite (5% vs. 1%), diarrhea (4% vs. 4%), and palmar-
                                                [55]
               plantar erythrodysesthesia (3% vs. 11%) .
               Cabozantinib
               Cabozantinib is a tyrosine kinases inhibitor with activity directed to MET, VEGFR2, FLT3, c-KIT, and
                   [56]
               RET . This drug was initially approved by FDA on November 2012 for the treatment of metastatic
               medullary thyroid cancer with dosage 140 mg daily. In April 2016 Cabozantinib was approved for the
               second-line treatment of advanced renal cell carcinoma after prior antiangiogenic therapy while in renal cell
               carcinoma at dosage of 60 mg daily.

               Cabozantinib was also investigated in HCC patients as part of a phase 2 randomized discontinuation
                   [57]
               trial ; a cohort of 41 patients with HCC was treated with 100 mg daily of drug, the disease control rate
               at 12 weeks was 68% with two partial responses. The efficacy resulted independent from a prior sorafenib
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