*4.3. Immune Checkpoint Inhibitors Combined with Tyrosine Kinase Inhibitors*

In addition to its well-known stimulating effect on angiogenesis, VEGF can promote immune evasion by directly and indirectly inhibiting infiltration and function of cytotoxic T-lymphocytes and increasing PD-1 expression on intra-tumoral CD8+ T-cells. In other words, the VEGF pathway is involved in the recruitment of immunosuppressive T-reg cells into the tumor. Thus, VEGF inhibition through TKIs or VEGFR-directed monoclonal antibodies might increase local antitumor immunity and favorably modify the immunosuppressive tumor microenvironment, thus enhancing the effects of ICIs [45]. On this basis, several Phase I/II trials testing combinations of anti-PD1/PD-L1 with anti-VEGFRs were undertaken and have already shown promising results in this research field, paving the way for Phase III trials that are currently in progress (Table 1) [46].

Among these studies, one trial tested the combination of nivolumab plus cabozantinib, with or without ipilimumab, reporting preliminary clinically meaningful responses [47]. As of today, the results of this study, which included 71 patients randomized to either nivolumab plus cabozantinib (*n* = 36) or nivolumab plus ipilimumab and cabozantinib (*n* = 35), are only partially available, and show that investigator-assessed ORR was comparable with that of nivolumab alone for the dual treatment arm (17%, 6 patients with PR) but reached 26% (9 patients with PR) in the triple treatment arm. The diseased control rate was good and similar in the two groups, being 81% for the dual treatment arm and 83% for the triple treatment arm. It is noteworthy that the median OS was not reached in either arm [47]. With regards to safety, grade 3 or 4 treatment-related AEs were observed in 42% of cases in the dual treatment arm and in 71% of cases in the triple treatment arm, leading

to treatment discontinuation in 3% and 20% of patients, respectively. However, no new safety signals were observed in either arm. Based on these promising findings, complete and updated results of this trial are eagerly awaited.

Another combination that is currently under investigation in patients with advanced HCC is that of pembrolizumab plus lenvatinib, which, in a Phase Ib study, showed good results with a median OS of 22 months and a 46% confirmed ORR [48]. Hence, this combination has been granted a breakthrough therapy designation by the FDA for advanced HCC patients who are not amenable to locoregional treatment, and it is currently being tested in a Phase III, international, multicenter clinical study (LEAP-002).
