ANTI-ANGIOGENIC THERAPY OF HCC

Treatment options for advanced HCC are limited, usually improving overall survival rather than curing the disease. These options include chemotherapy, radio-embolization, immune check-point therapy, and anti-angiogenic therapy.⁴⁴

Anti-angiogenic therapy was developed with the rationale that these drugs lead to destruction of the abnormally structured blood vessels resulting in tumor hypoxia and shrinkage.⁴⁵ However, Jain et al introduced the vascular normalization hypothesis that anti-angiogenic therapy restores the integrity and structure of the tumor-induced blood vessels without destroying these vessels.⁴⁶

Anti-angiogenic induced reduction in tumoral vascular burden induces hypoxic tumoral microenvironment. This hypoxia leads to accumulation of certain chemokines including programmed death receptor ligand 1 (PD-L1) which suppress immune cells and induces resistance to anti-angiogenic therapy, recent advances include the combination of immune checkpoint therapy with anti-angiogenic therapy to treat advanced HCC.^47,48

To date, the US Food and Drug Administration (FDA) has approved few anti-angiogenic drugs for HCC. Table 1 summarizes these drugs and their indications.^49–58

Sorafenib is an oral multi-kinase inhibitor that targets the activity of VEGF-2, PDGFR-β, and other signaling cascades, and has been the only approved systemic therapy for HCC for over a decade. Sorafenib upregulates P53 and decreases expression of matrix metalloprotease-2 (MMP-2) which suppresses cellular proliferation and invasion.^59,60 It is the only anti-angiogenic drug incorporated into the American Association for the Study of Liver Diseases (AASLD) guidelines for treatment advanced HCC (unresectable HCC).^44,61,62 (Figure 1). Although its indication of use is still vague, it is the first line of treatment in advanced HCC (with macro-vascular invasion or metastatic disease).⁴⁴

Lenvatinib is a more potent anti-angiogenic drug than Sorafenib, which acts through multi-kinase inhibition of VEGFR (more potent than Sorafenib), FGF receptors and PDGFR. Dual suppression of VEGF and FGF pathways results in concomitant suppression of both neo-angiogenesis and tumor growth. Lenvatinib is used in unresectable HCC with comparable results in overall survival between both Lenvatinib and Sorafenib.⁶³ Lenvatinib provides an advantage over Sorafenib with a longer time to progression as well as progression-free survival in patients enrolled in the trial.⁶⁴

Regorafenib and Cabozantinib are tyrosine kinase inhibitors which are the only anti-angiogenic drugs that were seen to be advantageous as a second-line therapy in patients who progressed on Sorafenib. Regorafenib and Cabozantinib show statistically significant improvement in overall survival and progression-free survival over the use of placebo in these patients.^54,55,65

Ramucirumab is a monoclonal antibody that inhibits the VEGF axis through blocking the activation of VEGFR-2. The FDA recently approved the use of Ramucirumab based on Phase 3 trial (REACH-2) that demonstrated effectiveness of this drug in patients who progressed on Sorafenib with AFP ≥ 400 ng/mL. It showed an increase in overall survival and progression-free survival with comparable results as Cabozantinib and Regorafenib.^57,58

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