Advances in the treatment of liver cancer. The state-of-the art

The past several years have been a time of great excitement for the HCC community. We have seen successful phase 3 studies demonstrating incremental improvements in overall survival for patients with advanced HCC. Until 2020, these studies have largely been driven by efficacy of VEGF directed therapies including TKIs (sorafenib, lenvatinib, regorafenib, cabozatinib) and the monoclonal antibody to the VEGF receptor ramucirumab. Last year, we saw the approval of the combination of the anti- PD-L1 antibody atezolizumab and the VEGF directed antibody bevacizumab. This approval was based on the results of the IMBRAVE150 study and was the first study to improve overall survival in the front-line setting since sorafenib’s approval in 2008. It also validated the approach of combining PD-1/PD-L1 inhibition with VEGF inhibition and provided level 1 evidence for IO in liver cancer. A recent study in Asia, ORIENT-32, with sintilimab and bevacizumab biosimilar injection delivered similar results. The rationale for dual targeting of these pathways is based on laboratory studies demonstrating the VEGF inhibition changes the inflammatory milieu in the tumor microenvironment to one favoring tumor attacking immune cells which in combination with the restored immune activation with PD-1 interference provides for synergy. With that in mind, several studies are now evaluating the VGEF TKIs in combination with IO approaches including the combination of lenvatinib and pembrolizumab, cabozantinib and atezolizumab, regorafenib and nivolumab, and others. While the VEGFR targeting by these drugs theoretically should have similar effects as VEGF targeting, there may be additional benefits from inhibition of other targets these multi-kinase inhibitors block. Clinical data is suggesting these combinations are active in HCC though the toxicity profile differs as compared to the combination of two antibodies. Whether or not these combos are active against the same groups of patients or differentiate themselves is yet to be seen. In addition, the question of whether these combinations may work after front line IO -VEGF combinations needs to be explored. Already these combinations are being looked at in earlier stages of liver cancer as well. We will review these data and concepts in the lecture.