Post Conference Perspectives: Immunotherapy Combinations for Unresectable HCC - Episode 5

Immunotherapy in Unresectable HCC


Richard S. Finn, MD: In our management of unresectable liver cancer, we’ve really seen some dramatic changes in the past few years. For a decade or longer, all we had was sorafenib, which had shown stability to improve survival in the first-line setting. Then for many, many years we had numerous phase III failures, both in the frontline setting as well as in the second-line setting. In the past few years, we’ve seen the results of several phase III studies, which have led to approvals of new drugs in the first-line setting, such as lenvatinib, and in the second-line setting, cabozantinib, regorafenib, and ramucirumab.

There’s been a big interest in immuno-oncology [I-O] agents in all of cancer medicine, and this has eventually filtered down into the liver cancer space. Both nivolumab and pembrolizumab have received accelerated approval in the second-line setting based on phase I/II studies. But for immune checkpoint agents, at least as single agents, it has been difficult to get really strong, positive phase III data. For example, in the frontline setting, we saw at ESMO [the European Society for Medical Oncology Congress] in 2019 the results of CheckMate 459, which was an open-label study of nivolumab versus sorafenib. This study came very close to meeting statistical significance, but it did not. There was a lot of disappointment in that study. I mean, that study did confirm that nivolumab has a response rate in the 15%-to-20% range, but we cannot prove that it had better survival than sorafenib.

In the second-line space, published in the Journal of Clinical Oncology this year were the results of the KEYNOTE-240 study, which was a placebo-controlled study of pembrolizumab in patients who had progressed on sorafenib. This study actually showed a survival benefit with the addition of pembrolizumab to best supportive care. However, when we looked at the statistical design of the study, there were a few interim analyses as well as splitting of some of the alpha, the statistical power of the study between dual primary end points. Therefore, the study did not reach its statistical prespecified significance.

There’s been a big interest in I/O in this space. We know these drugs have response rates as single agents of 15% to 20% in both the frontline and second-line settings. We don’t have a good biomarker to identify who those patients are [who] get a benefit, so the strategy has turned to combining these agents with other drugs to try to improve the response rate. There’s been an interest now in combining I/O agents with some of the tyrosine kinase inhibitors, and also combining with bevacizumab. Specifically, atezolizumab and bevacizumab have been looked at in the IMbrave150 study.

The goal has been to increase response rates to single-agent checkpoint inhibitors, whether PD-1 [programmed cell death protein 1] inhibitors or PD-L1 [programmed death-ligand 1] inhibitors. There have been several strategies looked at. One strategy is combining these inhibitors with CTLA4 inhibitors. Studies are being conducted looking at that approach, just as it’s been done in other diseases. Also, the same data have evolved over time: That targeting VEGF does not just affect angiogenesis in tumors, but it does alter the microenvironment. Blocking either VEGF or the VEGF receptor can alter the T-cell subsets within the tumor microenvironment and can prep the tumor for more of an immune response when combined with a PD-1 inhibitor.

Transcript Edited for Clarity