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Systemic Plus Locoregional Combination Therapy in HCC

Insights From: Riccardo Lencioni MD, University of Miami Health System
Published: Monday, May 13, 2019



Transcript: 

Riccardo Lencioni, MD: So chemoembolization is one of the mainstays for the treatment of hepatocellular carcinoma [HCC]. For many practices around the world, this is actually the most popular treatment for HCC. Chemoembolization is especially recommended for patients with disease limited to the liver in the absence of extrahepatic spread of the disease and preserved liver function. While chemoembolization has been shown to improve survival, this approach has limitations. It is a focal treatment, and therefore even when a complete response is achieved in the target tumor, new tumors will most often develop in other territories inside or outside the liver.

So the ability of this procedure to keep response in place for a long time is limited. This is why, over the past several years, there have been several attempts to combine this locoregional approach with TACE [transarterial chemoembolization] with a systemically active drug. Now, one of the mechanisms that is supposed to be associated with tumor recurrence or progression after TACE is associated with the hypoxia that is induced by the procedure. Hypoxia has been shown in several experimental studies to be able to upregulate several mediators involved in angiogenesis such as hypoxia-inducible factor 1-alpha and VEGF. And therefore, in a way, the more you create an hypoxic environment, the more you potentially stimulate angiogenesis and therefore tumor recurrence. On this basis, there were past attempts to combine TACE with targeted therapies, particularly with kinase inhibitors that had demonstrated effect and demonstrated anti-angiogenetic effect.

Two large trials were conducted combining TACE with sorafenib versus TACE plus placebo—the SPACE trial, which was a global trial in the US [United States], Europe, and Asia—and the TACE 2 trial, which was conducted in the UK. Unfortunately, this trial showed that the concurrent administration of sorafenib and TACE is feasible, toxicity is manageable, however, the effect in terms of time to progression and survival was very limited. The hazard ratio for survival in the combination arm against the TACE alone arm was 0.90 in SPACE and 0.91 in TACE 2, so very similar outcomes, suggesting that in clinical settings this supposed synergistic effect of TACE with these targeted therapies is limited. Unfortunately, more recently, similar negative results were reported for other drugs. Brivanib was tested in combination with TACE and the phase III trial was negative. Orantinib was also investigated in a phase III setting in Asia, and this trial also turned out to be negative.

Now, the new area for research is the potential synergistic effect between TACE and checkpoint inhibitors. We know that checkpoint inhibitors are able to activate T cells and to keep response in place for a long time. On the other hand, only a certain proportion of patients show response to checkpoint inhibitors. Now, several preclinical and early phase clinical investigations have suggested that TACE can enhance antigen exposure, can enhance T-cell activation, and therefore there is a rationale for combining TACE with checkpoint inhibitors in an attempt to induce a more durable response and hopefully to improve progression-free survival and overall survival.
 
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Transcript: 

Riccardo Lencioni, MD: So chemoembolization is one of the mainstays for the treatment of hepatocellular carcinoma [HCC]. For many practices around the world, this is actually the most popular treatment for HCC. Chemoembolization is especially recommended for patients with disease limited to the liver in the absence of extrahepatic spread of the disease and preserved liver function. While chemoembolization has been shown to improve survival, this approach has limitations. It is a focal treatment, and therefore even when a complete response is achieved in the target tumor, new tumors will most often develop in other territories inside or outside the liver.

So the ability of this procedure to keep response in place for a long time is limited. This is why, over the past several years, there have been several attempts to combine this locoregional approach with TACE [transarterial chemoembolization] with a systemically active drug. Now, one of the mechanisms that is supposed to be associated with tumor recurrence or progression after TACE is associated with the hypoxia that is induced by the procedure. Hypoxia has been shown in several experimental studies to be able to upregulate several mediators involved in angiogenesis such as hypoxia-inducible factor 1-alpha and VEGF. And therefore, in a way, the more you create an hypoxic environment, the more you potentially stimulate angiogenesis and therefore tumor recurrence. On this basis, there were past attempts to combine TACE with targeted therapies, particularly with kinase inhibitors that had demonstrated effect and demonstrated anti-angiogenetic effect.

Two large trials were conducted combining TACE with sorafenib versus TACE plus placebo—the SPACE trial, which was a global trial in the US [United States], Europe, and Asia—and the TACE 2 trial, which was conducted in the UK. Unfortunately, this trial showed that the concurrent administration of sorafenib and TACE is feasible, toxicity is manageable, however, the effect in terms of time to progression and survival was very limited. The hazard ratio for survival in the combination arm against the TACE alone arm was 0.90 in SPACE and 0.91 in TACE 2, so very similar outcomes, suggesting that in clinical settings this supposed synergistic effect of TACE with these targeted therapies is limited. Unfortunately, more recently, similar negative results were reported for other drugs. Brivanib was tested in combination with TACE and the phase III trial was negative. Orantinib was also investigated in a phase III setting in Asia, and this trial also turned out to be negative.

Now, the new area for research is the potential synergistic effect between TACE and checkpoint inhibitors. We know that checkpoint inhibitors are able to activate T cells and to keep response in place for a long time. On the other hand, only a certain proportion of patients show response to checkpoint inhibitors. Now, several preclinical and early phase clinical investigations have suggested that TACE can enhance antigen exposure, can enhance T-cell activation, and therefore there is a rationale for combining TACE with checkpoint inhibitors in an attempt to induce a more durable response and hopefully to improve progression-free survival and overall survival.
 
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