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Key Takeaway 2: Initial Systemic Therapy in HCC

Insights From: Richard Finn, MD, Geffen School of Medicine at UCLA
Published: Thursday, Aug 15, 2019



Transcript:

Richard Finn, MD: For a decade, we only had 1 drug that had been proven to be effective in liver cancer, and that was sorafenib. Sorafenib was a big breakthrough in the management of liver cancer. We never had phase III data that showed that a systemic treatment could improve survival, and it did that successfully with a hazard ratio of 0.69, or a 31% decrease in the risk of death. Interestingly, it extended survival without inducing real responses. It was very uncommon to get a response.

It improved survival by slowing progression, and the drug has a very clear safety profile. Typically, hand-foot skin reaction, GI [gastrointestinal] toxicity, anorexia, diarrhea, fatigue, and such things that can be managed. In a population of patients with underlying liver disease, it was tolerable. It was not like other small molecules that had failed in liver cancer because of toxicity, or chemotherapy, which carried toxicity. It was the right drug for the right disease.

Given that it had no responses, the median survival benefit was about 3 months over placebo. The feeling was that it would be very easy to beat, and it would usher in the new generation of molecules in liver cancer. As it turns out, that was not the case. We had numerous failures, and still to this day, nothing has beaten sorafenib. Nothing has been shown to be better than sorafenib in improving survival. We do have other drugs available for liver cancer, and in the frontline setting there is 1—lenvatinib—which was approved about 2 years ago now.

Lenvatinib is a small molecular inhibitor of several kinases, similar to sorafenib. It does hit the VEGF [vascular endothelial growth factor] receptor, but it also has very potent activity against the fibroblast growth factor receptor [FGFR]. The FGFR family is very important in angiogenesis and resistance to VEGF targeting, and is also significant in liver cancer as a proliferative driver. Early studies showed in single-arm studies that lenvatinib had some activity in liver cancer, and that led to the REFLECT study, which was a large, global, phase III, open-label study of lenvatinib versus sorafenib. It accrued over 950 patients and its primary endpoint was noninferiority. It intended to show that lenvatinib was noninferior to sorafenib. That doesn’t mean that they’re equivalent, but that it’s not significantly worse. If it met noninferiority, then they would try to prove superiority. There were secondary endpoints like PFS [progression-free survival], TTP [time to progression], and safety. That was a positive study, and it met its noninferiority endpoint.

Survival with sorafenib was about 12.3 months, and with lenvatinib, it was about 13.5 months, but that was with a hazard ratio of 1.06, which met its noninferiority endpoint. The response rates between the 2 arms of the study were striking. For the first time, we had a drug approved in frontline that had a single-agent response rate that was higher than sorafenib. We measure not only the size of the tumor, but its enhancing component, using the mRECIST [modified response evaluation criteria in solid tumors] criteria. Liver tumors have a very characteristic enhancement. We saw that with sorafenib, that was around 9% or 10%. With lenvatinib, it was about 20% by investigator assessment.

That was very striking. Still, even though it had a higher response rate, we could not see that the overall survival was significantly different. We did see recently in a subanalysis that with either drug, if you respond, you tend to live longer than if you don’t respond. For the first time, we’re starting to see data that if you can induce a response with a drug, regardless of the drug, you might live longer with liver cancer. That’s a new finding. Lenvatinib did improve progression-free survival. It also improved time to progression, and things that are surrogate endpoints—response, TTP, PFS. However, OS [overall survival] was the same.

There were some unique characteristics of the study. Lenvatinib is dosed by weight, whether patients get 12 mg or 8 mg. The cutoff is 60 kilograms. If they’re heavier, they get the higher dose. Also, the REFLECT study excluded patients who had main portal vein invasion. That’s not something that has been done in other sorafenib studies, and that might explain this longer survival of 12 months with sorafenib.

Toxicity is different between the 2 drugs. Lenvatinib is a very potent VEGF inhibitor, and we see a little more hypertension and proteinuria, which are both effects of targeted VEGF access. These need to be watched for. Both drugs can have GI toxicities like diarrhea, though sorafenib has a higher frequency of hand-foot skin reaction. These are all important differentiators, and for patients I’m seeing in clinic who are Child Pugh stage A who are appropriate candidates for systemic treatment, if they have bulkier tumors, or they need a response versus just stable disease, I’m tending to go with lenvatinib frontline instead of sorafenib.

Transcript Edited for Clarity
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Transcript:

Richard Finn, MD: For a decade, we only had 1 drug that had been proven to be effective in liver cancer, and that was sorafenib. Sorafenib was a big breakthrough in the management of liver cancer. We never had phase III data that showed that a systemic treatment could improve survival, and it did that successfully with a hazard ratio of 0.69, or a 31% decrease in the risk of death. Interestingly, it extended survival without inducing real responses. It was very uncommon to get a response.

It improved survival by slowing progression, and the drug has a very clear safety profile. Typically, hand-foot skin reaction, GI [gastrointestinal] toxicity, anorexia, diarrhea, fatigue, and such things that can be managed. In a population of patients with underlying liver disease, it was tolerable. It was not like other small molecules that had failed in liver cancer because of toxicity, or chemotherapy, which carried toxicity. It was the right drug for the right disease.

Given that it had no responses, the median survival benefit was about 3 months over placebo. The feeling was that it would be very easy to beat, and it would usher in the new generation of molecules in liver cancer. As it turns out, that was not the case. We had numerous failures, and still to this day, nothing has beaten sorafenib. Nothing has been shown to be better than sorafenib in improving survival. We do have other drugs available for liver cancer, and in the frontline setting there is 1—lenvatinib—which was approved about 2 years ago now.

Lenvatinib is a small molecular inhibitor of several kinases, similar to sorafenib. It does hit the VEGF [vascular endothelial growth factor] receptor, but it also has very potent activity against the fibroblast growth factor receptor [FGFR]. The FGFR family is very important in angiogenesis and resistance to VEGF targeting, and is also significant in liver cancer as a proliferative driver. Early studies showed in single-arm studies that lenvatinib had some activity in liver cancer, and that led to the REFLECT study, which was a large, global, phase III, open-label study of lenvatinib versus sorafenib. It accrued over 950 patients and its primary endpoint was noninferiority. It intended to show that lenvatinib was noninferior to sorafenib. That doesn’t mean that they’re equivalent, but that it’s not significantly worse. If it met noninferiority, then they would try to prove superiority. There were secondary endpoints like PFS [progression-free survival], TTP [time to progression], and safety. That was a positive study, and it met its noninferiority endpoint.

Survival with sorafenib was about 12.3 months, and with lenvatinib, it was about 13.5 months, but that was with a hazard ratio of 1.06, which met its noninferiority endpoint. The response rates between the 2 arms of the study were striking. For the first time, we had a drug approved in frontline that had a single-agent response rate that was higher than sorafenib. We measure not only the size of the tumor, but its enhancing component, using the mRECIST [modified response evaluation criteria in solid tumors] criteria. Liver tumors have a very characteristic enhancement. We saw that with sorafenib, that was around 9% or 10%. With lenvatinib, it was about 20% by investigator assessment.

That was very striking. Still, even though it had a higher response rate, we could not see that the overall survival was significantly different. We did see recently in a subanalysis that with either drug, if you respond, you tend to live longer than if you don’t respond. For the first time, we’re starting to see data that if you can induce a response with a drug, regardless of the drug, you might live longer with liver cancer. That’s a new finding. Lenvatinib did improve progression-free survival. It also improved time to progression, and things that are surrogate endpoints—response, TTP, PFS. However, OS [overall survival] was the same.

There were some unique characteristics of the study. Lenvatinib is dosed by weight, whether patients get 12 mg or 8 mg. The cutoff is 60 kilograms. If they’re heavier, they get the higher dose. Also, the REFLECT study excluded patients who had main portal vein invasion. That’s not something that has been done in other sorafenib studies, and that might explain this longer survival of 12 months with sorafenib.

Toxicity is different between the 2 drugs. Lenvatinib is a very potent VEGF inhibitor, and we see a little more hypertension and proteinuria, which are both effects of targeted VEGF access. These need to be watched for. Both drugs can have GI toxicities like diarrhea, though sorafenib has a higher frequency of hand-foot skin reaction. These are all important differentiators, and for patients I’m seeing in clinic who are Child Pugh stage A who are appropriate candidates for systemic treatment, if they have bulkier tumors, or they need a response versus just stable disease, I’m tending to go with lenvatinib frontline instead of sorafenib.

Transcript Edited for Clarity
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