Frontline Lenvatinib versus Sorafenib Treatment in Advanced HCC


Comprehensive insight on the selection and use of frontline tyrosine kinase inhibitors for patients with advanced hepatocellular carcinoma.


Tanios Bekaii-Saab, MD: Anthony, we keep talking about IO [immuno-oncology] and IO combinations. We still have other elements in our armamentarium, the TKIs [tyrosine kinase inhibitors] such as lenvatinib or sorafenib. Who are the patients where you would pick one of these TKIs as your first-line option?

Anthony El-Khoueiry, MD: The easy answer is that patients who have clear contraindications to immunotherapy, so active autoimmune disease; basically patients with a distant history of autoimmune disease, there’s more data indicating that they may be able to tolerate IO, it’s active autoimmune disease or disease that’s required recent immunosuppression. This would be the bulk of patients who would get a TKI. Otherwise, it would be a decision that someone doesn’t want to have intravenous therapy or doesn’t want to travel for treatment. It would be more of a convenience.

Tanios Bekaii-Saab, MD: What about a Child-Pugh B patient?

Anthony El-Khoueiry, MD: That’s a great question. Arndt brought that up earlier. The best data we have for a Child-Pugh B is single-arm data or registry data. We have a cohort of CheckMate-040 [NCT01658878] that looked at Child-Pugh B7 and [B]8 patients. These are select Child-Pugh B, not requiring active paracentesis, not actively encephalopathic, but B7 and B8. It showed that it’s feasible to give them nivolumab. The adverse effect profile was like Child-Pugh A, response rate approximately 12% so not very far off. The median OS [overall survival] was 7.6 almost 8 months. There was a signal for safety efficacy, and it was a single-arm study. We know from sorafenib that it can be used in Child-Pugh B mostly from the Gideon registry that had a large patient population of Child-Pugh B where you know you can dose it and give it safely. Child-Pugh B is a prognostic marker. We must understand that this is a competing cause of death, and we must know who to treat with decompensated liver disease. Not everybody should be treated because they may die of their liver cirrhosis, but for the “good Child-Pugh B,” there are two choices currently, sorafenib or single-agent PD1 based on the nivolumab data.

Tanios Bekaii-Saab, MD: Lenvatinib?

Arndt Vogel, MD: Maybe if I can add something. One point is the underlying liver disease, and as pointed out, in the past we have thought that sorafenib would specifically benefit patients with hepatitis C infection. This was sort of joint. The meta-analysis was very clear on that. If you look at the most recent phase 3 studies, sorafenib performed well in the non-viral group. It was not that the immunotherapy did far worse, it was more that the median overall survival with sorafenib was far better than expected, 17 months in the CheckMate-459 study [ NCT02576509], and in the IMbrave study [NCT03434379] it was around 17 months. Sorafenib did well. There were some real data from Italy, which specifically looked at patients with fatty liver disease, more than 1000 patients, excellent liver function. Specifically in the group with NAFLD [nonalcoholic fatty liver disease] median OS was 22 months compared with 15 months in those without fatty liver disease. It was a single-arm and retrospective study so it’s difficult to say whether it’s prognostic or predictive, but the TKI’s are not doing poorly in NAFLD patients and the hepatitis C patients we are treating today, which have received the IDs whether hepatitis C is cured; they behave differently, at least compared to sorafenib. This underlying liver disease is still something we need to observe. Personally, it’s not a reason for me not to use a combination. In the COSMIC-312 study, the hazard ratio was well in favor for the IO combination compared to sorafenib. For combinations, this is not an argument against the disease. One point that I might add is in real-word setting, and specifically when we are talking about Child-Pugh B, we should not only focus on albumin and bilirubin. What we are seeing are also patients with good liver function, but severe portal hypertension, which are at risk for encephalopathy or ascites. In our real-world data, we have observed that patients with ATEZO-BEV [atezolizumab plus bevacizumab] are at a slightly higher risk for hepatic decompensation with new onset of encephalopathy and ascites. When we talk about liver function, it was nice to just talk about IB and Child-Pugh , and bilirubin and albumin, but in real-world data, we also need to look at other points and this decompensation includes ascites and encephalopathy.

Tanios Bekaii-Saab, MD: Your choice of TKI?

Arndt Vogel, MD: Currently, it’s lenvatinib.

Tanios Bekaii-Saab, MD: Why is that?

Arndt Vogel, MD: Because the real-world data we have collected is compelling. In the REFLECT in[ph] group, we have observed a median OS of 15 months, which was even better than in the REFLECT study [NCT01761266]. This is what I see in the clinic, that these patients are doing good. For the past 10 to 11 years we have used sorafenib, so I think there was a time to change and try something new. Sorafenib might be an option in Child-Pugh B as you just pointed out, because we have more evidence. These patients might also be at risk of encephalopathy when we treat them with lenvatinib or retrospective data. In patients with contraindication against the checkpoint inhibitor, but good liver function, it’s lenvatinib. In the REFLECT study, all secondary endpoints were improved, PFS [progression-free survival], TDP response rate of 20%. We can also discuss the response rate by mRECIST 40% by RECIST 20%. Professor [Shoji] Kubo [, MD, Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Japan,] has a nice abstract on the prognostic impact of response and he has nicely shown that the question is, what should we look at, mRECIST or RECIST 1.1. 20 percent response by RECIST 1.1, median OS in these patients was 24 months, which is good. mRECIST, which included 40% of patients, median overall survival of 18%. So, we can discuss mRECIST or RECIST 1.1 but I think the data is compelling.

Tanios Bekaii-Saab, MD: For someone with good liver function, contraindication to IO, you’re going with lenvatinib if the liver function is somewhat borderline, and then perhaps sorafenib.

Transcript edited for clarity.

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