Case 2: Adverse Event Management and Dosing of Frontline TKIs


Panelists consider the adverse event profile of frontline TKI therapy in patients with metastatic HCC and review options for dosing and dose reduction.


Ghassan K. Abou-Alfa, MD: Now that we covered quite a bit of data, I would say that there will be some critical component that we have to look into with our colleagues about the toxicity profile and dissect it with more details in regard to how to monitor and prevent them. This is the panel of different adverse events that did occur on the REFLECT study. Dr Yarchoan, of what we saw here, hand-foot syndrome, which was always the big fear on sorafenib, is way more present in the more than grade 3, 11% for sorafenib versus only 3% for lenvatinib. Diarrhea is apparent as well, but to be fair, not of any critical concern for either of the 2 drugs. Hypertension is clearly more present in lenvatinib. Appetite loss is subtly more present in regard to lenvatinib, same as the weight loss. What are your thoughts? How do you translate that to your patients? Teach us how you do it.

Mark Yarchoan, MD: These are both multi-tyrosine kinase inhibitors. They have overlapping toxicity, but clearly, the rate of specific toxicities is different. As you said, the thing I would take home is that lenvatinib causes less hand-foot syndrome but a bit more hypertension. I think that, because the overall survival is equivalent between these agents, we need to consider all factors when weighing the decision of lenvatinib versus sorafenib, and adverse effects are one of the things that we talk about. For patients with truly refractory hypertension, this is something I would probably shy away from lenvatinib for. I’ll say that hand-foot syndrome is by far the most annoying adverse effect for patients in my experience and a reason that I think many of us have started using lenvatinib in our practice.

Ghassan K. Abou-Alfa, MD: I totally agree with you. For almost 15 years, the fear for patients was hand-foot syndrome with sorafenib, and it’s nice to see new drugs, among which is lenvatinib, with almost no concern for the hand-foot syndrome. You’re right, the hypertension can be an issue, but at least, thankfully, you can try to adjust medications for it. This applies the same for appetite loss and weight loss, to enhance them with appetite enhancers. Of course, the preventive measure—I don’t know which doctor did this case—but it’s quite impressive that the doctor did it preventively. To go to another point based on the adverse events, it appears, despite all of that, on the REFLECT trial patients stayed on the therapy, on the lenvatinib, longer than on the sorafenib. Discontinuation because of adverse events was similar between the two, but at the same time, the ability to get another line of therapy was almost the same between the two. This is reassuring to the components that we are bringing up.

A rather important component is the issue of going back to the appropriate management of the dosing for the 2 drugs. Here we have the same indication, unresectable HCC [hepatocellular carcinoma]. The formulation is 200-mg tablets times 2 to get the 400 mg BID twice a day for the sorafenib versus 4-mg tablets for 3 times for the lenvatinib. For lenvatinib, you have the weight issue for the patient, more or less than 60 kg. We don’t see much of a weight limitation in the United States in our population. It might apply more in Asia. There is no doubt that certain hypersensitivity to sorafenib does occur, rarely, but it is still something to keep an eye on. At the same time, there’s plenty of warning precautions, like for any drug. I will not spend time to dissect them, but as Dr Yarchoan brought up, there are hypertension components.

Dr Salem, as an outsider to the world of systemic therapy as an interventional radiologist—to be fair, I consider you to be an expert in systemic therapy as well with all your hands-on expertise in regard to HCC—is there anything that jumps to mind in regard to those 2 profiles? Is there anything that would make you say, I would want this or I like that, or anything you’d like to discuss?

Riad Salem, MD, MBA: Yes, the only thing I’ve seen, Ghassan, over the last several years, obviously is more use of lenvatinib. These are patients who we see in interventional radiology [IR], and many times some of them, because of confusion regarding how to manage their hypertension, are hypertensive in IR for whatever reason. That’s the link that I make from an IR perspective, where some of these patients have to have their hypertension managed locally, on site, at least controlled, for various procedures. Some patients are getting lines, they’re getting ports, or they’re getting other biopsies, as you might imagine. A good understanding of that is very important in an interventional radiology setting.

Ghassan K. Abou-Alfa, MD: That’s great to hear. I’m going to summarize that, and then I’m going to jump to Dr Singal for a question and see what further comments he has. I would like to summarize the REFLECT study. It’s rather interesting. It came out of left field, and was a very smart approach of looking into noninferiority for survival. The study was positive clinically and statistically, showing noninferiority, but with certain improvement, PFS [progression-free survival] was about 3 times higher for the lenvatinib compared to sorafenib. The adverse events, as we saw, did favor the lenvatinib compared to sorafenib, and of course, the ample experience and not necessarily a pleasant one with sorafenib came as a challenge for us. The drug was beneficial for every person, independent of the different demographics or ideologies, etc. With this said, I have one point for Dr Singal, and I would love to hear his thoughts. Regarding the issue of the weight, please teach us, from the hepatologic standpoint, what it means and why this is important.

Amit Singal, MD: I think, Ghassan, there are a couple of things. The first is, in terms of something that stands out when you take a look at the prescribing information and the labels, one of the things is sorafenib is recommend to be taken without food, whereas lenvatinib can be taken with or without food. From an ease perspective, sometimes this makes it easier for patients to take lenvatinib than sorafenib where you’re taking this outside of meals. This may not be a concern if this is the only medication, but as we have many of these patients being comorbid, taking multiple medications becomes tough. Patients have to say, “I need to take this one in the morning, this one in the afternoon, this one with food, this one without food.” That flexibility sometimes helps with lenvatinib compared to sorafenib because you don’t have to say with or without food.

The weight-based dosing is different with lenvatinib than sorafenib. I think it’s something we have to keep in mind, although, as you said, in the United States, the number of people I see who are less than 60 kg I can count on 1 hand, maybe 2 hands over the last 10 years. It’s unfortunately fairly uncommon, particularly here in Texas, where we have a large patient population in 2 ways, individually and the general size of the population. I think most of the patients we see in our practice are treated with 12 mg, not 8 mg, but the real idea here is to get somebody on a dose that is tolerable so you’re not overdosing them and then running into the AEs [adverse events]. That’s really the big thing here.

Ghassan K. Abou-Alfa, MD: That’s extremely helpful, Dr Singal, and I’m glad that you bring up this important perspective in regard to the food intake with the drug, which definitely is in favor of the lenvatinib as well.

Transcript edited for clarity.

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