Amit Singal, MD

 This is very important to bring up, and another discussion that’s important in regard to later lines of therapy will come into play now that you’ve brought up the different choices. We’ll discuss this case, and I have a key element that I will discuss with our colleagues. This is a 63-year-old gentleman with a history of hepatitis C, chronic; his diagnosis started 8 years ago, no radiographic features of cirrhosis. It’s the same case we just spoke about. The patient has abdominal pain, performance status is good, mass in the liver of 2.7 cm, 3 satellite lesions. A biopsy confirmed HCC [hepatocellular carcinoma], unresectable. He had transarterial chemoembolization [TACE] 3 times, excellent response, got atezo [atezolizumab] and bev [bevacizumab], as we know. As the case continued, the patient who had all those therapies and got atezolizumab and bevacizumab, ultimately progressed. Now we have progression of the disease, and the question is what to do from there. Before I discuss some of the second-line therapies, I would like to ask Dr Yarchoan a very specific question. With atezolizumab and bevacizumab as first line, would you jump onto whatever the choice is in second-line therapy, or would you still consider lenvatinib after atezolizumab with bevacizumab?

 Great question. One of the challenges is with the new frontline options, we have very little data for what to do after bevacizumab with atezolizumab. It’s a bit of a tangent, but sometimes you do see these cases where you have oligoprogression after bevacizumab with atezolizumab. That’s not this case, but I think it’s worth mentioning. It used to be that we were very regimented. Patients with Barcelona Clinic Liver Cancer stage B got locoregional therapy [LRT]; advanced stage patients got systemic therapy. I think more and more, there’s a role for systemic therapy in intermediate stage disease, and more and more, I think there’s a role for locoregional therapies in advanced stage disease, particularly in the setting of oligoprogression. There’s more of a back and forth, and I don’t know if Dr Salem wants to say something about that. For patients like this who have new lesions, who have multifocal progression after bevacizumab with atezolizumab, I think many of us are reaching for a TKI [tyrosine kinase inhibitor] of some kind. I think it’s reasonable to use a first-line TKI like lenvatinib or sorafenib, or consideration of a traditional second-line TKI like cabozantinib. I think both are very reasonable options in this case.

 Thanks so much, Mark; you made 2 beautiful points. I will first address one with Dr Salem, and then I’ll carry on with the second one. Dr Salem, am I right when I meet a patient in the clinic and they ask me, “Can I go back to Dr Salem to get an embolization?” I always say, in HCC, everything remains on the table. Am I right?

 Yes, you’re absolutely right, Ghassan, and Mark brought up a great point, which is, yes, obviously with the LRTs, we think about the BCLCBs [Barcelona Clinic Liver Cancer stage B] and the advanced disease for systemic therapy. But more and more now, we are realizing that we should not function in a manner that is so regimented, and patients actually will fluctuate back and forth by stage. I do think that what Mark brings up is a very important point. There are many patients now, particularly with some of these therapies like lenvatinib and atezolizumab and bevacizumab, that give you very good responses, but for some reason at month 6, 9, 10, 12, 14, there’s only 1 small area that’s progressing. Rather than be regimented and change the entire therapy, you can think about a locoregional therapy. There’s a patient I just treated about 3 weeks ago who had massive bilobar metastatic disease, responded very well on systemic therapy, and had 1 small area that was clearly progressing on scans. We went in there and we radioembolized that small segment, and she stayed on her regimen. What we’re seeing is more options from a systemic standpoint, very well tolerated from a systemic standpoint, and again, because of the new locoregional therapies that give a good quality of life and are well tolerated, we can start to mix these things as part of clinical practice to make sure that we optimize all of the treatments for the patients.

 Absolutely, very well said. I’m very happy to see that I was right about assuring our patients that everything remains on the table. With this said, we’ll go back to the second point that Dr Yarchoan brought up in regard to the choices of therapy. These are the NCCN [National Comprehensive Cancer Network] guidelines. We have regorafenib, with required prior sorafenib exposure. We have cabozantinib, which ironically is the only drug that’s approved in second and third line; ramucirumab, with a requirement of AFP [alpha-fetoprotein] of over 400 ng/mL. I like what Dr Yarchoan mentioned; Mark, I agree with you that lenvatinib, sorafenib could still be remaining here. Dr Singal, when we used to meet in person at the meeting in Park City that happened every year with the transplant colleagues, we spoke about line-minus-1 therapy, ie, after atezolizumab and bevacizumab. We agree with Dr Yarchoan that you still consider a lenvatinib option, per se. Other recommended regimens are nivo/ipi [nivolumab and ipilimumab], we are still waiting for the final results, but it can be considered; pembro [pembrolizumab] is fully approved now; and nivolumab, as we discussed…with the FDA. I’m sure the NCCN guidelines will probably change at some point. And of course, there is the issue of the MSI [microsatellite instability]-high, but again, it’s extremely unlikely that we will address it in regard to HCC.

As we just heard from our colleagues, beyond second line we can consider still the therapies that were considered in first line, among which is lenvatinib. Here is a nice table of all the studies that occurred for regorafenib, cabozantinib, ramucirumab, nivolumab and ipilimumab, and pembrolizumab, plus placebo. All of those have either full approval, being regorafenib, cabozantinib, ramucirumab and pembrolizumab; and condition approval for nivolumab and ipilimumab. At least we have plenty of options in second-line therapy. You are right Mark, we’ve lived through this for a long while. It’s nice to see that after starting from nothing—20 years ago I used to tell patients to go home—look where we are now. These are incredible data that we should be all very proud of. I would say that discussions are appropriate to address the other therapies. I will ask it only as a challenging point, Dr Singal, is there any reason you can think of why, if a patient gets atezolizumab and bevacizumab, I would say no to lenvatinib and they should go, for example, to cabozantinib? Do you have any thoughts?

 I think, Ghassan, this is a data-free zone, so I don’t think I can say definitively that one is right and the other is wrong. I have to say, from our center, we use that T-minus-1 approach that you referenced, where we use sorafenib or lenvatinib after atezolizumab and bevacizumab, and then we save the prior second-line therapies now for the third line. I think one of the things we’re trying to do in our center, for example, with this large intrahepatic tumor burden, earlier recognition of TACE or TARE [transarterial radioembolization] failure, getting people onto first-line therapy so you can then go through second-line therapy, potentially third-line therapy. I know it’s a bit tangential to the choice here, but I think the choice is honestly less relevant than maximizing lines of therapy. That’s the big one, but I don’t think I would say one is right and one is wrong. It’s a discussion with your patient.

 I love the way you said it, which is maximizing lines of therapy. Wow, what a great discussion, really engaging. I would like to summarize. No. 1, I will start by reiterating what Dr Salem said, which is this is a multidisciplinary team at best, and the first item is something we are proud of. We hope you all, as you listen to us and hear from us, engage in the same way with your colleagues from the different disciplines about what’s best for your patients. We spoke about the importance of having the biopsy to confirm the diagnosis because of the pathologic necessity for that, added to what else we can decipher from these data for therapies.

No. 2, we spoke about local therapy, and Dr Salem beautifully referred to radioembolization and chemoembolization as 2 options, which of course, need the multidisciplinary team to bring them up. Then we spoke about the choices of therapy in first-line treatment. We spoke specifically about lenvatinib in detail, and we said it’s an appropriate therapy and it could be the only therapy sometimes, in case you have contraindications for the atezolizumab plus bevacizumab that we just spoke about. We held off on discussing further details of durvalumab and tremelimumab from the HIMALAYA study because, to be fair, it’s not approved yet. We spoke about the line-minus-1 in regard to pressing on from atezolizumab and bevacizumab to lenvatinib as an option, as Dr Yarchoan mentioned. I liked very much how Dr Singal wrapped it up by saying that with the second-line therapies, it’s a matter of how we can enhance further options of treatments so we can help enhance survival.

I would like to thank all of my dear colleagues for their thoughtful, great presentations and informative discussion. For our viewing audience, thank you for joining us for this 

® presentation. We hope today’s discussion was a valuable use of your time and that you acquired practical knowledge that can help you in your clinical practice. Thank you very much for your time.

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Expert panelists consider later-line treatment options for a patient with recurrent hepatocellular carcinoma. 

Case 4: Later Lines of Therapy for Patients With Recurrent HCC 

 Looking into the frontline therapies, maybe I’m little biased because I, on behalf of everybody including Dr Yarchoan, presented the HIMALAYA study, looking at a single dose of tremelimumab plus durvalumab versus sorafenib, looking for superiority, and also looking at durvalumab versus sorafenib looking for noninferiority. The multiple dosing of tremelimumab did not fare well. Patients did not do any better than with durvalumab single agent. There is this booster, jump starter effect of a dose of tremelimumab, 1 single dose, plus contribution of durvalumab. The data are here, but I of course would like to defer to Dr Yarchoan to discuss the data and give us his reflection on it.

 As someone who is relatively new to the field of HCC [hepatocellular carcinoma], I feel like I’ve come into this field at the best possible time, when we have so many new options. My hat goes off to people like Ghassan, who were treating this disease when really all we had was sorafenib. I think it’s great to have more options in the frontline setting. I think the appeal of this option is 2 things. The first one is that this is a truly non-VEGF option, so for patients at significant risk of bleeding, patients with recent surgery, recent strokes, variceal bleeding, it’s great to have a non-VEGF option, and one that actually beats sorafenib in terms of survival. I think the other feature of these data that stands out to me is just the durability of the responses. This is something we all expected based on the mechanism of action here with CTLA-4, but the 3-year survival of over 30% is a new benchmark in HCC and something we haven’t seen before with other therapies. This is an important first-line option for patients and something to think about for patients where you have time to see a response, for patients who can’t get VEGF therapy, and patients for which you really care about the 3-year survival.

 I couldn’t have said it better. Thanks so much, Mark, for your kind notes. You’re absolutely right; this is really changing the field altogether. But not every combination is a combination, because as much as we were excited about the HIMALAYA study’s positive outcome, the COSMIC-312 study, looking into cabozantinib plus atezolizumab versus sorafenib, did not deliver that well. The interim analysis did not show any statistical significance for overall survival. This is despite an improvement in PFS [progression-free survival]. The PFS story in regard to checkpoint inhibitors, as we’ve just mentioned, is questionable, but nonetheless, the survival is a key element. It’s enough that the final survival data were just reported barely over a month ago, and they were negative, leading to less interest and not pursuing further the cabozantinib plus atezolizumab.

This brings up an important question, which is, would it really matter what the combination is? It seems so. I will revise what we just spoke about, which is atezolizumab plus bevacizumab. We spoke about durvalumab plus tremelimumab. We can also talk about lenvatinib plus pembrolizumab, which is a study that’s still ongoing despite it having positive data in regard to the phase 2 study, which already is published in the 

, looking at this combination. The question I have for Dr Singal is, it seems it does matter what you’re combining therapies with, so hepatologically speaking, why does it matter?

 I would say from a hepatology perspective, obviously we want to see efficacy from these agents, but also safety and tolerability. I think to have these different treatment options, you can start to select this based on some of those other patient characteristics. For example, we already talked about if somebody has significant portal hypertension and a history of variceal bleeding, etc, you often are going to be less enthused about VEGF therapy. So atezolizumab and bevacizumab may not be possible, such as the case we discussed earlier. Now having something like durvalumab and tremelimumab would give you a non-VEGF option in that patient. By having all these different options with different combinations, you now have options that you may plug in for certain subgroups of patients. It’s a tough disease because it’s a disease within a disease, so you’re not only managing the HCC, but also the cirrhosis.

Comprehensive insight on several clinical trials analyzing frontline combination therapies for patients with unresectable hepatocellular carcinoma.

Case 3: Novel Frontline Combination Strategies for Unresectable HCC 

 Now that we covered quite a bit about lenvatinib, let’s look at the other options of treatment. One more case, a 63-year-old man this time, included hepatitis C about 8 years ago. At diagnosis no radiographic features suggestive of cirrhosis, a complaint to a gastroenterologist of abdominal pain, good performance status. He had a 2.7-cm liver lesion, 3 satellite lesions, confirmed HCC [hepatocellular carcinoma] by biopsy. It seems now we’re settling with the biopsy. The tumor was deemed unresectable, transarterial chemoembolization was performed 3 times, excellent response. But 6 months later there was multifocal disease in the abdominal wall, liver lesions, lung metastasis. He was still thankfully Child-Pugh A, BCLC [Barcelona Clinic Liver Cancer] [stage] C; weight is 80 kg, and AFP [alpha-fetoprotein] is very high at 24,000 ng/mL. This is a 63-year-old gentleman with hepatitis C, and at the same time, he had embolization multiple times after a confirmed diagnosis of HCC and now with multiple sites of disease and no concern for any bleeding, no varices, and no other contraindications. The therapies here are going to probably change, and I’ll again start with Dr Singal. In the first case we spoke about the concern for checkpoint inhibitors. Do you have any direct concern for checkpoint inhibitors here, and what would you recommend for therapy?

 Ghassan, this is a relatively straightforward case. The patient has hepatitis C, cirrhosis, compensated, doesn’t appear to have any autoimmune diseases, doesn’t appear to have any portal hypertension as far as we know from this case, no history of variceal bleeding, etc. I don’t see any contraindications from a checkpoint inhibitor perspective. He’s been treated for his hepatitis C, and he’s unlikely to have significant portal hypertension in this case. He still should undergo an upper endoscopy to confirm that, in my opinion, but assuming that does not show high risk of stigmata, this is a perfect patient for atezolizumab and bevacizumab.

 I love it. You could not have said it any better. I like what you stressed, the critical need for the endoscopy, and of course, if there are no varices, the atezolizumab and bevacizumab. Let‘s look into this. Yes, the patient did receive atezolizumab and bevacizumab, which makes total sense, and the treatment is ongoing. This is the Imbrave150 study, which is atezolizumab and bevacizumab versus sorafenib, looking at the superiority. The study tested for overall survival, absolutely positive. As we can see, the results were 19.2 months for the atezolizumab and bevacizumab versus sorafenib 13.4 months. It’s a tad different in regard to the PFS [progression-free survival], but I wouldn’t sweat too much over this because we’re now talking about checkpoint inhibitors. However, the study is positive. Dr Singal is right in regard to the option of treatment being atezolizumab and bevacizumab, and there is no doubt that the therapy is helpful. Compared to what Dr Yarchoan told us about the hands-on experience in regard to the quality of life, we see some improvement or some preservation of quality of life compared to sorafenib. Are you seeing this in your practice, Dr Yarchoan?

 Yes, it’s hard to understand how important this is. In oncology, we often have to balance clinical benefit with toxicity, and here we have an agent that not only improved survival, but also made patients feel better. That, for me, is the ultimate win. It’s something that I definitely have experienced in my clinic, and this is great. Although, on the flip side, I wish we were doing even better. Survival still lags many other tumor types, and it’s why I believe we need even better therapies.

 I like the way you gave a very nice objective analysis of that data, but nonetheless, when we take it within the context of what we’re talking about, it’s appropriately encouraging. This could be reflective of the ultimate response that we get, and I think here the data we’re showing from the IMbrave150 study shows the enhanced response for atezolizumab plus bevacizumab. The duration of response was also favorable, 18 months compared to 14 months for sorafenib. All is going in that direction that Dr Yarchoan brought up.

Dr Salem, I would like to bring in one other important component over here in regard to who those patients are who will benefit the most. These are data that you and I know and we spoke about, by Dominik Pfister, PhD, that suggested the patients with nonviral HCC, ironically, might not fare that well or better compared to the viral etiologies for HCC. Let’s take it 2 ways. From your perspective, as an interventional radiologist, do you ever care about the etiology when it comes to a radioembolization?And what are your thoughts on those data?

 Yes, we have looked at that, at least in the locoregional therapy space, and these types of analyses are hypothesis generating. You really can’t make that many conclusions from it. They are interesting, I’m sure they are generating other studies, but for us in the interventional radiology space, we look at the data in total, and we’ll discuss this with our hepatologist and our medical oncologist. We won’t really isolate and say, we will or won’t do this based on the etiology of your HCC. We will try to treat that patient individually. We’ll do the exact same thing irrespective of whether it is viral or nonviral etiology, even though there are some differences here. We’ll treat that patient the same. Now, I think some of the outcomes might be a little different, and some studies are ongoing, but it will not make any difference from the interventional radiology standpoint whether these subset analyses show that one group does better than the other.

 That’s very interesting and helpful. Dr Singal, as a pathologist, I would love to hear your analysis of those data, please.

 I think, Ghassan, it’s as Riad was saying. It’s interesting and hypothesis generating, but I think that the way these analyses were done, there is residual confounding between the nonviral and the viral etiologies. So I don’t think this means that we should change anything we do. If somebody is eligible for atezolizumab and bevacizumab for other reasons, I would not withhold the benefits of those drugs based on liver disease etiology. Once again, these are interesting studies, the basic science side of this was well done. The clinical aspects in terms of how this translates from mice to humans, I think, is much less clear. If somebody has NASH [nonalcoholic steatohepatitis] or alcohol-associated cirrhosis with large intrahepatic tumor burden or advanced stage HCC, we are still using immune checkpoint inhibitors. I don’t think that this changes management at this point, but we’ll have to see. I think further studies will need to be done, but it doesn’t change anything right now.

I’m very happy that all of us are seeing that these data are intriguing and bringing some perspectives, but at the same time, are not a determinant in regard to how we choose therapy. To our colleagues, as we are talking about atezolizumab and bevacizumab, which is a great choice, but as we just heard from Dr Singal and Dr Salem, please make sure you scope your patients. Don’t just go haphazardly because people can bleed on bevacizumab. In addition to that, as we are hearing the choice of therapy based on the checkpoint inhibitors, even though some data might suggest relatively less benefit, but still a benefit for the nonviral, it does not show data yet to decide to treat with one choice versus the other based on the risk factor. Everybody is still treated the same way.

In the setting of unresectable hepatocellular carcinoma, experts consider the role of frontline atezolizumab + bevacizumab given data from IMbrave150.

Case 3: A 63-Year-Old With Unresectable HCC Eligible for IO Therapy 

I’d like to look at some real-world data, and this is very intriguing. It’s showing that it’s reflective of a nice publication from barely few months ago. It shows that it wouldn’t matter who the patients are, you’ll benefit. However, independent of all of this, I bring up the Child-Pugh B story. Dr Yarchoan, would you have any reflection in regard to Child-Pugh B disease and lenvatinib? What are your thoughts, and how do you measure it or how do you handle it?

 The challenge is that all of our large phase 3 studies are restricted to Child-Pugh A disease, and so many of the patients we see in clinical practice are Child-Pugh B. It’s a shame that we don’t have more clinical data to guide decisions in this population. It’s a real challenge of treating this disease. I think, overall, for Child-Pugh B, this is a group of patients where, at least right now, many of us shy away from combinations like bevacizumab and atezolizumab due to lack of safety data. There was this analysis done of patients in the REFLECT study who started as out as Child-Pugh A but quickly became Child-Pugh B very early in the study. And in that group of patients, lenvatinib appeared to be still reasonably safe and well tolerated. That being said, I think we have more data for sorafenib in Child-Pugh A based on the GIDEON database and then also some data for anti–PD-1 in this group of patients, both retrospectively and prospectively. This is a challenging group of patients for sure.

I totally agree with you, and you have to remember that the Child-Pugh B is a transitional component. A B7 can be an A6, and A6 can be B7, but when comes to a rock solid B8 to B9, it’s different story. For the A6/B7, I would say yes, exactly as you nicely stated, you can have a bit of a maneuvering component that can help us one way or the other for the therapy.

A brief review of treatment options for patients with Child-Pugh B grade metastatic hepatocellular carcinoma.

Case 2: Treating Child-Pugh B Metastatic Hepatocellular Carcinoma

 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.

 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.

 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?

 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.

 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.

 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.

 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.

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

Case 2: Adverse Event Management and Dosing of Frontline TKIs 

 On the other hand, when it comes to the subgroup analyses—and this is where I would like to bring in Dr Salem—because of other components that might play a role and help us define if it matters whom we are treating, prior treatments, no prior treatments, extent of disease, etc, we see that the data shows that everybody benefited. Dr Salem, would you have expected or anticipated any different perspective here, or are you happy to see what you are seeing in the subsets?

 This is interesting. Obviously, when you look at subsets, they are, of course, hypothesis generating. They are interesting. The reality is in tumor board we look at them, we consider them, and that’s part of personalized decision-making. There was an effect pretty much across the entire spectrum of the patient population, and I think in the spirit of where we are these days, looking at the effect in the BCLC [Barcelona Clinic Liver Cancer] stage B patient population, it is particularly interesting. Is there a role for systemic therapy? Currently, a local regional therapy is the gold standard, so it just made it. The hazard ratio is 0.99 so it barely made it, but it appeared to have an effect on the BCLC stage B patient population. Now, more detail on who those Bs actually are, because as you can see from the new BCLC guidelines, there is a recognition that the BCLC stage B patient population is heterogeneous. It required further investigation. It is, in fact, as heterogeneous I think as some of the BCLC stage C patients, but what is the role of a systemic therapy? Clearly, as an interventional radiologist, I see that some BCLC stage Bs do well with a local therapy, and some do not. This is where the systemic therapy comes in and this provides us with a glimpse of the idea, let’s start investigating systemic therapy in this patient population. Is there a role and can we better define what that patient population is that will respond and do well with systemic therapy versus the one that should remain with a classic indication of a local regional therapy? That’s what we have here.

 I love what you said. I’m going to hold that thought because we’re going to come back to it. That promises a very good point that you bring in, in regard to the BCLC stage B and the systemic therapy. Independent of the prior therapy, independent of the different demographics being age, sex, region, performance status, body weight—which was a concern especially for 60 or less than 60 kilos—the benefit was, for both groups, independent of the AFP [α-fetoprotein] level, independent of the involvement of the vasculature and critically independent of the ideology. I know we’re tempted to think that some people will benefit more or less, but so far it has been the same. For the BCLC component, which I am finishing up in regard to what Dr Salem brought in, this is where I’m going to bring Dr Singal for the BCLC story. Amit, tell us about Dr Masatoshi Kudo, MD, PhD, who was the head of the REFLECT study [NCT01761266], in regard to the 7 criteria.

 Ghassan, I think you’re referencing his study where he took patients with larger intrahepatic tumor burden and did a propensity match analysis where he compared this between lenvatinib and local regional therapy, most commonly TACE [transarterial chemoembolization] in that study. Interestingly, those patients with larger intrahepatic tumor burden had better outcomes and better survival than patients who were treated with lenvatinib up front rather than local regional therapy upfront. When you take a look at the exploratory analysis of why he showed increased degradation in the liver score in those patients who were treated with local regional therapy compared to those patients who went down to upfront systemic therapy. This is a small propensity score and match analysis, retrospective in nature, risks of residual confounding, so it’s not the answer, per se, but it’s hypothesis generating and very interesting, and makes us think about if there are patients who are not BCLC stage C, not advanced stage, who actually have intrahepatic tumor burden liver localized disease, but should be treated with an upfront systemic therapy, particularly as we’ve seen advances in systemic therapy options and outcomes. As you and many know, there are now trials specifically evaluating this question of large intrahepatic tumor burden taking a look at randomization to systemic therapy versus upfront local regional therapy. I think we’re going to have more answers on this as we move forward, but I think the idea that Dr Kudo put forward in that propensity score match analysis is one of the big things that I think could change how we manage these patients moving forward.

 Thanks so much for reiterating what Dr Salem brought into the discussion. It’s quite fascinating and this is why we give credit to my dear colleagues. Dr Salem is insisting and impressing on all of us the multi­­spirit team approach where if a patient, as we just heard from Dr Singal, has a certain number of lesions in the liver, and at same time the size of the largest lesion if you add those 2 numbers—let’s say, for example, 4 lesions. Number 4 plus the largest lesion is 4 cm plus 4. Four plus 4 equals 8, it’s more than 7—this is where, ironically, the data has shown that patients can feel better with systemic therapy rather than with local therapy. I’m not implying that this should be happening, independently they are systematic, but it should be done within the context of the multispirit team approach that we are talking about. With this said, as we just summarized, sorafenib and lenvatinib showed noninferiority. Both show improvement to survival equally; No. 2 is PFS [progression-free survival], which was about 3 times higher for the Lenvatinib. At the same time, in the subgroup analysis, we see that lenvatinib faired very well for all of patients independent of their different variables or demographic components.

Now that we are into the era of second-line therapy, it will be nice to see, post study, what patients did. Understandably, for the patients who were on the lenvatinib arm, about a quarter of them did go to sorafenib because this was the only thing available at that time. For the sorafenib arm, because lenvatinib was not available, they went for some other form of therapy and some of them stayed on sorafenib which, by the way, is a practice that we’ve been practicing. At Memorial Sloan-Kettering, we started with the first study on sorafenib and, at the time, there was nothing else. We decided if there was no sorafenib when the short plan came out from the Barcelona group, we should keep patients on sorafenib because at least that maintains some control of the disease until better days. This is now evolving quite a bit. There was reported data that was presented, if I’m not mistaken, in January 2020 at GI [gastrointestinal] ASCO [American Society of Clinical Oncology] and it showed that the patients received sorafenib or lenvatinib on the REFLECT study. If you look at the survival after whatever they get as second-line therapy, it showed a critical improvement of outcome for lenvatinib, more than 26 months, which is the first we’ve seen as the highest, but of course within the context of the retrospective analysis nature of what we have seen.

Comprehensive discussion on the PFS subgroup data from REFLECT, which compared frontline lenvatinib and sorafenib therapy in metastatic HCC.

Amit Singal, MD | Authors

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