 Certainly, as we answer more questions, more questions are raised. As you said, Rich, we need more data. Speaking of more data, Riad, as you look at these systemic agents, you see that we have high-level evidence changing from the natural history of advanced liver cancer. Where do you see these drugs going in the future with how we manage patients?

 As you mentioned before, there are so many new advances over the last year, and these are all great things for patients. As you highlighted, though, it makes the decision-making in the advanced setting once you progress through the first line quite tricky. I would think, at some point, a refinement of the staging system might be in order, particularly now in the advanced setting.

Not only do we think that the BCLC -B stage needs to be refined—maybe there are certain Cs, the pattern that they progressed, the location of the disease, etc—but maybe there are things we can use to better identify which patient is going to respond to this type of treatment. It’s clear, based on the number of treatments, that a lot of patients are going to cross over from left to right to right to left. You’re getting great responses now, particularly with some of the I/O combinations and some of the LRT combinations, you have exceptional and spectacular responses.

We at our center have resected people who have advanced disease with metastatic disease that has been downstaged, and it has demonstrated such a good response that we re-present them and move things earlier. Now, all of a sudden, we resect them. It’s going to require a lot of rethinking as to the algorithm with which patients are treated. Combining these things is going to be very important. How that’s done, again, I don’t really know. Downstaging these patients to resection and transplantation is something that previously we would never think of, but now we’re seeing these great responses that make you think way outside the box and really represent what is true, individualized care. A patient responded so well, you’d never think of resection in this setting, and now you’re going to resect them.

 What about the combination of TACE (transarterial chemoembolization), or locoregional treatment, and these new systemic treatments?

 That’s the natural way to think about things. We know that locoregional therapies have a limited benefit. They’re going to progress anywhere between 6 and 15 to 18 months, depending on the study that you look at, which means they’re going to get something else. What that something else is, again, I leave that up to you guys in terms of best selection in the advanced setting.

The natural tendency and the academic and intellectual curiosity is: How best can I benefit from both things? How can I do a really strong cytotoxic therapy and use something that’s cytostatic and get a long TTP, a long PFS, and prolong the duration of response? The natural tendency is to figure out a way to mix these 2 things because I want my BCLC-B patients not to live 25 to 26 months; I want them to live 50 to 70 months. That’s what I aspire to. The curious thing here is how we can combine them in the proper patient in the earlier setting.

 There are a lot of exciting studies looking at all the combinations we touched on today, or most of them, in combination with surgery or ablation as true adjuvant studies, in combination, or to support locoregional studies. It’s very important that we refer our fit patients for clinical studies even if they’re candidates for standard of care. The only way we’ll continue to move forward is with research. This has been an excellent discussion. I’d like to thank my colleagues for joining me today. We hope you found the information to be valuable to your clinical practice, and we welcome your feedback in what we covered here today. Thank you all for watching this 

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Future Directions for mHCC

 We have atezolizumab and bevacizumab moving in the front-line setting. Potentially, these other combinations might be approved later. However, this leaves us with a high-level data gap, meaning the progress made with these new regimens gives us a question of what to do with sequencing the drugs that were approved after sorafenib. A patient theoretically gets atezolizumab/bevacizumab in the front line. Where do we go next, Amit? They progress. How do we think about this?

 Rich, you pointed out one of the key questions. One of the key limitations here is that the second-line trial was previously done after sorafenib, whether that’s sorafenib intolerance and progression or just sorafenib progression. We have regorafenib, cabozantinib, ramucirumab; all those second-line trials were done after sorafenib. We don’t really know what to do after failure of atezo/bev. I’ve heard from 2 main camps. There’s the T1 camp, where you basically go atezo/bev, then you have sorafenib and lenvatinib, and then you continue to use all the other agents as third line, so you just shift everything down. There are others who think that you basically put atezo/bev in the front line, and then you have a big box that has all your other agents, whether they were first line or second line previously. I don’t think we know the answer.

There is rationale to use some of these other agents after atezo/bev, so we know that bevacizumab hits the VEGF pathway. These TKIs (tyrone kinase inhibitors) hit other pathways that are beyond VEGF, whether that’s RAF1, FGF, c-MET, or AXL, you’re hitting higher up and are going to hit more pathways. You may actually have some disease stability or some response in some patients who progress on atezo/bev. Personally, I think that there’s little data or rationale to use single-agent I/O after failure of atezo/bev. Using the TKIs after failure of atezo/bev does make sense. In terms of the best way to do this, I don’t think any of us know.

 You bring up some interesting points. CheckMate459, which compared sorafenib to nivolumab, was a statistically negative study. Although, if we look at the survival in the nivolumab arm, it was over 16 months. Rich, for a patient who gets started on atezo/bev and doesn’t tolerate it and/or has proteinuria that can’t be managed or hypertension, do you see a role for offering that patient single-agent I/O?

 Single-agent I/O… even in my practice there are few cases where you may use this. One situation, as you mentioned, is that if the patient cannot tolerate the VEGF drug for many reasons—bleeding, proteinuria caused by it, hypertension caused by it—that’s something where we would consider using NIVO as a single agent. For patients with a borderline performance status, it may be that you don’t think intolerance to combination or TKI of the adverse effect.

As you know, the benefit of a single-agent checkpoint inhibitor, even though it doesn’t work for everybody, is that response rate seems to be 15% to 20% and is very well tolerated. That’s a key advantage of single-agent nivolumab. The bulk of the patients will probably get atezo/bev in patients who are Child-Pugh A, who are fit. However, if there’s a contraindication to combination or TKI—such as bleeding, if they have a history of bleeding, variceal bleeding—single-agent nivolumab may have some role in certain cases. Those are a couple of situations I would consider using a single agent.

 The thing that’s attractive about I/O, even before these positive phase 3 data with IMbrave150, was that if you respond, responses are very significant and long lasting. We don’t have a biomarker. We can’t select those patients based on a biomarker or a clinical parameter, or who will get the most benefit. There is an attractive clinical benefit that we see when patients have a good response. For patients who progress on I/O, Amit, Rich, Riad, are any of you comfortable giving an I/O combination after atezo/bev, eg, ipilimumab/nivolumab Is there a reason to think that ipi/nivo might work after atezo/bev? Rich ...from any of the other datasets?

 In non-GI kidney cancer, there are some data that if you fail an I/O, you can continue I/O and put in some TKI or other agents that could possibly resensitize. Once again, it’s not in HCC (hepatocellular carcinoma) data, but in other non-GI tumor types, there are some data that you could do that. Once again, I would like to see more data before I start doing that.

 Yes, there’s possibly a rationale that if you fail I/O first line with bevacizumab, you could potentially continue I/O and change the partners with a TKI or maybe another I/O to see if it works. That’s a trial that’s in the works to see if there’s any activity. I would like to see more data before I do it in my practice.

 Rich, as you start to see these other doublets that get evaluated, this is going to be more relevant. Do we use those in sequence, or do we choose one and then go to TKI? I’m sure that’s where you were going with this, but that’s where it’s going to be interesting to see what we do.

mHCC: Influence of PD-L1 Inhibitors on Second-Line Therapy

 The durvalumab/tremelimumab combination is being evaluated in the HIMALAYA study versus sorafenib, and since the study completed accrual, we’re waiting for the efficacy readout. At the same time, as I mentioned a few minutes ago, nivolumab and ipilimumab got accelerated approval in second line, based on 1 of the arms of the ever-expanding CheckMate040 study, which was a phase 1b/2 study. There, response rates were around 30% plus or minus, but in that study, 50% of patients needed steroids to manage their adverse events. Needless to say, it appears to be very active, and that regimen is in a front-line study, the CheckMate 9DW versus frontline TKI (tyrosine kinase inhibitor). There are other things going on as well, other combinations, like lenvatinib and pembrolizumab. That has very provocative data. There was an update at ASCO. Rich, did you see that data presented by Andy Zhu?

 Dr Zhu presented data. This was a combination of a TKI plus a PD-1, and the LEAP-002 study was presented. It had about 100 patients in this study. One thing you notice was that the response rate seemed to be a little higher than the typical combination of I/O–I/O. It was hovering around close to 40%. The median overall survival was hovering around 22 months. There’s a rationale for combining TKIs and I/O. The fact that a TKI will change the microenvironment of the tumor and allowing the immune system to kick in allows the I/Os to work better.

Based on the data that was seen at ASCO, the combination of TKI and I/O could be another combination that’s in the works. There is a phase 3 study going on right now that is comparing the combination of lenvatinib-pembrolizumab versus lenvatinib alone. From what the data suggest, we’re expecting it to be positive, but we have to wait for the final numbers to come out. This will add another weapon that we could use on these patients. atezolizumab/bevacizumab was approved so far. As you mentioned, Rich, there are a lot of front-line combination studies that are going on right now, and we’re waiting for the results. Maybe by next year, there will be 2 other combinations approved for first line.

 That would be a good problem to have for our patients. The more options available, the better outcomes will be. Again, pembrolizumab and lenvatinib was evaluated in the LEAP-002 study, which, like HIMALAYA, has completed accrual; we’re waiting for results. That regimen got a breakthrough therapy designation from the FDA. As we combine things, we generally start to see more adverse effects. Again, with the pembrolizumab/lenvatinib dataset, we see adverse effects for both, similar to IMbrave150, where we don’t tend to see synergy with the adverse effect profile of these 2 combinations.

At the same time, cabozantinib is approved in second line and is being evaluated with atezolizumab in a phase 3 study, the COSMIC-312 study. At this point, we don’t have a lot of early phase data to evaluate that specific combination. At ASCO, we saw some data with a new TKI, donafenib. This was studied first with sorafenib, mostly in China. Rich, given that this is a drug we’re not familiar with in the United States, can you comment about that dataset?

 The drug called donafenib is a TKI that’s molecularly very similar to sorafenib and regorafenib. It is a drug that blocks the VEGF and the RAF1 pathways and seems to be more potent than sorafenib. This was a trial done in China. The trial was a phase 2/3, nonsuperiority, randomized study comparing donafenib and sorafenib, and the primary endpoint of the study was overall survival. This drug showed there was a benefit of overall survival of close to 2 months, with 10 to 12 months favoring the arm of donafenib over sorafenib. There are 2 messages to take away from the trial. One is that this is the first TKI that has shown OS (overall survival) benefit of sorafenib. As you mentioned, lenvatinib was a noninferior study, so that’s important.

The second thing we must point out is that, because it was done in China with the bulk of the patients, 80% of the patients in both arms had hepatitis B. Why is that important? We know that sorafenib works much better in patients with hepatitis C. That has been shown. Therefore, because the trial was done mostly in China with mostly hepatitis B patients, the efficacy of sorafenib is probably a little inferior than some of the other phase 3 studies we’ve seen. Maybe that has something to do with it. Regardless, this is another TKI that has been studied in the first-line setting that has shown OS benefit...sorafenib, so that’s the significance. Unfortunately, this trial was done in China, so that drug will not be available in the United States. Maybe in the future it may come out with a combination in other studies.

 It reflects the global interest in this disease, given that it’s one of the leading causes of death worldwide. The incidence continues to rise.

ASCO 2020 Data for Treatment of Advanced HCC

 In the last 2 years, we’ve seen an incredible amount of approvals in liver cancer. In front line, we initially had just sorafenib, and then lenvatinib was approved; in late May, ATEZO (atezolizumab)/BEV (bevacizumab) was approved. In second line, we’ve had approval for regorafenib; from a phase 3 study, cabozantinib was approved in second line based on phase 3 data, both those studies versus placebo. We have phase 3 data with ramucirumab, the VEGF (vascular endothelial growth factor) receptor monoclonal antibody for patients who have an elevated AFP (α-fetoprotein), and that study was versus placebo. Three approved agents after sorafenib in the second-line setting.

Based on accelerated approval, we have both pembrolizumab and nivolumab approved for second line. Recently, we saw nivolumab and ipilimumab approved for second line based on accelerated and approval mechanisms. That’s an incredible amount of new options for us to use for our patients, and I think that will eventually lead to improved survival, even beyond what we’re seeing in recent datasets. With all that data in the past, there’s also a huge amount of data coming up in the future. At ASCO (American Society of Clinical Oncology annual meeting), we saw some very interesting updated data on the combination of CTLA4 (cytotoxic T-lymphocyte-associated protein 4) and PD-L1 (programmed death-ligand 1) inhibition with tremelimumab and durvalumab. Rich, can you walk us through that dataset, presented by Katie Kelley?

 Sure. As you mentioned, this was a trial, and it actually had 4 arms. One is a combination of using 2 different doses of DURVA and TREME, 1 using high dose of CTLA4, and the other 2 arms are of a single agent of activity of TREME alone and DURVA alone. The winner in this sort of pick-the-winner kind of trial was a high dose of TREME with a standard dose of DURVA, with response rate up to 28%. It’s interesting that the problem with combining PD-1 (programmed cell death protein 1) and PD-L1 with CTLA4 is the toxicity. We know that, as a single agent with either PD-1 or PD-L1, the response rate seems to be hovering around 15% to 20%. When you add in another I/O (immuno-oncology), such as a CTLA4, the efficacy seems to be a bit better, but at what cost? That was a concern, especially if you use a high dose of CTLA4.

This trial showed that the winner was a high dose of CTLA4 with TREME. This was exact response that we saw when you combined (ipilimumab) and nivolumab in CheckMate040 study. In a similar study, they also used a different dose and scheduling of the combination. In the winner of that study, the response rate seems to be very similar in all 3 arms. The one that had the longest OS (overall survival) benefit was the combination of high dose IPI with a standard dose of (nivolumab), the winner. For whatever it’s worth, there are 2 studies telling us that if you combine I/O to I/O, including PD-L1 and PD-1 plus CTLA4, the higher dose of CTLA4 seems to benefit the most when you combine, despite the toxicity, which is a concern.

ASCO 2020: HIMALAYA Trial for Advanced HCC

 Amit, is every patient going to get ATEZO (atezolizumab)/BEV (bevacizumab)? I don’t think everybody is going to fit that profile, so there’s probably still a role for the TKIs (tyrosine kinase inhibitor) in the front line. Can you talk about that, how you choose which TKI, and who might not be the great patient for ATEZO/BEV in your opinion?

 The IMBRAVE150 trial, as Richard mentioned, is a game changer and an exciting time for systemic therapy. All we have right now is the registration trial, which means that we have data in Child-Pugh A patients with a platelet count greater than 75,000 and who have an EGD (esophagogastroduodenoscopy) within 6 months, control of their varices, and no history of recent variceal bleeding. We don’t have safety data to extend that out to other patients.

Some of the “definite patient populations” that you would consider TKI-based therapy for are those patients where we don’t have data showing safety of ATEZO/BEV, i.e., patients with more advanced thrombocytopenia; patients with more advanced liver dysfunction; potentially Child-Pugh B7 or B8 patients; or patients with large varices or recent variceal bleed. These are patients in whom we would consider other therapies.

When we think of therapies that have data for Child-Pugh B, we think of 2 main agents. We think of sorafenib, where we have post-marketing data with GIDEON, and then we think of nivolumab, where we have a small amount of data that came out of CheckMate040  showing safety in Child-Pugh B patients. In that subgroup, you can consider 1 of those 2 agents.

There may be other patients who choose to get TKI-based therapy for other reasons. You want to say they don’t want fusions, etc, and that they want to be on oral therapy at home. In these patient subgroups, I think we’re really left with a choice of sorafenib versus lenvatinib in terms of the front line setting. Rich, you already mentioned the REFLECT trial, which compared sorafenib versus lenvatinib and showed noninferior differences in survival, as well as significant benefits in terms of secondary endpoints, including overall response rates and time to progression.

Overall, in terms of efficacy, you know the 2 are relatively similar, although, in some patients, you may want to get some benefit in terms of the response rates. In terms of safety, you see that the proportion of people who have an adverse event (AE) is similar between the 2 drugs, but the AE profile has some differences. With sorafenib, we see higher rates of hand-foot skin reaction. With lenvatinib, we see higher rates of anorexia, as well as hypertension and proteinuria.

For select patients, the way that I do it is I think through the AE profile where there may be patients who really are averse to that hand-foot skin reaction, or patients who are averse to having high blood pressure or proteinuria. I use the AE profile. Once again, there may be patients where you really want to get that objective response rate as the difference between the 2 TKI agents.

Role of VEGF TKIs for Treatment of HCC

 Can you talk about toxicity profile? We have 2 intravenous drugs given once every 3 weeks versus sorafenib. There were some very interesting patient-reported outcome and toxicity data presented by Peter Galle at ASCO GI (American Society of Clinical Oncology annual Gastrointestinal Cancers Symposium) earlier in the year.

 First, let’s go over the toxicity profile. In this study, there were no new or unexpected toxicities—effects we see in both arms. It is what we expected. If you look at all grade 3 to 4 toxicity events in both arms, they were about the same. They was slightly more hypertension in the combination arms. As expected, there was more of an issue with hand-foot-skin reaction with the sorafenib arm. It seems like the dose interruption, or any kind of a dose reduction of treatment, was much higher in the arm of sorafenib.

One other thing they looked at is the patient-reported outcome, which is now recognized as the important endpoint of cancer. In this study, they also looked at those data with 2 questionnaires, and they found out a combination of ATEZO (atezolizumab) plus BEV (bevacizumab) delayed the decline in quality of life compared with the study arm of sorafenib. It was comparing 10 months with 4 months.

Not only does the combination really improve the possible overall survival of PFS (progression-free survival) and response rate, but it’s also able to maintain the quality of life with a combination, which is very important when you treat patients.

 To have great efficacy data is one thing, but to have this favorable adverse-effect profile and PRO (patient-reported outcome) data is very supportive to making this a frontline go-to regimen. As you highlighted, not everybody will be a candidate for this. One of the issues in liver cancers is that all our phase 3 studies, regardless of stage, have focused on Child-Pugh A patients—patients well compensated with their disease—and that is largely because that’s where we can show an improvement in survival versus patients who are very decompensated and might succumb to their liver failure before cancer-related death.

Things are changing because there are patients who have decompensated liver disease that is maybe driven by the size of their tumor and their tumor burden. This is something we’re going to have to explore moving forward: patients who have large tumor burden, now that we can get responses—and we’ll talk about some of the newer data with upcoming combinations—where we’re seeing consistent responses in the 30% range, plus or minus, that are really benefiting patients and making them feel better. The dataset in Child-Pugh B need to be explored further. Safety is very important in that group.

The other issue that has come up with our patients of underlying liver disease, underlying hepatitis, has been the issue of infection. Amit, as a hepatologist, should we be concerned about treating someone who has hepatitis with these new regimens?

 When we think of hepatitis, there are really 2 types of hepatitis that are most common in the setting of HCC (hepatocellular carcinoma). We think of chronic hepatitis B and chronic hepatitis C. In terms of most of the studies, there is required antiviral therapy and control of hepatitis B. That is standard of care for any agency patient undergoing systemic therapy, particularly because most of these patients have underlying cirrhosis.

In contrast, hepatitis C typically does not need to be treated prior to starting systemic therapy. There are all the data with I/O (immuno-oncology) therapies, as well as TKI (tyrosine kinase inhibitor) therapies, to show that it’s very safe to treat people with active viremia.

Rich, one of the interesting questions that comes up is that as we’ve started to see HCC-related survival improve and survival extend, the question is: Should you consider hepatitis C treatment to reduce the risk of liver-related mortality? We don’t know the answer to that, so it’s not a necessity. You will see potential data come out in terms of evaluating that latter question. Could there be benefit to treating hepatitis C in these patients because of the marked transformation of the systemic therapy landscape?

 It’s an important concept because autoimmune hepatitis has been a concern with the PD-1, PD-L1 inhibitors. In reality, that doesn’t seem to be more of an issue in the liver cancer population than others as far as this incident.

Safety of PD-L1 Inhibitors in mHCC

 Rich, you’re a medical oncologist at Moffitt Cancer Center, so you’re a great person to comment on some of the new data in liver cancer. I’ve been very blessed and fortunate to be involved with the IMbrave150 study. Could you go over some of that data and its impact in the past month since its approval?

 The treatment of advanced HCC (hepatocellular carcinoma) for medical oncologists have come a long way. As you know, many years ago, the only drug that was available for the TKI (tyrosine kinase inhibitor) was sorafenib. Since then, we’ve made some progress with lenvatinib. Recently, you were part of the IMbrave150, a large phase 3 study comparing ATEZO (atezolizumab) plus bevacizumab with sorafenib as standard of care.

The rationale is that single checkpoint inhibitors, such as nivolumab or Keytruda (pembrolizumab), they have a single-agent activity as well, anywhere from 20% to 50% as single agent, even though the phase 3 data never really panned out. You may recall that, in the past, bevacizumab also has been studied as a single agent as well, with the response rate hovering for a multi-phase 2 study around 10% to 12%. The rationale for combining bevacizumab is that you actually reduce the VEGF immunosuppression, and, thus, allow promoting of the T-cell infiltration to the tumor. Basically, change the microenvironment for possible immunotherapy to work better.

The IMbrave150 was a randomized phase 3 study, 2-to-1 randomization, comparing the study arm, which was ATEZO (atezolizumab) plus bevacizumab versus sorafenib. It had a co-primary endpoint with progression-free survival and overall survival. The outcome was very positive. There was not only improvement in response rate but the combination, which hovered a little over 30%, and there was improvement in PFS (progression-free survival). A median OS (overall survival) the last time it was presented was not reached in the combination arm compared with sorafenib. This was one of the first trials out there in the first-line setting that showed a benefit over a TKI of sorafenib.

Based on these data, I think the NCCN (National Comprehensive Cancer Network) changed its first-line guidelines to include the combination of ATEZO (atezolizumab) plus BEV (bevacizumab). Based on the trial, it is superior to sorafenib. Therefore, now in our practice and in other institutions as well, this is the combination of a choice in a patient who’s the right fit. When I say ‘right fit,’ these are patients with Child-Pugh A who do not have any history or a variceal bleeding history. The key point here is that, in the study that we participate in as well, all the patients must have an EGD (esophagogastroduodenoscopy) done and have the varices banded before they went on to the study, which we don’t typically do. In the right patient population, the combination of ATEZO (atezolizumab) plus BEV (bevacizumab) is the new standard treatment for advanced HCC.

 This is really a hallmark study in that it’s the first time sorafenib has been beat. You alluded to the data from the REFLECT study, which was lenvatinib versus sorafenib, a positive study but positive for noninferiority. The overall survival endpoints were not statistically significant in that study, but lenvatinib did improve PFS and response rates.

IMbrave150, though, takes that to a different level; we have response rates now of 27%, and the median duration hasn’t been reached. Survival has a hazard ratio of 0.58 versus an active control, which no study today has, but it’s not because of lack of trying. No study today has shown that survival data, as well as PFS; hazard ratios are 0.59.

IMbrave150 Trial: Frontline Treatment of Advanced HCC

 Riad, you participate in a lot of tumor boards, and you’re recognized around the world as an intervention radiologist. Can you talk us through the role of locoregional therapies for intermediate stage liver cancer, or those that are multifocal—confined to the liver, not invading the blood vessels?

 You heard Amit talking about the BCLC (Barcelona Clinic Liver Cancer) staging system, and that’s something we incorporate in our tumor board. With respect to BCLC stage B specifically, one of the recommendations from the BCLC is that intermediate stage disease is treated by chemoembolization. Radioembolization is a close competitor, and it’s based on studies from 2002, showing an improvement in survival when compared with best supportive care.

My role as an interventional radiologist is to make sure we can deliver this type of treatment in a safe manner using selective injections and proper patient selection—making sure we follow patients’ imaging and liver functions, as well as making sure patients can benefit from all available treatment options. One of the things that we have traditionally been limited by is that we have locoregional therapies for BCLC stage B and few treatments after that.

Now, with the advent of positive randomized clinical trials with better survival, we have the obligation to make sure that when we apply locoregional therapy, we do it in a careful manner. We review them at MDT (multidisciplinary tumor board), and we carefully make sure that we’re able to transition the patient to another treatment option from which the patient will potentially benefit in overall survival based on all the data we’ll be talking about today.

 You bring up some important points. You know, some patients with intermediate stage disease may still be curable? That’s the importance of being seen at a large center, often a transplant center, for an opinion. Even though these patients might not stay there, the cure for transplants are a moving target. Some patients with intermediate disease are amenable to being downstaged as locoregional treatment, whether radioembolization or chemoembolization—things I generally defer to my interventional radiologist to choose. Then there’s a group of patients; they’ll probably be intermediate stage disease, and locoregional treatment is their definitive treatment.

We know patients will move between stages. Maybe they’ll start intermediate and, over time, if they’re not one of those curable patients, they might become advanced, Barcelona stage C. They might even stay Barcelona stage B but max out on what you can do as an interventional radiologist. Can you talk about those 2 scenarios, that group that is definitive Barcelona stage B, and the different ways they might progress?

 There’s a wide range of patient presentation in BCLC stage B, and that’s one of the areas of controversy and discussion, that the BCLC stage B stage should probably be subcategorized even further. There are indeed those patients that are early stage B that get some form of locoregional therapy, and they start to progress. Those patients are still technically BCLC stage B but are failing locoregional therapy, and those patients should be transitioned to systemic therapy.

There’s another group of patients, on the other spectrum of the BCLC stage B, the advanced stage Bs as we call them, who clearly have multifocal bilobar disease when applying a locoregional therapy using the principles we all agree to: selective injection, careful injection, not treating the entire lobe or the liver at the same time. That is something we believe in and we’ve observed. Many of us in the universal radiology space believe there are those Bs that are best treated using systemic therapy. That’s an area of interest for future research. Again, they’re still technically Bs but are probably best served by some form of systemic therapy.

 We have the good fortune of having experts on the line. Amit, in the context of an MDT (multi-drug therapy), how do you guys decide on these issues about refractory to TACE (transarterial chemoembolization)?

 Rich, you and Riad bring up important points here, that not all stage Bs are created equal, and not all stage Bs are treated the same. As we had mentioned, you have these early stage Bs that can be adequately and aggressively treated, and those patients can be downstaged to transplant. That is a critical point because we have to remember that surgical therapies, resection or transplant, still are for the best long-term survival. This is the way patients can survive 5, 10, 20 years. That is a very critical thing for us to get patients to when possible. I’m sure this is something with the evolving landscape as a systemic space. We’re getting to see people who go from that advanced-stage group who can actually be downstaged all the way to their early stage and can even be considered for these surgical therapies.

As we had mentioned, you are going to see people who stage shift to the right, ie, going from locoregional to advanced stage. These decisions are best made in a group where you have all those disciplines coming together, looking at the imaging together, and actually talking about what the best therapy is to give at each individual state, at each individual timepoint—not only 1 timepoint but throughout the timepoints as patients progress along that path.

The important thing with HCC (hepatocellular carcinoma) is that this isn’t just a feel-good concept. This is a concept supported by data showing that appropriate treatment is given, you give more curative therapies, and survival is prolonged in the setting of a multidisciplinary program. This should be considered the standard of care for HCC in the United States.

 That’s a good segue into a lot of the advances we’re seeing coming about in the liver cancer space. For those patients who are not curable, there are some things we can generally agree on: Patients who have extrahepatic spread; patients, as Riad described, who have bilobar disease that’s multifocal; large tumors with symptoms; and patients who typically have macrovascular invasion on imaging. You know, you do a scan, and they have invasion to the main portal vein or branch thereof; those patients are unlikely to be curable. Those patients have historically been included in clinical trials with systemic treatment. Look at phase 3 data. All of them have about 20% of patients who are still at Barcelona stage B but have progressed on locoregional treatments or may not have been a candidate upfront.

Initiation of Systemic Therapy for mHCC

®presentation. We’re going to spend the next 45 minutes on recent advances in frontline therapy for advanced liver cancer. I’m your host, Dr Richard Finn, from the Geffen School of Medicine at UCLA in Los Angeles, California. Today I’m joined by 3 of my colleagues who are renowned experts in the treatment of liver cancer: Dr Richard Kim from the Moffitt Cancer Center in Tampa, Florida; Dr Riad Salem from Northwestern University Feinberg School of Medicine in Chicago, Illinois; and Dr Amit Singal from UC Southwestern Medical Center in Dallas, Texas. Let’s get started.

There have been a lot of interesting data in the liver cancer space over the past few years, even in the past few weeks. Amit, liver cancer is a very complicated disease; before we get into all the recent data, as a hepatologist, will you give us some background about liver cancer?

 Rich, as you know, HCC (hepatocellular carcinoma) is very common, particularly when you consider this as a global problem. It’s the fourth leading cause of cancer-related death worldwide. One of the interesting things about HCC is that it typically happens in the setting of chronic liver disease. Over 90% of these occur in the setting of psoriasis, and this sets up a couple of singularities when you’re treating this disease. The first is that, given the differential blood supply to the tumor in the setting of a cirrhotic liver, we’re able to diagnose this oftentimes by imaging alone.

In that clinical context of having someone with psoriasis, or chronic hepatitis B, in the setting of having a lesion that has arterial enhancement and delayed washout, you can actually call that HCC with 95% to 97% certainty, thereby precluding the need to do a biopsy for diagnosis. The second thing is that when we consider treatment options, we can’t just consider how big the tumor is or how much tumor burden there is; you also have to consider the background of liver dysfunction. It’s important that we work as a multidisciplinary team—including hepatologists, interventional radiologists, and medical oncologists—and really consider the broader clinical context of all these factors when we’re thinking about treatment options.

 Those are some very interesting points. One, we don’t need a biopsy to make a diagnosis. That’s unusual for most cancers we treat. When we talk about imaging, we’re talking about a triple-phase, dynamic CT (computed tomography) scan, or MRI (magnetic resonance imaging). Is there a role for PET (positron emission tomography) in liver cancer?

 PET scans, as you’re implying, are used for many cancers in terms of staging. For HCC, we find that it is not very FDG (fludeoxyglucose F 18) avid, so the sensitivity of PET for HCC is actually low. It’s not built into the routine staging protocol for HCC lesions.

 You mentioned the word staging. Riad, I’m going to bring you into the conversation because, as an interventional and diagnostic radiologist, you play a pivotal role in staging. Amit, we don’t always consider the radiographic staging, or what I call anatomic staging, but also physiological state. That’s where the Barcelona criteria comes in, BCLC. Can you give us a brief overview of that?

 The Barcelona Clinic Liver Cancer staging system, or the BCLC, incorporates 3 different factors. It incorporates the tumor burden, the degree of liver dysfunction, and the patient performance status, or ECOG performance status. Based on these 3 factors, we’re able to stage people into different stages, ranging from: zero (0), which is very early stage; to ‘A’, early stage; ‘B’, intermediate stage; ‘C’, advanced stage; and then ‘D’, which is terminal stage.

One of the unique things about the BCLC is that it actually gives you treatment recommendations: It’s associated with a treatment allocation system as a starting point, with curative therapies traditionally reserved for those patients at their earliest stages; locoregional therapies, such as chemoembolization or radioembolization, largely delivered to patients in the intermediate stage; and systemic therapies, historically largely given to patients in the advanced stage.

 This is actually a curable disease when found early in patients, triaged to resection, or even liver transplant, but most patients aren’t going to be candidates for that.

Richard Kim, MD, Moffitt Cancer Center

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