 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.

Videos

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 S. Finn, MD, UCLA Health

Articles

Safety of PD-L1 Inhibitors in mHCC

IMbrave150 Trial: Frontline Treatment of Advanced HCC

Initiation of Systemic Therapy for mHCC

Overview and Diagnosis of HCC