 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.

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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.

Overview and Diagnosis of HCC

This has been an amazing discussion with an amazing group of colleagues. Thank you all for participating. Maybe we can leave the audience with a final thought. I’ll start with you, Dr Bekaii-Saab.

Thank you. This was a wonderful discussion. What we’re seeing is an incredibly transformative effort in liver cancer. The days of about 10 years ago, where we had no options whatsoever and a meager survival, are being transformed into a lot of options, from immuno-oncology to TKIs to combinations. With survival, patients are getting closer to 2 years from a meager 7 months and continue moving upward. So these are exciting times.

To second what you said, Richard, I will pitch for continued enrollment in clinical trials but also for multidisciplinary care. We still see many patients not being directed to the right therapy or not having multidisciplinary evaluation, and this is critical for outcomes in hepatocellular carcinoma. I also look to our hepatology colleagues. We’ve said it multiple times: We are treating 2 diseases at once. Therapies that may address the underlying fibrosis, the underlying portal hypertension, are still critical to improve cancer outcomes as well. That’s my parting philosophical commentary.

I’ll summarize also, but what both Tony and Anthony said is that we see our systemic therapy options moving both earlier and later in the spectrum of disease, as we are seeing unprecedented efficacy. More options for patients failing TACE [transarterial chemoembolization] or before they have a chance to or need to, and also multiple lines of therapy are now a possibility.

I would also echo what’s been said. These are exciting times for what’s a devastating condition to have. As a provider, I would make a push for us to think more in terms of considering biopsies in more carefully selected cases, so we can glean additional data, especially in the future, if we do have more targets for therapy. Additionally, we should work closely in our multidisciplinary teams and with our colleagues in surgery and interventional radiology to educate them on the data in this regard and really try to emphasize that we should be considering strongly initiation of systemic therapy while patients remain in Child-Pugh A status.

Amit, it’s always hard to be original at the end. But I know you can do it.

I’m going to start by reiterating the point about multidisciplinary care, particularly when we think about stage migrations. With all the combination therapies that are coming around, it even makes it much more important. The fact that this has been associated with improved survival really highlights that it’s important. Rich, to your point of trying to be original, I’m going to end where we started with the whole surveillance discussion and the fact that early detection is really critical. We’ve seen a lot of advances in the advanced-stage setting, which are really exciting. We really have to work as a community to promote surveillance, to really find all these cancers as early as possible so we can deliver curative surgical therapies if and when possible.

Yes, and it’s so exciting to be able to talk to patients now and say, “We are not only improving survival but have a high chance of getting responses.” We’re getting a handle on managing toxicities and a different type of toxicity. It’s just a very exciting time to be an investigator in the liver cancer space, and for physicians in the community to have an arsenal of options to help patients live longer. With those closing thoughts, I’d like to thank you again, our viewing audience. We hope you found this 

® discussion to be useful and informative. Stay well. Thank you very much.

HCC: Applying Recent Data Into Practice 

We have a lot of tools in our toolbox now, and we spent a lot of time talking about how best to use these. Obviously, there are still a fair number of data gaps, but let’s look to the future. We heard at ASCO about a new TKI actually 2 of them, but donafenib was a TKI that beat sorafenib. Apatinib is another VEGF multikinase inhibitor that had data from China showing that it improves survival versus placebo in the second-line after a population that had mostly chemotherapy in the frontline. Moving away from the TKIs and checkpoint inhibitors, we’re seeing an interest in cellular-based therapies now, certainly in liver cancer. There are modified T-cell approaches geared toward AFP, traditional CAR T-type approaches versus AFP and even glypican 3 [GPC3], another protein that’s expressed in liver cancer. Katie, what are your thoughts about the next 5 years? What’s the next big breakthrough? I won’t hold you to it.

It’s really hard to project. Although I’m also excited to see the direction of these cellular therapies, they are a level of intensity in terms of the preparative regimen and the tissue requirements for profiling, and it’s particularly difficult for HCC given the comorbid liver disease and comorbid viral disease in some cases. It’s a higher bar than many other tumor types. So I’m eagerly awaiting the efficacy results. We’ll be paying attention to the toxicity in those studies and with close detail.

One of the game-changing results would be a biomarker of I/O monotherapy response because PD-1 or PD-L1 inhibition, there is a reproducible percentage of 15% of patients who have extraordinary responses to monotherapy. That would be the game changer that helps us in our sequencing and helps us interpret our combination data, because when you have this powerful undisclosed biomarker among your results, it makes it very difficult to compare studies and results apples to oranges. That’s the game changer I’d like to see us focus on, difficult though it may be.

 There have been a lot of interesting data, right? There’s a whole story around beta-catenin mutations and their association with response to I/O. There are signatures that have been associated with various T-cell infiltrates or an immune “hot” liver cancer versus an immune “cold.” Those are all very exciting, but I am challenged because the melanoma group hasn’t come up with that. The lung cancer group doesn’t have a great story. Will liver cancer be able to leapfrog those areas that have been at it so much longer? Hopefully, yes.

The other thing is that in the next 5 years, hopefully we’ll see some of these systemic drugs moved into earlier-stage settings. There are a whole host of studies looking at chemoembolization in combination with doublets of I/O and singlets of I/O, as well as the traditional postresection adjuvant-type studies, using these after curative approaches. It’s a very exciting time. Still, we need to refer patients to clinical trials in all stages because, at the end of the day, clinical trial enrollment is always a challenge. The majority of patients in any disease are typically not clinical trial candidates. When we do see someone who’s fit—Child-Pugh A, minimal portal hypertension—it really behooves us to try to get them into a research program. Hopefully now, in the future, we’ll see the COVID-19 crisis settle down, and that will help us revamp our research priorities in patient care.

HCC: Emerging Therapies Under Investigation

Last year, we had exciting data with atezolizumab-bevacizumab. Preceding that was the disappointment of the CheckMate 459 study. That was frontline nivolumab versus sorafenib, and to be honest, even a few months before that, we had the KEYNOTE-240 study, which was pembrolizumab versus placebo. When we saw that pembrolizumab versus placebo didn’t meet its primary end point, a lot of us started getting concerned: How will nivolumab beat sorafenib? Tony, what are your thoughts on CheckMate 459? Were you shocked by those results? Any surprises that came out of that?

To say I’m shocked, the answer is no. I have it on the record, so it’s not posthumous. I have it on the record predicting difficulty for nivolumab as single agent to beat sorafenib, and not because sorafenib is a fantastic drug, by any means. It’s a problem of how we measure effect, as all of you have mentioned. One is this: Every one of those agents as singlet benefits few; it doesn’t benefit most. The problem is, when you start measuring around the medians, you’re going to be in trouble, because the median is really where most of those patients who will not respond to one will not respond to the other. They’re going to collapse that median, and they’re going to come close together.

With the nivolumab versus sorafenib, I must say, a little bit of a disappointment in the fact that the survival benefit was not, even at the tail end, much more impressive. We must be missing the mark with having the proper biomarker for singlet versus doublet versus now we’re looking at triplets. Unfortunately, the answer is no, but also glad that this was a short-term disappointment because then the atezolizumab-bevacizumab came to actually bring back up the immune therapy landscape back into HCC. Pembrolizumab versus placebo versus a nonactive control, whereby we know every TKI [tyrosine kinase inhibitor] actually won the war versus a placebo, but then we have pembrolizumab not doing the same, including a hazard ratio around the PFS of 0.71, which, if we look at regorafenib or cabozantinib or even ramucirumab in 400 ng/mL, the hazard ratio was 0.49, which tells us that there is a very small subgroup of patients that benefits just from the 1.

I think that discussion is over at this point. There may be a few patients, as Anthony mentioned—maybe a Child-Pugh score of 7 and 8, where you feel compelled that the TKIs are going to be problematic, and a doublet doesn’t make as much sense. But perhaps these are the patients you give a hail Mary nivolumab-pembrolizumab perhaps. Other than that, I think single-agent PD-1 or PD-L1 inhibitor is certainly not an option for 99% of our patients at this point.

One thing we saw from both CheckMate 459 and KEYNOTE-240, the single-agent I/O studies in front line and second line is a lot of patients: 20% to 30% of patients in the control arm went on to get a single-agent PD-1 inhibitor. Certainly that could contaminate an OS end point. But 2 things: You mentioned PFS was not dramatically different, which you would think is where the second line wouldn’t affect as much, the second line choice or the choice beyond progression. Atezolizumab-bevacizumab did improve OS, despite all these other things, which suggests that maybe our best chance for improving OS is up front. But sequencing will still be an issue, right? From the beginning of our discussion, you’d say 80% plus or minus might be the ones who get a doublet up front, but still there will be a role for single-agent TKIs for various reasons. Anthony, is single-agent I/O done in liver cancer?

I largely agree with Tony that it’s not necessarily done, but there will be a very small subgroup of patients where you may find it useful. For the patients with compromised liver function, you may feel like that’s their best option, or for patients who did not qualify for atezolizumab-bevacizumab up front, they’re going to get single-agent PD-1 in later lines of therapy. It’s a much smaller population. Tony just really pointed to the key issue, which is that benefiting a small subgroup of patients very well was not sufficient when we look at medians to get these agents’ approvals. Unless we have a biomarker to select for single agent, it’s going to be difficult to have significant usage of these drugs as single agents.

To the other extreme, Anthony, we talked a lot about doublets and single agent. Are triplets on the horizon?

Well, yes. We’re oncologists, so we like to pile things on top of one another. We saw some data from the GI Cancer Symposium in 2020, in January—this seems so long ago. We saw data on ipilimumab-nivolumab plus cabozantinib. This is another cohort of CheckMate040. In this cohort, there were 2 arms, nivolumab plus cabozantinib versus nivolumab-ipilimumab plus cabozantinib. What’s intriguing is, if you look at the triplet, the response rate was again in the 30% range or high 20%. The response rate did not go beyond what we see as doublets. However, with the nivolumab-cabozantinib doublet, there was a median OS of 21 months. With the triplet, the median OS had not been reached. Similarly with the triplet, if you look at disease-control rate, it was really around 90%. That comes at a cost: 70% grade 3 and 4 treatment-related adverse events, right? Especially elevated liver enzymes, so liver toxicity was more significant in the triplet arm. Will there be room for these triplets? It’s going to depend on the risk-benefit ratio—how much toxicity are we paying for how much benefit. That remains to be seen at this point. It continues to be very experimental, in my opinion.

Combination Regimens for HCC Treatment

The teaser here is the responses, when they occur, can be very dramatic, and they can happen very quickly. I mean, you don’t even need imaging per se sometimes for patients who have symptoms—not necessarily decompensated, but patients who might be having pain, and they start feeling better. Increasingly, that’s more numbers of patients. It’s not the single-digit sorafenib responses or the high response rate with lenvatinib that did not have a long duration of response. It would be great if there was a biomarker or something that could help us. Certainly, we’ve seen AFP fall fairly quickly—if patients make AFP, but that’s only two-thirds of patients. Katie, you’ve done some work on AFP in the context of clinical trials, and there was some interesting biomarker work at ASCO. Could you fill us in on that?

AFP is a really interesting biomarker in that it can be a prognostic biomarker. That’s how you know it best, that across stages of HCC [hepatocellular carcinoma], it portends a worse prognosis: patients going to surgery, getting a TACE [transarterial chemoembolization], getting systemic therapy. Having a high AFP at the outset of their therapy is prognostic of a worse outcome. It is also now a predictive biomarker, in that it can portend which patients will respond to and benefit from ramucirumab. That’s the first predictive biomarker in HCC and a landmark in that context. We think that’s because the tumors that have high AFP expression tend to correlate with angiogenesis and VEGF pathway signaling, thus their responsiveness to VEGF R2 monoclonal antibody, or ramucirumab in this case.

The third kind of biomarker that I’m particularly interested in as a tool is the role of AFP as a biomarker of response. This acknowledges the limitations of standard imaging and how difficult in some patients it can be to determine if the tumor is growing or shrinking, or where is that tumor, particularly for these infiltrative or diffuse phenotypes. We’ve seen that for several drugs, including ramucirumab, as well as now cabozantinib, both antiangiogenic agents, the changes or the kinetics of AFP after start of treatment are strongly associated with outcomes, including PFS and overall survival, as well as with radiographic response. Those are rare with those classes of drugs. For advanced patients, about 75%, 70% will have an AFP greater than 29 g/mL at baseline. For those patients, we really should try to investigate AFP as another response marker to make these early interpretations. We need to look at this by class of drugs, because the response patterns and kinetics may be different for I/O therapies than for antiangiogenics. But it is a cheap, easy, noninvasive way to augment our response assessment.

I try to focus patients away from it. Sometimes they get very nervous because, to your point about the kinetics, it might not fall from week to week. I think all of us feel that it going down is better than it going up. To your point, probably more research is needed to say that this is a criterion to change treatment. I don’t know of any other cancer type where that’s come to maturity with using tumor markers to change treatment decisions, maybe…

 PSA, I was going to say. PSA is probably the closest.

Certainly. Probably there, it’s AFP as well. But in the liver cancer space, a little more work is needed. All these phase 3 studies are collecting AFP data and will give us a rich area to look at.

One area that being looked at very aggressively with various platforms is circulating tumor DNA [ctDNA], not only to get genomic DNA to identify alterations to pursue but also to look at changes in ctDNA over time as a marker of prognosis and predictive value for benefit. There was an interesting study at ASCO looking at some of the data from the single-agent atezolizumab-bevacizumab earlier studies that showed that using this Natera platform—which actually makes a personalized ctDNA probe based on a patient’s genetics and their specific tumor, and following that over time that in patients who had a very early response in their ctDNA—they seemed to be ones who had a very long-term survival. It’ll be very interesting to see how that technology matures over time. Katie, I’m pretty sure you had done some data with circulating tumor cells as well, right? Probably the precursor to circulating tumor DNA. Is that moving forward, or is it being surpassed by these new technologies?

There are a lot of different platforms that have shown that circulating tumor cells in the peripheral blood are associated with poor prognosis, macro-vessel invasion, more advanced disease. Both in early stage patients after resection—for example, the existence thereof correlates with recurrence, and likewise also for prognosis in advanced. These are really limited so far, to my knowledge, to retrospective data sets and have not been studied prospectively. Though again, it’s an intriguing prognostic tool with a lot of studies suggesting a role.

Yeah, it’s another area in the liver cancer space that will hopefully supplement our clinical decision-making in the future.

Emerging Biomarkers in Hepatocellular Carcinoma

We’ve talked about all this excitement, and we’re big cheerleaders for all the clinical research going on. Some of that is in our own self-interest, but for patients, the options are amazing. But let’s be honest. Are there patients in second-line who aren’t candidates for treatment? Maybe they get frontline, and it’s time to stop. What do those patients look like to you?

This conversation has, thankfully, focused a lot on the patients we assume will get to second-line and have that option. We’ll be fortunate enough to maintain their liver function and their performance status, and that would certainly be a good problem to have in that setting. There are going to be patients who first achieved a durable response and then started to progress and developed decompensation of their liver function because of the progression of their tumor burden. Or patients who are intolerant—depending what that intolerance is to the first-line regimen, they may or may not recover enough to progress to second-line therapy. We may see, but hopefully it will be a small percentage of our patients for whom we’re not able to pursue second-line therapy. As we learn more about the options first-line with combination therapies, hopefully we’ll be able to figure out which ones are more likely to be able to go on to second-line options and what that would look like after.

Something that’s been very intriguing to me in practice: We’ve always seen patients who have a very large tumor burden in the liver. They’re borderline decompensating, right? It’s hard to know, is this patient just cirrhotic, or is this big tumor pushing them over? If they had a response, they would feel better. They would regain some liver function. I’ve actually had a few patients more recently with whom the discussion is, “You have a very advanced tumor. You presented very late, unfortunately. We have some drugs that have fairly high response rates, and you might not qualify for a clinical trial, given your physiology. I suspect if your tumor responded, you would get better.” This is a risk-benefit discussion with patients now that we have regimens that have high response rates. Amit, what’s your thought on that? Is there a way we can tell how much is underlying liver dysfunction versus tumor burden? Sometimes, these patients have big portal vein thromboses; sometimes they just have a lot of tumor in the liver. What do we do?

You know, Rich, it’s an interesting question. We all have these patients who, as you’re saying, presented with large tumors, some degree of liver dysfunction. You talked to the patient, you treated them, you had a response, and the liver function actually improved. The patient went from a Child-Pugh B to an A as the tumor responded. This is, once again, a nice problem to have, because it means our therapies are actually improving, and we’re seeing better responses.

The one thing I use is their natural history coming into this. The patients who are easier are the patients who were already in the system. For example, before they presented with their large tumor, you started to see their liver function decline over time. For those patients, you can say more confidently that this is related to slow deterioration and true liver dysfunction. The ones that are tough are those patients who present up front—so new to your system—as a Child-Pugh B. Let’s say with a large tumor, plus or minus some portal vein tumor thrombus. I have to say that, at least personally, I don’t know of any great way to tell if somebody’s liver dysfunction is related to their tumor versus their underlying liver disease. It’s worth a discussion with that patient, that if you can have a well-tolerated regimen, it’s worth a shot. Then see what their liver function does—the test of time. There are some tests where you can see how well the background liver is “functioning.” But I don’t think those have been well evaluated in this specific setting to use in clinical practice at this time. There are research tools that are being evaluated to give us a sense of “liver function.”

Anthony, should every patient get I/O before we call it a day in liver cancer? What are your thoughts?

The point you’re making is critically important, but I want to move a little beyond the anecdotal to look at the CheckMate040 Child-Pugh B cohort. This is a unique prospective cohort of Child-Pugh B7 and B8 patients who were treated with single-agent nivolumab. To second what you both have said is that when you look at those patients, the ones who responded, the response rate was 11%, 12%. The majority—80%, 90%—actually moved from Child-Pugh B to Child-Pugh A.

These were carefully selected Child-Pugh B patients. There were only 7 or 8, no paracentesis in the last 3 months, no active encephalopathy in the last 6 months. Maybe using those types of parameters—you know, if the patient has a large infiltrative tumor, portal vein invasion, and a high bilirubin and low albumin, that puts them in Child-Pugh B. But you’re requiring paracentesis. They don’t have hepatic encephalopathy. Those patients might benefit from treatment of their tumor. Irrelevant of what the cause of the decompensation is, if you’re starting to require paracentesis and you have hepatic encephalopathy, the prognosis becomes quite poor. I’m not sure it’s wise to try to treat the cancer at that point from a quality-of-life perspective, from a public health perspective, etc.

This goes back to your prior point, Rich, of having 2 diseases at once. It’s a disease within a disease. As your liver function starts to continue declining there, your mortality is really being driven at that point by your cirrhosis, not your HCC [hepatocellular carcinoma]. I agree with Anthony that at that point, it doesn’t necessarily make sense to continue treatment if you’re starting to truly have significant liver dysfunction.

HCC: Liver Function and Treatment Decisions

We’ve talked about a lot of the efficacy discussion about choosing something beyond progression frontline. Katie, you had commented about the use of regorafenib in the inclusion for RESORCE was to tolerate prior sorafenib. Part of that was to mitigate, I think, the adverse-effect profile of regorafenib and sorafenib, given their overlap. Amit, could you give us some idea about how adverse effects of these drugs influence your choice of treatment, including frontline? We talked about bleeding issues, but hypertension, proteinuria—some of these are class effects. But every molecule has some unique aspects.

This goes back to the question that Tony asked. When you put this all in 1 box, you’re going to have these options you have to choose. As we’ve seen, there are no head-to-head data that suggest that 1 TKI [tyrosine kinase inhibitor] has better efficacy than the other. As you said, there’s a class effect. Some of these AEs are similar, but there are small differences in terms of the proportion of patients who experience any specific AE. For example, comparing sorafenib and lenvatinib, you basically see that sorafenib gives you a higher proportion of hand-foot-skin reaction, whereas with lenvatinib, you’re more likely to have proteinuria, hypertension, and maybe constitutional symptoms like anorexia. Depending on how your patient is doing at that time, when they come to the second-line therapy, some of these AEs may actually help you in terms of distinguishing which therapy you’re going to choose. We’ve already referenced the fact that regorafenib and cabozantinib have similar AEs. But with regorafenib, it’s really with the idea that they were well selected. As Katie mentioned, they had to be on sorafenib for 20 of 28 days to get into regorafenib. It’s unknown if you went directly into regorafenib if you would have had more or worse AEs.

From my standpoint, these subtle differences in terms of AEs are maybe one way you can choose which TKI you’re going to use in the second-line setting and potentially even what AEs they come out of atezolizumab-bevacizumab with. If you use atezolizumab-bevacizumab, and they have some proteinuria, you may be less likely to use lenvatinib in that setting, given that you can have proteinuria with lenvatinib. If they come out and have poorly controlled hypertension, it’s the same kind of decision-making in terms of knowing that lenvatinib is more likely to give you hypertension. Outside of us actually hitting the jackpot and starting to have some biomarkers to help select this, unfortunately, we’re continuing to use these more gross and obtuse measures in terms of trying to decide among these.

As Tony mentioned, I’m hoping, knock on wood, that this is a short-term problem. These other new trials of combo therapies are promising. Some of them have finished enrollment, and we should see data. I do think the future is going to be combos. It’s going to be combo 1 and then sequencing to combo 2. It doesn’t take away how we choose. But that the idea of having to choose between TKI monotherapy 1 and TKI monotherapy 2, I think that discussion goes away.

Katie, what’s your take on that discussion?

It’s good to have these choices. Just as we practice the art of oncology in other tumor types, like in colorectal cancer, a patient with an ileostomy and a lot of diarrhea will choose FOLFOX [5-fluroracil, leucovorin calcium, oxaliplatin] over FOLFIRI [5-fluroracil, leucovorin calcium, irinotecan] in the first-line. In breast cancer, a patient with neuropathy may guide our first-line choice of therapy. The degree of hypertension and whether a patient has had immediate hand-foot syndrome or prohibitive hand-foot syndrome on their prior therapy should be the kinds of things we use to guide some of our decision-making, and it’s really great to have the choices that allow us to tailor by toxicity and comorbidity. Of course, in addition to the efficacy outcomes, which are paramount, having these choices really does help us individualize therapies.

Anthony, the toxicity from CheckMate040 with CTLA4 inhibition and PD-1 inhibition includes 50% use of steroids. That’s a high number, I think. Many of us think about that and its implication for using that regimen in second-line compared with a TKI. Certainly, we’re not seeing response rates of 32% with TKIs. That’s a very impressive number. You have a fair amount of experience with this combo. What’s your thought about it? Are these protocol-dictated use of steroids? Or are these real toxicities?

Certainly some of it is protocol dictated. When we quote 50%, this is using 40 mg of prednisone or higher. So 40 mg would be less than the 1 mg/kg standard that we would start with. This is almost all steroid usage. If you look at that, most of it was driven by skin toxicity like dermatitis, about 20% were hepatitis-type events, and then colitis. There was some pneumonitis as well, but the numbers get pretty small for that. What’s important is that over 90% of these events were reversible. Actually, a majority of these patients with immune-mediated events were rechallenged and were able to get treated again. It’s a tough regimen. There needs to be caution. There is a high need for steroid usage, obviously, in some patients. But it’s a manageable toxicity in the sense that if you are careful, you know when to do it—when to stop the regimen, use steroids—you can have most patients recover and even reinitiate therapy. It has to be a regimen that’s reserved for the right patients, so good performance status, Child-Pugh A. As you alluded to, what’s promising there is not just the response rate. It’s this intriguing OS in second-line of over 20 months.

Right? In the right patient, this could be a beneficial regimen. Again, how does it fit post–atezolizumab-bevacizumab? No one knows. This is something we already discussed.

Reena, from the hepatology standpoint, a lot of the drugs we use cause proteinuria. In colon cancer, with bevacizumab, proteinuria never got us too concerned. Do we need to think about it differently—the proteinuria we see, either from the TKIs or bevacizumab or ramucirumab, for that matter—in patients with underlying cirrhosis, or not really?

Not really, Rich, at the Child-Pugh A stage. Certainly as patients start to progress in their level of decompensation, we worry about that more with the renal dysfunction they may experience anyway. But generally, no. As long as we’re monitoring it—many have started to become accustomed to that with lenvatinib in this space, already starting to check for proteinuria. If we apply it to a more decompensated patient or a Child-Pugh B7, for example, going forward, if data allow, then we would need to be monitoring for proteinuria more closely in the cirrhotic patient.

Safety Profiles of Novel Therapies for HCC

I’m going to challenge all of you because of the rapidly changing landscape. We’re not curing most patients. Atezolizumab-bevacizumab does have, and all the I/O combos seem to have, this 30% plus or minus group that appears to be very long-term survivors. All of us have used these drugs and probably see patients who are cured. Presumably, patients are going to go beyond their second-line agent, even patients who get prolonged stable disease from frontline. All of us hope these drugs are being used earlier in the disease course, as we talked about before using them. Before we see patients who are decompensated, as we get more liver cancers that are earlier in detection, and the whole staging system hopefully will move to the left, to earlier-stage disease and using these drugs earlier. Patients will be going to third- or fourth-line. We can all say what our preferred sequence is, at least for second-line. Obviously, the data get even less supportive as we go to third or fourth line. Tony, do you see a role for sequencing TKIs [tyrosine kinase inhibitors]? Or do patients get frontline I/O combination, second-line TKI, and then we stop because there are no more data? What’s your thought?

We haven’t stopped before, so why stop now?

I don’t disagree that we’re going to get more patients hopefully to third-line. That’s the natural history: When you do really well in the first-line, you start doing better in the second- and the third-lines. The point is, we’re going to have to sequence. Hopefully, we’ll have more studies to fill these spaces. Let me go back to 2 things. Your second-line has to be a TKI. There’s no doubt about it. You have 4 options you all talked about. I have my preferred 2. I think Katie aligned with that as well. We have 2 agents that have proved value. That doesn’t discount the others. My least preferred remains sorafenib, frankly. I don’t think I’m going to waste much thought about it. I’ll have 3 to work with, 2 favorites in the second-line, and in the third-line, if I do regorafenib, I’m going to look at cabozantinib. If I do cabozantinib, I will do probably regorafenib. You can still argue for lenvatinib as well, perhaps. I’m not sure. I want to go back to the point. There were interesting data from ASCO that looked at nivolumab plus ipilimumab in patients who failed nivolumab. It is not inconceivable that a dual checkpoint inhibitor—adding the CTLA4 inhibitor in patients who failed atezolizumab-bevacizumab, whether in second- or third-line—may actually pull some weight. Of course, it needs to be studied. Theoretically, we’ve already seen that in RCC [renal cell carcinoma]. We see some of it in melanoma. It’s not inconceivable that you can continue to salvage patients with I/O. Just change the partner. If the partner is bevacizumab in the first line, atezolizumab-bevacizumab, when you fail atezolizumab-bevacizumab, did we really fail the bevacizumab or the atezolizumab or both? Can we go to wherever? I/O of choice plus, say, lenvatinib or cabozantinib or regorafenib, which hits multiple other targets, including some that will reverse the VEGF effect on immunosuppression or the VEGF effect on the tumor. I went through the point that we’re not going to make a bigger difference in those patients until we start asking combination questions in second- and third-line, not just limited to first line, where most of the landscape right now is. I hope it’s not going to take us another 10 years to figure out that this is what we need in second and third line.

That’s really excellent commentary, because as we’ve heard before, there are several combinations being developed. I asked Anthony about CTLA4 and I/O, but there are TKI combinations—lenvatinib-pembrolizumab, atezolizumab-cabozantinib—and they’re all being studied frontline. Let’s say they get approval. You can use only 1 frontline. Does that mean there’s no role second-line? Those are very difficult questions to answer, these sequencing-type studies. I don’t know when we would even have that data. It would take time to try to answer that. As we see, the natural history of liver cancer is getting longer. We can likely tell patients who are Child-Pugh A frontline that median survival is probably 2 years, I suspect. Obviously, the IMbrave150 data read out very quickly, and the long-term follow-up from the treatment arm has not matured. We know that there’s a 42% decrease in the risk of death with that combination up front, but it’ll take longer follow-up to see what the true medians are. That median is going to reflect what they get not only front line but also in subsequent lines of therapy.

Sequencing of Novel Therapies in HCC

You mention the single-agent tremelimumab data. I think a study that many of us have overlooked that the first checkpoint inhibitor looked at in liver cancer was Bruno Sangro’s study with tremelimumab from several years go. There were some toxicity issues at that time, which I think now we might not get so concerned about. But at the time, we’re with our thinking, there were some issues with hepatitis and transaminitis. Katie, there’s RESORCE, there’s CELESTIAL. Tony introduced this idea of we’re going to these drugs now. What are your thoughts in the context of the data that we have from RESORCE and CELESTIAL and incorporating that into our current mindset?

I think looking specifically at the regorafenib and cabozantinib choice in a second-line TKI context, I do think that it’s important to remember the regorafenib resource eligibility criterion of--requirement of a meaningful dose of sorafenib, at least 400 milligrams per day for 20 out of the last 28 days. I think we shouldn’t discount this key inclusion criteria because it does bear on patients’ risk of toxicity as well as potentially their susceptibility to that target pathway. I tend to use regorafenib really in patients who have had prior sorafenib, though again, I think there are cases where we might extrapolate to a different TKI. But I think that’s an extrapolation. I think in patients who haven’t had prior sorafenib, cabozantinib has the best level one evidence for its use in the second-line context. I think there’s also intriguing flexibility for cabozantinib in that the phase 3 trial included second- and third-line patients and patients with prior nivolumab, for example, so patients with prior IO therapy were included, admittedly a small subset. But their outcomes appeared to track with the overall population in a report from the post-nivolumab and post-sorafenib third-line population that was presented at the EASL Liver Cancer Summit this year in 2020. So, I think in that context, regorafenib is a drug best for patients who have had prior sorafenib. Cabozantinib is more flexible in the second- or third-line context, as well as a subset of patients with prior IO.

Regorafenib or Cabozantinib for Second-Line HCC

Tony, what’s your thought about TKIs after atezolizumab/bevacizumab? I mean, are we going to first-line TKI, which would be sorafenib/lenvatinib, and then second-line TKI? Or is this step zero, and then we have first-line, second-line? What are your thoughts?

No, it’s not step zero. It’s step one and it displaces your first-line sorafenib, so I’m not going to put sorafenib after it. It’s gone. Lenvatinib has not proven to be any better than sorafenib, so I’m not going to waste my purpose or my time thinking about this. My life has become simpler. I have a good first-line, atezolizumab/bevacizumab for most patients. My second-line is going to be the same second-line I struggle to use, plus simplified--I mean, I think regorafenib or cabozantinib. There’s nothing to say that lenvatinib is going to be better than regorafenib or cabozantinib in that setting. And very few patients will make it to the third-line. I think ramucirumab, in my viewpoint, is a goner at this stage. When bevacizumab fails, I’m not sure ramucirumab on its own is going to salvage it. I’d rather have a dirty multi-kinase inhibitor such as regorafenib or cabozantinib. Both of them have good targets that essentially revert back the resistance to VEGF or the resistance, actually, with regorafenib. You hit so many different targets, you can also argue that you hit more targets than we know, including some of the targets--like CSF1R and others, that are relevant to IO. The future is probably to enhance activity through combinatorial strategies across multiple lines. I mean, one thing we’ve seen--and we see that in lots of different malignancies. But specifically this one is that one agent--I don’t care which one you look at, whether it’s lenvatinib, whether it’s sorafenib, whether it’s nivolumab, whether it’s pembrolizumab, cabozantinib, I mean, you name it. One agent pulls a little bit of an advantage. Two agents are pulling much more of an advantage. So it sounds to me that ultimately, the questions in the second-line will have to focus similar to the first-line on combinations. But right now, in clinic, my life has become a little simpler for now until we get the results of all these other studies and then figure out what to do with them, it’s atezolizumab/bevacizumab, then it’s regorafenib or cabozantinib.

There’s six of us on the panel here, and you get six different opinions. But Amit, how do you think about it?

I think somewhat like Tony, but a little bit differently in different aspects. I agree obviously with atezolizumab/bevacizumab, with IMbrave150, I think all of us agree that atezolizumab/bevacizumab is a game changer. It’s going to be the standard first-line therapy for the vast majority of patients. In the second-line, I personally am putting everything in one big box. I am personally saying that you can choose sorafenib, lenvatinib, cabozantinib, and regorafenib. I do agree that ram, I don’t think that that has a major role now with atezolizumab/bevacizumab in the frontline. I personally am putting ram on the back burner. But the other four, I’m putting in one big box in the second-line setting, with the caveat that resource required sorafenib tolerance. And so maybe, I guess, regorafenib would be third-line for me if somebody goes on sorafenib to select those who can tolerate regorafenib. But I personally--otherwise, I’m not just throwing away sorafenib. I am still keeping that in that second-line box.

You have to decide between those four. You have the patient in front of you. And you have those four, and you’re saying--and I don’t disagree. They’re probably somewhat in the same range. The question is, how do you pick one versus the other. I think you need to argue that sorafenib is probably the weakest link. So that’s easy; that goes. Ramucirumab goes. Lenvatinib is okay, it’s not better than sorafenib. I mean, you take a study that’s noninferiority, and we make a lot of conclusions out of it. It’s still a noninferiority study. And you have two level-one evidence, albeit it’s in sorafenib failure, but two level-one evidence agents in the second- and third-line. I mean, you have to choose one of those four—

[Interposing] Yeah, I mean, those were versus placebo, the cabo and rego studies. Len study was an active control. I mean, personally, I still look at it front-line TKI, then second-line TKI. So maybe after progression, I would consider sorafenib or lenvatinb and then go to one of the other third-line or second-line, which are now third-line agents. One thing that very much I appreciate your comment about, it simplified things, because I think moving IO front-line takes it out as an option in second and third-line. But I’m very intrigued by CTLA4 and PD-1 inhibition. And I’ve looked into other malignancies, because certainly in melanoma and lung cancer where IO has been front-line for some time, they’ve been struggling to find that magic regimen when IO stops working. I don’t think that anyone has come up with it. I mean, is there data to think about using nivolumab/ipilimumab, for example, in second line after progression on atezolizumab/bevacizumab? Anthony, what’s your thought?

There’s currently no current data on doing this nivolumab/ipilimumab data that’s out there and the led to the accelerated approval was post-sorafenib. As you mentioned, in other malignancies now, we have evidence of nivolumab/ipilimumab working as a second-line regimen post-PD-1. So, there may be room to evaluate this in this setting. The question, though, again--and maybe always a theoretical question--will CTLA4 alone do the same in the second-line setting. I mean, the tremelimumab alone data from Katie’s study presented at ASCO 2020, to me, is intriguing still. But I think what it’s coming down to is there’s going to be ample opportunity for additional studies--not just opportunity. There’s an absolute need for additional studies in second and third-line with either novel agents or looking at different immune targets beyond PD-1 in that space.

Selecting Second-Line Therapy for HCC 

The evolving landscape of liver cancer is just incredible to me, how fast things are changing and how well our patients have the potential to do now with all the available drugs. With the approval of lenvatinib in 2018, it left us with some unanswered questions, because at that time, we had several drugs approved in second-line, but that second-line data was all done after sorafenib. I think many of us have practiced that if a drug is approved second-line after sorafenib, and we choose lenvatinib in the front line, then we could go to cabozantinib second-line or regorafenib without necessarily having level 1 evidence that it would work, that the choice of frontline therapy, how well does that influence second-line therapy. But again, we didn’t have any strong data sets for all that. Now, we see more progress. I think the lack of data in certain scenarios does reflect progress. Now that we have atezolizumab and bevacizumab front line, essentially IO in the front line, and I think we have said that the majority of patients probably were eligible for systemic treatment. This will be the go-to regimen because of the efficacy data. But what does that do for all the molecules we have beyond that? What’s the new second line? Reena, can you put some of this into context? Certainly because many of the TKIs [tyrosine kinase inhibitors] are VEGF-plus, and even ramucirumab, which is approved second line for patients with elevated AFP is a monoclonal antibody to the VEGF receptor. What are your thoughts on how clinicians are going to integrate all this data?

It’s a great question, and I think, Rich, it’s something that really remains for us all to determine what’s the new sequence or new algorithm going to look like. I certainly think that we can make some comments, one is that your point and Katie’s point earlier about the fact that there are other targets for these TKIs beyond just VEGF. When we think about second-line agents, and we look at regorafenib or cabozantinib, certainly thinking about the AXL and MET, or TAM pathways, or even FGF, there are certainly other targets beyond what atezolizumab and bevacizumab may necessarily cover entirely. I think there’s a role still for looking at those agents in the second line. Also, the question is, will some consider sorafenib or lenvatinib to be placed or shifted into being second line, even though that’s not where they were studied. And will we just shift our whole algorithm? I think the other part is the question of would you try a checkpoint inhibitor after a patient’s on atezolizumab and bevacizumab. And the question there, I think, is really what is the data?I don’t think we have that data per se, whereas in CELESTIAL, for example, we had at least a quarter of patients who have been previously on 2 lines of therapy before, and a very small percentage of patients on IO. We have a little bit of data there, but after atezo, how would you approach using another checkpoint inhibitor, I think, is a great question, and one that we can discuss as a group. I think if we look at the phase 1b RMF data, it was a little bit lackluster in terms of seeing just the single agent atezo response, and so the other options with TKIs would still be all on the table at this point.

Second-Line Treatment for Hepatocellular Carcinoma

We now know that durvalumab/tremelimumab has completed its phase 3 HIMALAYA study. And that’s durvalumab/tremelimumab versus sorafenib in the frontline setting. Those data are eagerly awaited. Similarly, nivolumab and ipilimumab are in an ongoing phase 3 study versus sorafenib. Given atezolizumab/bevacizumab’s approval, we hope that study will continue to move along, given that the standard of care is evolving, at least in the United States.There’s also interest, though, in not only combining IO and IO or IO and IV drugs, but also IO and TKIs [tyrosine kinase inhibitors]. COSMIC-312 is looking at atezolizumab with cabozantinib, which is a multi-kinase inhibitor to VEGF, CMET, and AXL, which we know is approved in the second-line setting, and now trying to move that to the frontline. That study is ongoing. I don’t know that we’ve seen much early data with that combination as far as efficacy, but at ASCO 2020, a story that’s been evolving over time has been data with pembrolizumab and lenvatinib. Anthony, why don’t you fill us in with the latest take on that update?

At ASCO, we saw a slightly bigger data set from a phase 1b with the combination of pembrolizumab and lenvatinib. About 100 patients, and with longer follow-up where we saw that the RECIST 1.1 response rate with the combination was at 36%. So certainly, again, this repeating theme of 30% range of response rates with these combinations. With modified RECIST, there was a 46% response rate. Again, I’m quoting both, because it’s important to be careful when comparing these response rates and make sure that we’re comparing apples to apples. More importantly, if we think about beyond response, the median PFS with this combination was in the n 9-month range. The median OS, again, very promising, hitting the 18- to 20-month range. So again, the toxicity is certainly higher than using the single agents alone, but within a manageable range if one knows what to expect with these combos. The discontinuation rate was about10% to 14%, depending if they looked at both agents or single agents of what was stopped. So again, a manageable profile. This combination is currently being evaluated in a phase 3 setting with LEAP-002 comparing pembrolizumab/lenvatinib with lenvatinib alone

:Sorry, Richard. We may end up with multiple combinations in the first-line as different options. And I just wanted to say, the challenge will be, are these combinations going to be used just based on physician preference and a slightly different toxicity profile? Or will there be other markers that help us select among the different combos in the first-line?

it’s incredible, right? If we think back of where we were at the beginning of our discussion about just having sorafenib and then the advance with the approval of Lenvima to where we are now in just 2 or 3 years, it’s a rapidly changing landscape. One of the things I wonder about is, is it the same group of patients; we’re getting 30% plus or minus with all these regimens, I think you could say. Is it the same group of patients who are benefiting from CTLA-4, PD-1, as from VEGF PD-L1 from TKI PD-1. Katie, what are your thoughts on that?

: I think that’s becoming a really interesting question and draws us back to our eternal quest for a good biomarker. I think if we return to the durvalumab/tremelimumab circulating T-cell profile data that we talked about earlier with that phase 2 regimen, it’s a really intriguing idea to use that as a tool—as a marker, at least, for immune activation, if it bears out as a true biomarker response in the HIMALAYA study. So of course, we need to validate with an independent set. It may be it only holds true for a CTLA-4 population. But again, that kind of an assay to tell us, are we on the right track to really prompting an immune response with a given combination is what we need to discern the efficacy in different subpopulations. I think, just to echo again what Anthony was alluding to with the combinations of the TKI plus immunotherapy, I think it is really interesting, as we consider also that not only are the TKIs adding an anti-angiogenic effect that removes the immune suppression of the VEGF pathway in the tumor microenvironment, they also have their own independent targets for both Lenvima as well as cabozantinib, for example. If we take cabozantinib, it inhibits suppressive elements like tumor-associated macrophages and myeloid-derived suppressive cells that through the TAM family kinases, that if we were to identify exactly the mechanism, we might be able to choose which combination works better for certain patients now that we have so many more tools with positive results.

:Certainly room for optimization, for sure, as we see this evolving data.

Novel Combinations to Treat HCC

I think IMbrave validated for the first time in a phase 3 study the importance of immuno-oncology [IO] agents in the liver cancer space. It’s taken a long time to get there. But we have one of the pioneers with us today, Dr El-Khoueiry. You saw a vision for this maybe early on with nivolumab in the CheckMate-040 study. CheckMate-040 has evolved over time, initially single-agent nivolumab and now recently another accelerated approval in second line of nivolumab/ipilimumab. There are a lot of data out there about new combinations. Can we increase the response rate of single-agent IO with combinations, the efficacy? IMbrave looked at VEGF antibody and PD-L1. Tell us about the exciting work going on here.

: Thank you, Richard. As Tony alluded to earlier, there are different rationales for the different combinations. I would put them into 3 groups: anti–PD-1 agents with VEGF antibodies like atezolizumab/bevacizumab, anti–PD-1 agents with TKIs [tyrosine kinase inhibitors] that target the VEGF axis plus other targets, and then the PD-1/CTLA-4 combinations. And we’ve seen data for both nivolumab/ipilimumab, as well as durvalumab and tremelimumab.

There are different rationales for these 3 categories of combinations. So maybe spend 2 seconds on the nivolumab/ipilimumab or durvalumab/tremelimumab. The idea here, the way I explain it to patients is that we are removing 2 brakes off of the T cells, not just the PD-1 inhibition, but the CTLA-4 as well. And in CheckMate-040, there was a separate cohort that evaluated this combination of nivolumab and ipilimumab with different doses and different schedules of ipilimumab. And the same thing you will see with durvalumab/tremelimumab as well, because the dose and schedule of CTLA-4 may affect toxicity and efficacy. Briefly, with nivolumab and ipilimumab, the combination got the accelerated approval in second line post-sorafenib. The combo that received the approval is nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab maintenance as a single agent. And there, we saw responses in the 30% range, 31% to 32%, 8% complete response, and intriguing median overall survival in an uncontrolled setting. This is a single-arm study of 22 months.

Now, of course, this comes at some cost of toxicity. Certainly, the grade 3 and 4 treatment-related adverse events were slightly above 50%, and half the patients required some steroids for immune-mediated adverse events, including 20% immune-mediated hepatitis-type events. So this is definitely a therapy that has to be chosen for the right patient and managed carefully. At the virtual ASCO [American Society of Clinical Oncology annual meeting] 2020, Katie, who’s with us today, presented data on the durvalumab/tremelimumab. Again, same concept of PD-1/CTLA-4 inhibition where we saw there were 2 different doses of tremelimumab evaluated:75 mg for 4 doses, kind of similar to the nivolumab/ipilimumab, versus tremelimumab 300 mg given once up front and then continuing with durvalumab alone. There were 2 other arms in that study. It’s a bit of a complicated study, how it’s evolved. But there was a durvalumab single arm and tremelimumab single arm. And the punchline is that with the tremelimumab 300 mg combination, the high-dose CTLA-4, even given once, we saw a promising median overall survival of 18 to 19 months, certainly within the range of what we saw with nivolumab and ipilimumab, with a manageable safety profile. Again, certainly, the grade 3 events were higher than with single agents, but manageable. And intriguingly enough, even with single-agent tremelimumab, there was a promising median OS [overall survival], in my opinion, that’s above 15 months or so. Certainly a repeating theme here with these combinations.

Yes, Katie, I’ve always been impressed with this 1 dose of tremelimumab lighting a fuse. Can you comment on the science on that a little bit? It’s impressive to me.

It’s quite interesting. I think the evolution of that arm, which as Anthony mentioned, evolved along the way of the trial, came from pharmacodynamic data from both durvalumab/tremelimumab in lung cancer, as well as some similar data from nivolumab/ipilimumab in melanoma, which showed that a population of both proliferative, as well as a different population of activated T cells, could arise in a burst after the first dose of tremelimumab and that the extent of this T-cell proliferation and activation was dose-dependent. Intriguingly, this burst of T cells—this is in peripheral blood, by the way—this proliferation of activation of T-cells really occurred just after the first dose. It wasn’t recapitulated with sequential dosing. So really raising the hypothesis that you’re activating T cells in the periphery and potentially in lymph nodes and allowing them to become activated after the first dose, but perhaps there isn’t the same measurable benefit with sequential dosing. That led to the premise of the durvalumab/tremelimumab priming dose arm.

Which speaks to the idea of understanding something and then trying to optimize it. And I think CheckMate-040 and the study presented with durvalumab/tremelimumab are these studies that are trying to optimize how to dose and to maximize efficacy.

Immunotherapy in Liver Cancer

Like most studies in advanced liver cancer, front-line, second-line, these are always done in patients who have Child-Pugh A liver disease. We can discuss the applicability of these data sets to the general population. One thing with bevacizumab, which we evaluated many years ago, actually, even in the sorafenib days, because we’ve known antiangiogenics might play a role in liver cancer because it’s a very hypervascular tumor. There’s been interest in targeting VEGF for some time, one of the things that slowed down bevacizumab, I think, a little bit back a decade ago was the concern that anti-VEGF agents can cause bleeding.Now, in IMbrave, as in some of the newer studies with other agents in liver cancer, endoscopies were done within 6 months of coming on study if you had not had one. Amit, as a hepatologist/GI [gastroenterologist], I think probably that group of doctors would be a little more engaged moving forward as this regimen rolls out.

:Yes, I think, Rich, this really, once again, goes back to that same concept of multidisciplinary care, and people working as teams. I think that this will require oncology working closely with gastroenterology to help facilitate that upper endoscopy. Although we have noninvasive means of identifying patients who are at low risk of varices in patients with cirrhosis, we don’t know if those same noninvasive means apply to patients with HCC And so at this time, I really do think, as you’re saying, that it’s important for all patients who are going to be undergoing atezolizumab/bevacizumab to undergo an EGD [esophagogastroduodenoscopy] and to make sure that those varices either don’t exist, or if they exist, that they’re adequately controlled before doing this regimen. To Tony’s point of this regimen being tolerated so well, with a low risk of bleeding, I do think that part of that was because of this requirement of undergoing the EGD and having the varices under control from their local provider.

Yes, I think that was an important point I was going to add. Bevacizumab is not heparin. It’s not an anticoagulant. I don’t think we need to look at patients so fragile. But again, patients are selected, right? Katie, you had a very thoughtful editorial in 

 about this study. But you also had some reservations and some thoughts. Could you build on that?

I think this echoes what Amit also said, that we know from the bevacizumab monotherapy data and from the randomized data in combination with erlotinib that it does have a meaningful risk of upper GI bleed in particular, but also events like perforation and, to some degree, arterial thromboses, particularly in patients with Child-Pugh stage B or worse liver function who have higher risk for portal hypertension and GI bleeding. I think that while I absolutely embrace the regimen as our new first-line standard in patients who are Child-Pugh A who have had an adequate endoscopic evaluation, I don’t think yet we have the data to support extending this to the Child-Pugh B population without careful examination and discussion of risk, because we just don’t have the data, and we do have reason to worry about bleeding risk.

: Reena, what about viral hepatitis and the use of drugs like atezolizumab, a PD-L1 antibody? Has that come up for the gastroenterology group, the hepatologists?

I think it’s definitely an area where we have to impart the education to the community-treating physician, as well as at the academic centers, to make sure that our partners are aware that for patients with hepatitis B in particular, we have to make sure that they’re at least virally suppressed or at reasonable levels and on antiviral therapy to control their hepatitis B. Hepatitis C, as we saw in the trial data for patients, both with CheckMate, as well as here in IMbrave, we can successfully treat patients who have viral hepatitis with these regimens. The key is that we’re co-managing the multidisciplinary care, as has been said by others, and in particular, for the hepatitis B patients that they’re being treated with antiviral therapy.

Yes, I think this regimen was approved 2 weeks ago or so. And I think we are all very excited to get this out into clinical practice, because as Tony commented, we filled those voids that we always wanted in front line. We have improved survival, improved response rates, durable responses with a very favorable patient-reported outcome data set and safety profile. Amit, did you have any final thoughts on that?

Yes, I was going to add one thing. I think Katie brought up the idea of the patients with Child-Pugh B, and we talked about the EGD. But the other requirement of the trial was the platelet count. And so the other thing that we do see are these patients who are Child A but have more significant portal hypertension with lower platelet counts. And I think it’s also worth remembering that even if you do an EGD in those patients, we don’t have safety data, and those patients also may be at higher risk of bleeding. I think the nice thing about the TKIs [tyrosine kinase inhibitors] is that we had a lot of real-world data and these extended patient populations. So we have safety data of sorafenib in patients who are Child-Pugh B and even some selected patients who are Child-Pugh C, patients with significant portal hypertension. I think that we are going to need these data in atezolizumab/bevacizumab in these extended patient populations who aren’t included in this trial.

There’s thrombocytopenia, and there’s thrombocytopenia, right? And in the IMbrave150 study, they allowed patients with platelet countsdown to 75,000. So that should capture a lot of our patients who are Child-Pugh A.

Yes. I think, Rich, it’s important also not to forget that other than the PD-1 and PD-L1 inhibitors, every agent that’s available to our armamentarium is primarily a VEGF inhibitor. And actually, my worst case of bleeding was in the first days of sorafenib, with a patient who went on sorafenib, had a wound that was closed for more than a year in the belly, and after a month on sorafenib, came to the hospital with the wound dehisced, and the guy was bleeding profusely. The point is, bevacizumab’s issue is, of course, that it’s a long-acting VEGF, and it’s difficult to control per se. But all agents carry a risk, all the oral agents. With Child-Pugh B, we have very low data with any of the TKIs. In fact, even though sorafenib has some real-world data, it’s really not impressive. We haven’t really made a dent in the patients who are Child-Pugh B yet. We make a lot of assumptions. But that group of patients does incredibly bad, regardless of what we do to them.

Yes, and that’s the challenge of having 2 diseases in 1.

HCC: Treating Patients With Atezolizumab/Bevacizumab

I don’t think the TKIs [tyrosine kinase inhibitors] are going away front line. Even though we’re learning about a lot of exciting data with immuno-oncology [IO] agents, a lot of the evolving data are in combination with TKIs. Recently, we saw the approval of bevacizumab and atezolizumab in advanced liver cancer. And this, I think, is a real game-changer. Tony, can you give us your insights into that new data set?

Thank you, Rich. Certainly, the landscape is changing, and changing very rapidly. As you said, I still remember the days even before sorafenib, there were absolutely no options other than doxorubicin and toying with tamoxifen and Megace. Today, we have so many options. It got quite confusing for a while, with a lot of first-line and second-line options and a lot of fast-track approvals. It made the landscape a little bit confusing and complex, good and bad. And then come the data with IMbrave150 with atezolizumab and bevacizumab. We’ve had some disappointments with nivolumab versus sorafenib, which did not pan out. And there was a whole question about are we on the right track with immune therapies and whether we should move forward, move away, find subsets. So, it got even more complex, and a little bit of disappointment until we saw these data, which do consolidate the importance now of moving into dual IO combinations, whether non-IO plus IO, VEGF plus IO, or IO plus IO. But focusing on the atezolizumab and bevacizumab, it made a lot of sense to add a VEGF inhibitor to a PD-1 or a PD-L1 inhibitor.

VEGF plays a role in immunosuppression; blocking VEGF seems to essentially reverse some of that immunosuppression, primarily promoting T-cell infiltration into the tumor. That enhances the activity of these PD-1, PD-L1 inhibitors, and that would set the stage for IMbrave150 with atezolizumab plus bevacizumab versus sorafenib, which was a phase 3 trial that was first reported out at the ESMO Asia Congress, with an update on PROs [patient-reported outcomes] at ASCO GI This was a study that had 336 patients with 2 co-primary end points, including overall survival and progression-free survival . And response rate as a secondary end point, PROs and the quality-of-life measures, etc. The study hit every one of those points with a positive mark. Improvement in survival, improvement in progression-free survival, although the median progression-free survival was not as impressive, it’s the hazard ratio, that 30% of patients who seemed to derive the most benefit, with a hazard ratio of 0.59.

Interestingly, as expected, the toxicities were mostly hypertension in the atezolizumab/bevacizumab. And sorafenib is exactly where you expect it to be, with hand-and-foot syndrome, fatigue, and others. It’s quite a challenging drug. But most importantly, when looking at patient-reported outcomes, quality of life, and overall noxious toxicities, atezolizumab/bevacizumab essentially wins on every one of those points. So, you get better survival, better PFS, better response rate, better quality of life, PRO, better toxicity profile. You win on every point, and it brings back this flavor of immuno-oncology into the first line. I think that is a game changer. That changes how we treat patients in the first line for HCC, I’d say for most patients. It can’t be for all patients. There are certain caveats. But for, I’d say, 80%, 90% of our patients, that’s going to be the standard.

Amit Singal, MD, UT Southwestern Medical Center

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