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.

Videos

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.

IO and VEGF Inhibition in Hepatocellular Carcinoma

I think these concepts are critical for the community physicians to have an understanding of, especially now that we not only have new front line, second line, but even drugs beyond that, third line, fourth line. And historically speaking, Katie, 10 years ago, who would have even thought we’d be having this discussion? And so it’s a very exciting time for liver cancer. With that in mind, I think we should delve into some of the data that are driving a lot of this excitement.

Historically speaking, before we had sorafenib’s approval in 2007/2008, as you’ve touched on, Katie, locoregional treatment filled a void, right? We had patients who had progression in the liver despite vascular invasion. Even patients who might have small extrahepatic disease would continue to get locoregional treatment. And the approval of sorafenib in 2008, which I think many people are familiar with now, that data, the SHARP study which showed a 31% decrease in the risk of death with sorafenib versus placebo. At that time, a placebo-controlled study could be done because no systemic treatment had been shown to improve survival. And we saw that for the first time, median survival was improved with a systemic drug with an adverse effect profile that is manageable, I would argue. VEGF adverse effects such as hypertension and proteinuria were not so severe with sorafenib, but more commonly, GI toxicity as well as hand-foot-skin syndrome were typically the dose-limiting toxicities. And we learned how to manage sorafenib, the full dose being 400 mg twice a day. And many of us have learned to dose adjust or use supportive care measures to keep patients on sorafenib.

The approval of sorafenib left us with a lot of unmet needs, I think. Specifically, we wanted something that did better than sorafenib. We needed something to do when sorafenib wasn’t working. We needed something when patients could not tolerate sorafenib, despite supportive care measures. I remember giving interviews in 2008 about what does the next 4, 5 years of liver cancer look like. And I said, "Sorafenib’s ushered in the golden age. We’re going to have so many new approvals.” I was off by about a decade. But we tried for a long time and had numerous negative studies. And this was not because of lack of trying. But I think our insight into how these drugs work and our expectations in clinical trial design just were not mature enough. Sometimes, you need to fail a few times to learn.

That changed in 2018 with the REFLECT study, which was the lenvatinib approval. We saw with lenvatinib that we had a new drug, a new option for liver cancer. When we looked at the survival data, it was noninferior, so it was no better and no worse, essentially, for its effect on overall survival. But it did delay progression. It did have a little different adverse effect profile as far as a lower incidence of hand-foot-skin syndrome, a higher incidence of hypertension. And it did have higher response rates. By RECIST, we saw response rates of around 18%, 19%. That was new, because sorafenib, while it improved survival, which all of us, I think, would agree is the most important end point in our liver cancer studies, it didn’t give us a high response rate. I think it was challenging for other physicians in the space to appreciate the importance of a drug that can improve survival but doesn’t necessarily shrink tumors.

Since that time, we’ve had a number of TKIs [tyrosine kinase inhibitors] approved, mostly in the second-line space, which we’ll talk about. Recently at ASCO [the American Society of Clinical Oncology annual meeting], we saw some interesting data with a novel TKI, donafenib. And this was the first time we saw a small molecule beat sorafenib. This study was done essentially in China, so its applicability to the Western population that we see, I think, is still lacking. But interestingly, this was one of the first TKIs that beat sorafenib and had a little more favorable adverse effect profile for TKIs.

Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma

Reena, we want to find liver cancer early because presumably it’s the most curable—resection, transplant, even radiofrequency ablation in small tumors. How do we think about the clinical aspect of liver cancer, specifically staging? Can you speak to Barcelona [Clinic Liver Cancer staging system]? Because I think that’s probably what people hear the most now. It’s used the most, the BCLC.

Yeah, that’s correct. Most commonly, we’ll use the Barcelona Clinic Liver Cancer staging system, or BCLC. And through the multidisciplinary liver tumor boards that I think most of us participate in on this panel, that’s really where we tend to link the staging with treatment options for patients. The advantage of BCLC being that it’s combining not just the tumor burden, but also the specific liver function as judged by the Child-Pugh status of the patient, knowing that most of these patients have a background of chronic liver disease or cirrhosis, and then also integrating the performance status, so all 3 parts, and then being able to further subdivide them into the options for treatment and prognosis.

 Probably the most common group of patients we see at presentation are patients with intermediate liver cancer. If anyone thinks otherwise, please let me know. Certainly, we see all stages. And hopefully, as we have earlier diagnosis, we’re seeing more patients with stage 0 or stage A, which is curable. But a lot of them are stage B, which are intermediate. These are patients who generally have well-compensated liver disease and multifocal tumor in the liver but do not have extrahepatic disease and do not have invasion to the vasculature. Historically, the standard of care for these patients has been locoregional treatment, such as chemoembolization and increasingly radioembolization with Y-90 [yttrium-90]. Some of these patients will be considered for transplant, they can be down-staged to transplant. I think this is a whole other discussion beyond the scope today, but I think highlights the point that these patients should be seen at a multidisciplinary program for an evaluation because of the importance of surgery and interventional radiology expertise. As compared to those patients who we’re talking about who are advanced, a lot of those patients would get systemic treatment, who have symptomatic disease, they have extrahepatic spread, or they have vascular invasion into the blood vessels of the liver. Certainly, a patient can stage-migrate. Someone with intermediate disease can progress beyond TACE [transarterial chemoembolization], or locoregional treatment, and become truly advanced, or even a patient who has [BCLC] stage B intermediate disease without vascular invasion or extrahepatic spread might be a patient for systemic treatment.

So Katie, all of us here see a lot of these patients, and we rattle these terms off pretty easily. But I think in clinical practice, as we have evolved into so many more treatment options, it’s going to be very important for the people in the trenches in the front line in the liver cancer space in oncology clinics, and hepatology clinics and GI [gastrointestinal] clinics, to have an understanding of this. Could you build out the multidisciplinary platform and stage migration and treatment decisions?



: I think this is a great area of discussion, and it’s important to reiterate the historical context here to remember that really, from 2007 until 2017, we had but 1 treatment available for systemic therapy, which was sorafenib. After that, there were clinical trials certainly, but very limited options for the majority of patients. That led to the evolution of locoregional therapy as the predominant mainstay of therapy for intermediate and sometimes even early advanced stages of HCC [hepatocellular carcinoma], and it’s really incumbent upon us now to reexamine the data, both for liver drug therapies, but also place it into context of the new systemic therapies. I think it’s important for us to remember that we do have limited prospective data for liver-directed therapies, particularly in the more advanced BCLC stage B space where the patients are having more than 3 to 5 lesions or getting more than 1 or 2 TACE procedures. Beyond those thresholds, we don’t have randomized trial data to confirm outcome benefit in large prospective trials. Likewise, we know from radioembolization trials that patients with more advanced stages of disease really do better with sorafenib, where there is no survival benefit to radioembolization in randomized trials compared to sorafenib in more advanced patients.

I think now that we have level 1 survival benefit in patients with unresectable, incurable HCC, including BCLC B or intermediate-stage patients, we need to be very careful about the use of locoregional therapies in patients who might have a survival benefit preferentially from systemic therapy. There are tools at our disposal to use, not all of them as well-validated as we may like, but for example, the prospective hepatic arterial embolization prognosis score that can help stratify patients according to their likelihood of benefit from TACE procedures, or patients who have already had a TACE procedure to look at toxicity and response such as the ART [Assessment for Retreatment with TACE] score. Those can help us potentially triage patients to switch over to systemic therapy, depending on their performance and their scoring. Now, all of this is complicated and absolutely enhances the importance of the multidisciplinary tumor board contexts, because these are complex decisions and lots of variables, including not only tumor response, but also liver function or deterioration thereof. I think that with this increase in options for systemic therapies, it requires us in medical oncology to become more present in the multidisciplinary tumor board setting to help guide and educate on the multiple therapies that we now have available.

You bring up some very important points. One of the concerns I think in continuing locoregional treatment beyond progression is that it could affect liver function. Amit, I know you’ve done some of these analyses. Continued locoregional treatment, while it’s very focused, very targeted, can you comment on its effect on the liver function over time?

Yes, what we see is that as Katie mentioned these scores, you can see that some people, when you go through locoregional therapy, you start to see basically off-target effects. You see some degree of injury to the background liver, and when you do this over and over again, just like any chronic injury, you can have deterioration of liver function. The most important reason that we have to consider this is because essentially, if somebody has worse liver function, then we may not be able to actually use these systemic therapies. I think that’s why we’re all becoming much more cognizant in terms of this appropriate time to transition and trying to maximize not only the benefit of locoregional therapy, but also maximizing the benefit and the availability of these systemic therapies.

Locoregional and Systemic Therapy for HCC

Reena, could you walk us through your patient who has an ultrasound in the background of chronic liver disease and has a nodule? How do we work that up?

Typically, for the majority of patients, the mainstay of diagnosis is going to be with dynamic multiphasic CT or MRI, preferably MR for purposes of sensitivity and specificity characteristics. We try to reserve doing a biopsy in, generally, under 10% of cases, if we see atypical features on the multiphasic imaging. That’s most commonly what we do. There are still areas, both from the imaging standpoint, as well as tissue diagnosis, where we have some limitations in diagnosis. One of the things that we certainly hear about as a diagnostic tool for a lot of other oncologic diagnoses is PET [positron emission tomography] scan and we tend to order this less frequently or rely on this less commonly for a diagnosis of HCC [hepatocellular carcinoma]. Much of that has been based on the lower sensitivity for detecting HCC generally felt to be inadequate to consistently rely on that for purposes of sensitivity of diagnosis. Some of the data that have come out have suggested that the level of differentiation of the tumor can be associated with characteristics of FDG [fluorodeoxyglucose] uptake. A more poorly differentiated HCC, for example, would be more likely to be PET-avid, and that may help in diagnosis of metastases in the future. There are also some data emerging looking at other tracers, radiotracers, that could expand on our utilization of PET scan in the future.

You bring up a great point that I think a lot of us in the cancer medicine research area are very sensitive to, certainly because of how it’s impacted other cancers we treat, and that is tissue. Here is a disease where you just said we only get tissue on less than 10% of patients historically because we can make the diagnosis noninvasively with CT or MRI, and that PET/CT doesn’t necessarily add much or actually might miss some tumors. So, if we don’t have tissue, how are we going to move to personalized medicine in liver cancer? Is there a role for these molecular testing modalities?

Certainly there’s a need for it, especially in this condition. One of the historic challenges of the molecular markers in testing in HCC has been the varied genetic profile. I think as more and more clinical-trial-based data have emerged, the hope is that we’ll be able to more reliably apply molecular targets, with the aim of precision medicine in mind for HCC as well. Historically, we’ve relied on AFP [alpha-fetoprotein]. I know Amit touched on AFP for screening purposes, and later on, we’ll talk about it more in terms of what we know in terms of AFP correlating with response to treatment. I think the goal is to expand the molecular targets and apply that to the individual patient and their treatment. There are more emerging data, though. I’m looking at some of these targets in HCC and circulating tumor DNA or doing liquid biopsies, all oncologic diagnoses, but applying that to HCC as well, and through that developing hopefully some reliable assays in the very near future that we can use both for screening and diagnostic purposes.

Anthony, how often do you end up sending NGS [next-generation sequencing] on your patients with liver cancer? Is that something you do at the get-go, like you might do in cholangiocarcinoma versus this disease?

: Certainly not. I think most of the NGS work that we do or others do is related to research. At this point, when we look at HCC, most of the targets that are altered in this disease appear to be not druggable, at the moment, at least. The more frequent alterations are not easily targetable with specific drugs. Now, this is changing gradually, as Reena mentioned. We do see targets such as 

, and others that are evolving. Many clinical trials are coming that are more tailored to specific alterations. So I think at this time, the clinical utility is limited, unless the patient has refractory disease and still has conserved liver function, where you may find an alteration that could be targeted, mostly in a clinical trial.

Katie, how about at UCSF [Helen Diller Family Comprehensive Cancer Center]? Do you biopsy everybody and send it for molecular testing?

 That’s a great question. I think particularly with the advent of more treatment options for both HCC as well as cholangiocarcinoma, our tolerance of a misdiagnosis or missing the most common alternate diagnosis of a biliary tract cancer is much lower. Even putting molecular profiling aside, we are tending to do biopsies for patients with advanced disease prior to systemic therapy much more frequently than before in patients who are fit for systemic therapy. Again, I agree with Anthony’s point that we don’t have a great established clinical target yet for NGS profiling in HCC, and I hope that will change with FGFR or 

 and other targets. I think it’s more that now that we do have multiple therapies, both for HCC and cholangiocarcinoma, we really don’t want to miss the alternate diagnosis.

Sure. There are a lot of exciting things in that diagnosis evolving over time.

Hepatocellular Carcinoma: Diagnostic Work-Up

You mention the word “surveillance.” Liver cancer is an interesting disease because like a lot of cancers, I guess it’s curable. But you commented on people who are at high risk. Should we be checking alpha-fetoprotein in these people? Is that how we identify this disease early, or any thoughts on that?

 With this identifiable target population and the vast difference in prognosis between early detection and advanced detection, despite advances in the advanced stage, it’s really important that we find this early so we can apply curative treatments, like you said. Surveillance is typically recommended using abdominal ultrasound with or without alpha-fetoprotein. The data suggest that alpha-fetoprotein actually does add something when you use it with ultrasound. Current recommendations, at least based on the data we have, suggest you should be using the two in combination every 6 months in any patient with cirrhosis.

 Reena, you’re a hepatologist, and you’re seeing these patients before necessarily the oncology community does. What about for patients who are obese from fatty liver disease and NASH [nonalcoholic steatohepatitis]? Is ultrasound the perfect test for them?

: That’s a great point, Rich. You’re absolutely right. In that patient population, we’re certainly challenged with the performance characteristics of ultrasound, in the obese male population, the growing fatty liver population, and any time a patient has ascites as well, these are limitations to the characteristics of ultrasound.

One of the things that I find frustrating, though I think I understand, is the US Preventive Services Task Force [USPSTF], they make the recommendations for screening, colonoscopy, mammogram. Still, screening for liver cancer is not something they’ve recommended. Reena or Amit, can you speak to the reason for that?

 Rich, the data for surveillance are good, but not optimal. What we have in the setting of cirrhosis is that we have many cohort studies, and largely retrospective cohort studies with limitations, like lead time and length time biases. When a randomized-controlled trial was attempted in the past, it actually failed to accrue and had to be shut down. I think without this level 1 data, the USPSTF has been reluctant to put forward a recommendation for HCC [hepatocellular carcinoma] surveillance. I think we’ve seen this in other cancers, where these recommendations are somewhat rushed out, then the USPSTF has to pull back. I think that given this controversy, for example, with prostate cancer screening, breast cancer screening in younger women, we’re finding that these organizations would rather have the data be there up front so they can make a recommendation, and everyone can feel truly confident that that is the right thing to do.

Surveillance for Hepatocellular Carcinoma

® titled, “Hepatocellular Carcinoma: Practical Implications of Emerging Data.” I’m Dr Richard Finn from the David Geffen School of Medicine at UCLA. I’m joined by an outstanding faculty today for a discussion, including Dr Bekaii-Saab, from the Mayo Clinic in Arizona; Dr Anthony El-Khoueiry, from USC Norris Comprehensive Cancer Center here in Los Angeles; Dr Katie Kelley from the University of California San Francisco Helen Diller Family Comprehensive Cancer Center; Dr Reena Salgia, from the Henry Ford Health System; and Dr Amit Singal, from the UT Southwestern Medical Center.

Today, we are discussing a number of topics regarding the use of systemic treatment in advanced liver cancer. We’ll discuss the latest research in the field, including from the ASCO [American Society of Clinical Oncology] 2020 virtual meeting, and the impact of recent clinical trials on making decisions around treatment selection.

Let’s get started with our first topic, early stage liver cancer. Amit, could you walk us through some of the epidemiologic factors in regard to the development of early liver cancer and how we can impact our patients?

Yes, I’m happy to, Rich. First, it’s exciting to be part of this great panel. As we know, HCC [hepatocellular carcinoma] is the fourth leading cause of cancer-related death worldwide, and we know that it’s not evenly spread across the world. The highest incidence and mortality rates are in East Asia and Africa, and this is driven by high rates of hepatitis B in those areas. In the United States, this is a cancer that’s gaining more attention because of the rapidly rising incidence and mortality rates. When you look at the last 15 years assessed by SEER [the Surveillance, Epidemiology, and End Results program], HCC has had one of the largest rises in incidence among all common cancers. It’s projected if this continues that HCC could become the third leading cause of cancer-related death here in the United States. One of the unique things about HCC is that we have an identifiable target population. It primarily develops in those patients with chronic liver disease, and over 90% occur in the setting of cirrhosis. This can happen from any host of chronic liver diseases, including viral hepatitis, like hepatitis B or hepatitis C. There is a certain proportion due to alcohol-related liver disease. And we’re finding more and more is related to what is now called metabolic-associated fatty liver disease, which is liver disease that happens in the setting of obesity and diabetes. As those become more common in the United States and worldwide, we’re seeing more HCC related to this etiology.

: We’ve heard a lot about the new advances in hepatitis C treatment, right? Is liver cancer going to go away now that we’ve cured hepatitis C?

: I wish that was the case. You’re right that when we treat viral hepatitis, we see a nice drop in the HCC incidence. But the first thing is that once you have cirrhosis, that doesn’t go away completely, you don’t eliminate that risk. Those patients still have an annual incidence rate above 1%, and therefore continue to need surveillance and need to be observed for the development of HCC. Even if we get rid of viral hepatitis, as I said, we still have large proportions that are related to alcohol and metabolic-associated fatty liver disease, and increases in those areas are likely largely offsetting any decreases in HCC-related viral hepatitis. I don’t think this is a disease that is going to go away anytime soon.

Richard S. Finn, MD, Geffen School of Medicine

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