Dr. Ghassan Abou-Alfa:
Welcome to The ASCO Post Roundtable Series on updates in hepatobiliary cancer. I’m Ghassan Abou-Alfa, from Memorial Sloan Kettering Cancer Center, New York. Joining me today are two of my colleagues.
Dr. Rachna Shroff:
Hi everyone. I’m Dr. Rachna Shroff from the University of Arizona Cancer Center.
Dr. Richard Finn:
Hi, Richard Finn. I’m a medical oncologist at the Geffen School of Medicine at UCLA and the Jonsson Comprehensive Cancer Center. Thanks for having me.
Dr. Abou-Alfa:
Today we’ll be discussing recent updates in hepatocellular carcinoma and biliary tract cancers, and integrating these new developments into four patient case studies. Our first installment will focus on front-line therapy in metastatic hepatocellular carcinoma. Let’s talk about a 71-year-old woman with a history of hepatitis C, which was attributed to a dental intervention with nonsterile instrumentation 30 years ago. The patient was treated with interferon to no avail, and received direct acting antiviral therapy with sustained virological response 5 years ago. Now we've cured the hepatitis C and presumed no concern for the development of HCC (hepatocellular carcinoma). The patient was then lost to follow up. Until now, when she presented to the emergency room with severe right upper quadrant pain. The CT scan, done as part of the evaluation of the chest and the pelvis, showed four phase liver imaging with a 10-cm liver mass in the right side of the liver, and 10 bilateral lung nodules up to 2.5 cm in size. In addition, a 1-cm bone lesion was noted in the T spine. Overall, the patient has hepatitis C, liver disease, and potential lung and other bone metastases. Dr. Shroff, would you do a biopsy for this case?
Dr. Shroff:
I think this strongly looks and sounds like a case of hepatocellular carcinoma in a patient with underlying hepatitis C. There is also possibly cirrhosis, assuming that the radiographic imaging meets the LI-RADS criteria. And I would definitely recommend an AFP as well. I don't know if you need to perform a biopsy, assuming that those radiographic criteria are met. I would not rush to it, but we would need to make sure that the imaging is compatible with that.
Dr. Abou-Alfa:
Let me reflect on that. But let's hear your thoughts, Dr. Finn.
Dr. Finn:
I largely agree with that. If this patient has cirrhosis, a history of hepatitis C, is not enough. But if they have evidence of cirrhosis on imaging or laboratory assessment, and do have criteria that meets the LI-RADS criteria, LI-RADS 5, being very sensitive, very specific for liver cancer (not 100%), I would not necessarily pursue a biopsy. The question is, how does it change our management? Molecular studies have not impacted our decision-making on liver cancer. This could be another malignancy and, cholangiocarcinoma is in the differential. But in someone who does have cirrhosis and it's LI-RADS 5, we could say with pretty good confidence that this is liver cancer.
Dr. Abou-Alfa:
Thank you, Dr. Shroff and Dr. Finn. I totally agree with what Dr. Finn said, the cirrhosis is a key component to really assess what we are dealing with here. Understandably, a patient with hepatitis C, no doubt, is more likely to have cirrhosis, because after all this is how HCC develops in patients with hepatitis C. But on the other hand, I would say that maybe the biopsy might still be needed. I would like to further enhance my answer today, because as we just heard at the latest ILCA meeting in Madrid where there was a big debate about the LI-RADS evaluations the radiologists who really built the LI-RADS system pretty much stated that, after all, we don't have data in regard to the setting in metastatic disease. And if anything, most of the LI-RADS evaluations are coming from early-stage disease. And as such, with lack of data, I would say a biopsy might be needed. And I agree with Dr. Finn, that we must ensure that we confirm the diagnosis and that it is appropriately correct. Knowing this, we know very well that, the LI-RADS at later stages of disease, starts degrading in regard to its value and reaches a certain sensitivity and specificity in the 60% to 70%. I like that not only will the biopsy help us confirm the diagnosis but also will help us know the genetic makeup of the disease. Dr. Shroff is one of the world’s experts on this topic. Interestingly, we are not aware of that many therapies for hepatocellular carcinoma based on targeted therapy. That is why we're not doing that many biopsies after all. If anything, in one of the efforts that were reported from Memorial Sloan Kettering, we looked into the next-generation sequencing of patient with hepatocellular carcinoma. And it was a rudimentary and early approach of evaluation, where we looked and we found that patients might fall into three categories or along three pathways. One of them is WNT/β-catenin, p53, and we call the third "other" because we didn't know more. I would say so far, and based on the read from our colleagues in radiology, LI-RADS is great, but we are short of really assessing what's cirrhosis and what's not, even though we can't suggest it. But number two is that the LI-RADS data is not really the one that was evaluated in the advanced stage disease.
However, for now we're going to put this at rest, and go ahead into the therapy. To remind you, Dr. Finn and Dr. Shroff, a 71-year-old lady, with hepatitis C, and now we have a liver lesion. Let's assume we did the biopsy on the liver mass, we have spread of the disease in the lung, we have the bone lesion as well. My question to you then is, (I'll start this time with Dr Finn) what do you recommend as first-line therapy for the patient with HCC in that setting?
Dr. Finn:
There are still some pieces of information that we want to know about this patient. Staging in liver cancer takes two pieces. One, the anatomic stage, which we know very well. This patient has metastatic disease to the lungs and the bone and advanced cancer. The other part is what is her liver function? Because if we look at the competing risks for the outcome for patients with liver cancer, the prognostic things are not only tumor burden, but their liver function. And that is why we want to know if this patient has portal hypertension? Are they thrombocytopenic? Do they have upper GI varices, do they have varices that could bleed? What is their bilirubin, albumin, INR? Does she have a history of ascites, encephalopathy? Things that could go into the Child-Pugh class? Because certainly, depending on those things we could determine what we have available and what is appropriate for her treatment. There's been a lot of advances in first line treatment of liver cancer that have really changed the natural history of this disease, but patient selection is key.
Dr. Abou-Alfa:
I very much like what you said, Dr. Finn. It is very important. For our dear colleagues who are listening to us. It's very critical to note that, what Dr. Finn gave us a presentation of is that when we talk about the patient with HCC, our knowing that it is stage four HCC is not enough. We really need the answer with regards to the liver performance, and at the same time look into those components that can really help decide what the therapy looks like. Let's assume, and this is exactly what happened with this lady. Let's make sure that, yes, her Child-Pugh scoring is Child-Pugh score A, great liver functionality, relatively speaking. And number two, yes, she was endoscoped and there are no varices. Dr. Shroff, in that setting, what would be your therapy?
Dr. Shroff:
I love the fact that I get to answer this, since Dr. Finn is sitting right here. But in the setting of somebody with very well-preserved liver function, which albeit all of the studies that we have really is, in that group of patients with Child-Pugh A cirrhosis, and in somebody who does not have any varices at risk for bleeding, I think the gold standard for me would be to move to atezolizumab/bevacizumab in combination for this patient. And I think that to me, to date, the data that we have, is the strongest and has demonstrated the greatest impact in terms of outcomes in overall survival for a patient like this.
Dr. Abou-Alfa:
Fair enough. And I totally agree that the IMbrave150, that Dr. Finn was actually the lead investigator on, showed us improvement in survival in regard to the atezolizumab plus bevacizumab. That's what we like to do very much among ourselves as dear colleagues. So of course, Dr. Finn, there is something else we can use for the patient. It may not be approved by the FDA yet, but do you have any thoughts?
Dr. Finn:
Sure, there are several available options. We must keep in mind, the biggest impact in the past few years has been the introduction of immunotherapy: PD-1, PD-L1 inhibitors, and then combinations thereof. With that in mind, for many years, we have had sorafenib and lenvatinib as well, in the front-line setting. But we see that, again, the greatest improvements in disease control and improvements in survival are with IO combinations. IMbrave150 looked atezolizumab and bevacizumab. While we wait for the FDA approval, we've seen in the HIMALAYA study (data that you presented at ASCO GI this year and subsequently published in NEJM Evidence in June). This is a very provocative study because it looks at dual immunotherapy, two checkpoint inhibitors, in the treatment of liver cancer in the front-line setting. The so-called STRIDE regimen looks at durvalumab, PD-L1 antibody, in combination with tremelimumab, a CTLA-4 antibody. Interestingly, this regimen, which differs a little bit from ipilumumab and nivolumab, which is approved in the second line setting, involves four doses of CTLA-4 loading. With the STRIDE regimen, patients get a single dose of tremelimumab upfront in combination with durvalumab, and then continue on durvalumab every three weeks. This study showed that, compared to sorafenib, we had an improvement in survival as well as an improvement in objective response rate. There was not a significant change in PFS, however it was very well tolerated, actually lesser adverse events than sorafenib, though obviously immune-related adverse events occurred with this regimen. So that would certainly be another choice. Personally, I would go with IMbrave, atezolizumab/bevacizumab in this patient, because I think the objective response rate is higher and we saw a greater risk reduction for survival with atezolizumab/bevacizumab, as well as a PFS improvement.
Dr. Abou-Alfa:
Yeah, thanks so much to both of you, and no doubt this is kind of very intriguing, because data continues to evolve rather very rapidly in front of our eyes. Actually, literally, all of us attended two important meetings, the ILCA meeting in Madrid, as well ESMO in Paris. A lot of data came out in those two meetings, from which, the LEAP-002 study of the pembrolizumab plus lenvatinib, was surprising. I In a way, we respect that it did not show a benefit, even though, interestingly, it showed a rather unexpected superior benefit for the TKI (lenvatinib) of 19.2 months, which we've never seen before. On the other hand, in ILCA, we saw a retrospective analysis that looked into the atezolizumab plus bevacizumab. They looked at the AB-Real study retrospective analysis, and they came out with the real world data, with a median survival only of 15.73 months. I think it's still great when compared to the IMbrave150. I'll ask two questions here, one for each one of you. Number one, Dr. Shroff, in regard to the LEAP-002 study and with the lenvatinib 19.2 months, within the context, we don't know the full detailed data yet because there's no manuscript. What are your thoughts on it?
Dr. Shroff:
I think that this is a good problem to have, in the sense that we are learning that some of our single agent TKIs are performing better than what we saw initially in the REFLECT study. I think some of this also has to do with overall better care of patients, with their liver function and preservation of liver function, and the ability to get sequential therapies, and the number of therapies that are available to our patients. As such, we're looking at what is a really different landscape in terms of treating HCC compared to when the initial lenvatinib data came out. I think we now have two separate studies that are looking at a TKI and IO combination, between COSMIC and LEAP-002, and I think there's probably something to be said that that combination is different than a monoclonal antibody against VEGF with IO. I don't know that you can rationalize that the study was negative simply because of the lenvatinib arm doing better. But, I do think that it speaks volumes to the fact that lenvatinib is clearly a good single agent option for patients for whom you may not be able to offer IO based approaches. I think that's an important thing to keep in mind, because there are patients who can't undergo immunotherapy-based treatments.
Dr. Abou-Alfa:
I love what you said. Good problem to have, no question. Dr. Finn, what are your thoughts on the AB-Real study retrospective analysis, considering that our colleagues in England actually reported that outcome?
Dr. Finn:
I think real world data is important because not every patient that we see in the clinic reflects a phase III, randomized, placebo-controlled study inclusion criteria, etc. Also, I think we look for trends in that real world data. Obviously, if it is uncontrolled data, it's very difficult to derive conclusions. Certainly, safety is very important when we look at real world data. Also, the size of the data set matters; some real-world data sets are well over a thousand patients, as we're seeing with regorafenib for example, and the REFINE study, vs this data set from the UK, which I think was relatively small. But I think it assures us that the regimen is safe and well tolerated. Hence, I think for those of us who have had experience with the regimen, we see that as quite active, especially when we start seeing objective responses, something that we are not used to seeing in liver cancer.
Dr. Abou-Alfa:
I totally agree, and thank you so much for both your opinions on this. If anything, we can conclude that maybe a biopsy is a key diagnostic confirmation in metastatic disease, after all. Another point is, as we just heard from our colleagues, the first line therapy is, that doublets with immunotherapy or doublets with immunotherapy plus an anti-VEGF will be very valuable. And this is based on the many trials that we discussed. We also have lenvatinib now, that kind of came out with an improved survival rate. And just wondering about, is it the population? Is it what patients receive as secondary therapy? Or is it simply, it's a great, powerful, and very important tyrosine kinase inhibitor. Two important points that we did not discuss, but very important to bring to the attention of our colleagues are: Number one, the patient had, if you recall, one lesion in the bone. Interestingly, this definitely can be more metastases, because after all, now there's data that shows that 30% patient with HCC can have bone metastasis. And number two, the issue of hepatitis C: Remember the patient was cured from hep C, and now she has recurrent HCC. Let's assume that, after all, there is a potential that the HCC will reactivate itself, because there's a potential it can. Now we have data that looks at treatment of HCV in the context of HCC, and maybe yes, it could be suggested as well, as per the data reported by Singal and colleagues. We'll pause here, and we end the discussion of this case. Please see the other segments for further discussion about the latest data in hepatobiliary cancer, or visit ascopost.com.
