Dr. Ghassan Abou-Alfa:
Welcome to The ASCO Post Roundtable series on hepatobiliary cancer. I am Ghassan Abou-Alfa from the Memorial Sloan Kettering Cancer Center in New York City. Joining me today are two of my colleagues. I’ll let Dr. Shroff introduce herself.
Dr. Rachna Shroff:
Hi, everyone. I am Dr. Rachna Shroff from the University of Arizona Cancer Center. Thank you for having me.
Dr. Ghassan Abou-Alfa:
Thank you so much for being with us. And Dr. Finn?
Dr. Richard Finn:
Hi. I am Richard Finn, a medical oncologist at the Geffen School of Medicine at UCLA and the Jonsson Comprehensive Cancer Center. It's good to be here.
Dr. Abou-Alfa:
Great seeing you both. Thank you so much. Today, we will be discussing recent updates in hepatocellular carcinoma and biliary tract cancer and the integration of these new developments into four patient case studies. Our second installment will focus on second-line therapy and beyond in hepatocellular carcinoma. Dr. Shroff and Dr. Finn, let's go ahead and look into our case on second-line therapy and beyond in HCC. We have a 63-year-old gentleman with a history of nonalcoholic fatty liver disease diagnosed with hepatocellular carcinoma metastatic to bilateral lungs, in adjunct to perihepatic and retroperitoneal lymph nodes. The patient had no response after 2 months of therapy on atezolizumab plus bevacizumab. Now presenting with progression of disease and multiple lung nodules and new right adrenal metastasis. With this, we'll start with Dr. Finn. What will be your choice for second-line therapy?
Dr. Finn:
This is a concerning case, because this is someone who pretty much blew through, for lack of a better term, one of the most active regimens that we have, which is atezolizumab/bevacizumab. For a patient whose best response is progressive disease with this regimen, we know that their survival is limited. I am going to assume that, even though they've progressed, this patient has maintained performance status and preserved liver function, hence they're a candidate for systemic treatment. As you know, we do not have prospective randomized data to tell us what the best treatment for this patient is. This is a new era post-front-line IO in the management of patients with advanced liver cancer. With that being said, we have many drugs that have been shown to improve outcomes for patients in the settings they've been looked at. Sorafenib and lenvatinib in randomized front-line studies. Regorafenib, cabozantinib, ramucirumab in second-line studies. Right after sorafenib, not even, let alone prior atezolizumab/bevacizumab or let alone prior lenvatinib. Also, in the United States, we have accelerated approval for ipilimumab and nivolumab after prior sorafenib. Pembrolizumab is approved after prior treatment with sorafenib. We have data in the front-line setting demonstrating that durvalumab and tremelimumab is better than sorafenib. Here's a patient who progressed on IO and I think that's not a good prognosis, but I would offer this patient lenvatinib, which I think is a reasonable front-line TKI for this patient. Honestly, I'm concerned that a singlet is not going to offer this patient what we really want for them, which is long-term disease control and even a response. There is some data with CTLA4 and PD-1 inhibition in patients who progress from prior IO. For example, there's been data with ipilimumab/nivolumab in the kidney cancer literature, as well as from Hong Kong, from Thomas Seattle's group in the liver cancer literature, where they've seen response rates of about 16% or so in both diseases. That might be something we consider for this patient. How do we rescue the patient who has progressed on front-line IO? That's the real challenge for us. I think as far as standard of care, single agent TKIs are acceptable, reaching out of the box considering CTLA4 an IO combination or even a TKI/IO combination.
Dr. Abou-Alfa:
Thank you so much, Dr. Finn. You bring up very, very important points. And let's dissect all of them, because you touch on key elements over here that can help our colleagues. Before we do that, and I'm going to go back to you with one question. But let me ask Dr. Shroff, in regard to the second-line therapy choice. As you can see, Richard had sighted for us all the choices of therapy. And as you and I know some of them are really evaluated in first-line therapy other than in second line, and the question to you is, would you consider that now that we really got the atezolizumab/bevacizumab as first-line therapy, would automatically jump to second-line treatment? Or do you still give a chance to first-line therapy like sorafenib or lenvatinib? How do you read this? What is your choice?
Dr. Shroff:
I think Dr. Finn said this really well in the sense that this is essentially a data-free zone and we're really extrapolating here. I think in somebody who we are now basically resetting and starting with atezolizumab/bevacizumab, I think it's very reasonable knowing that an appropriate next choice would be a VEGF TKI to use one of what was initially thought of as front-line TKIs. My preference would be lenvatinib over sorafenib. Given that we are learning more and more about this drug, I think it is a better choice from a VEGF TKI perspective. I agree that I don't necessarily think that you would be "wrong" to consider cabozantinib or some of the other options. It's just more of a question of how we can sequence this assuming that these patients are able to make it to second-, third-, fourth-line therapies. How can you use the tools in your toolbox, one by one? I do agree that for somebody who has essentially had progressive disease through atezolizumab/bevacizumab, it's a harbinger of this being a really aggressive disease state and I don't really know how much we're going to do. It makes me wonder about the outcome of this therapy in the setting of considering rechallenging with immunotherapy and offering an anti-CTLA4 again to somebody who progressed right off the bat to checkpoint. I would really lean towards the VEGF TKI with the recognition that we may be in trouble for this patient.
Dr. Abou-Alfa:
Great. You bring two important points here and I like the way you stated it, which is technically we have assets: sorafenib and lenvatinib. We don't want to lose them and jump onto the second-line options. But at the same time, you are not faulting where we really think that after all this is a cabozantinib era for that patient, now that they failed on first-line therapy. As you said, and I totally agree with you Dr. Shroff, we really don't have good data on that. But I think, we can see that all three of us are not ready to toss out the lenvatinib and the sorafenib, because there could still be value in them. Now, I'll go back to Dr. Finn. You mentioned in the beginning that it's a very concerning case and I totally agree with you. You said that because after all the case got a great regimen and still no benefit. However, I would like to ask you, if besides that there was no benefit from the atezolizumab plus bevacizumab, which of course can happen with any therapy, what is the possibility that the patient could have developed antibodies to the atezolizumab after all? What's the story there?
Dr. Finn:
You're referring to anti-drug antibodies (ADAs), which occur with most biologics with some incidents. Atezolizumab of the anti–PD-1 antibodies has been reported to have the highest frequency of these antibodies. They are not auto-antibodies. They are acquired antibodies, so we don't have them innately but they're acquired over time. Also, in the FDA label for atezolizumab/bevacizumab, it suggests that patients who develop ADAs do not benefit as much. At this point, we don't have a clinical test for ADAs. The dosing of atezolizumab is designed to hopefully counteract the ability of these ADAs to interfere with its activity. And in this case specifically, it was such a short exposure, right? Progression, boom, right off the bat. I don't know that we can say that ADAs are playing a role in resistance here. It's really going to be clinical judgment when we come to an expertise, because we're in a data-free zone as Dr. Shroff said. Clinical judgment on how to manage this patient.
Dr. Abou-Alfa:
I think you said it right. And this is really where it's a bit of an unknown, it becomes a clinical judgment component. But at least, I'm glad that you brought it up and we have to be cognizant of that specific anti-drug antibody as you said, which is the most common or happening more in atezolizumab compared to other checkpoint inhibitors. Now, I would like to reverse the question and go back to Dr. Shroff one more time. Let's assume for argument’s sake and only for educational purposes for our colleagues, that this patient started on lenvatinib single agent. Then, let's assume there's progression on lenvatinib. In that setting, what will be our second-line therapy?
Dr. Shroff:
It would be important to just acknowledge that hopefully there was not some contraindication to doing immunotherapy. But presuming that's the case, again, with recognition that there is no prospective data that supports this, I think my feeling would be to move to an immunotherapy-based regimen. Now, as Dr. Finn explained, we have the option of nivolumab/ ipilimumab, but again, if it were up to me, if there was not a contraindication to considering something more of a VEGF with IO combination or maybe a durvalumab/tremelimumab combination. I think both of those would be in the space that I would gravitate towards. Some of it, I think might be driven by how the patient did on lenvatinib and whether or not they had some response, did they have a duration of response, did it seem that VEGF inhibition did something? If it seemed like this patient just blew right through a VEGF TKI, I would consider a more of a durvalumab/tremelimumab approach. This is taking into consideration that there isn’t a study that supports that.
Dr. Abou-Alfa:
By all means, that is really very important. I like very much what you said Dr. Shroff, because after all we're seeing that there is a little bit of a two-way street in regard to the vertical use of first, second-line therapy, because ultimately, we're trying to make sure we give the opportunity for all patients to get all the options possible. Interestingly, we're also getting a horizontal back and forth in regard to sometimes even treating patients with systemic therapy for presumably a local disease. Now, they're available for local therapy or vice versa as well. But let's go back to our case one more time. Dr. Finn, you brought it up that maybe we can "rechallenge" the patient to go to checkpoint inhibitors. Tell us what data is available from any entity, not only HCC. And the question is, if you were to challenge with checkpoint inhibitor, is it a matter of just changing the anti-PD-1/PD-L1 or also changing what you're combining with?
Dr. Finn:
That's an excellent question. As I alluded to the data that I'm most familiar with in this era, this data comes from the kidney cancer realm, which is where front-line IO has also played a big role and then there is some data in the liver cancer space given that these drugs have only been around for a few years in the front-line setting. Interestingly, both data sets give similar results which are response rates of around 15% to 20% with CTLA4 and IO combinations, CTLA4 and PD-1 combinations after other front-line IO. The real question for this patient is how much time do I have to try different regimens, right? Is this a patient who has progressed so quickly and I only have one last shot before they decline so much that they can't tolerate treatment or is this patient someone who's really going to go to third- and fourth-line? In which case at the end of the day, they will see many different drugs available. And I think the attractiveness of continuing the IO approach is to try to get a response, to try to put out this fire. And there's a study, for example, in Europe currently and also going to be open in the U.S. for patients who get atezolizumab/bevacizumab at progression, they would get atezolizumab/lenvatinib vs lenvatinib alone in this study. A very interesting practical approach changing out the VEGF from a pure VEGF antibody like bevacizumab to a multikinase inhibitor like lenvatinib, which we see increased response rates in the front-line setting. These approaches, I think, are very interesting. We're waiting for data, but we do have some of these tools available to us in the United States because of approvals of so many options. Also, I think, we really need to advocate for our patients and try to get them whatever we think is the best option.
Dr. Abou-Alfa:
Thank you so much for that. We can see how much Dr. Shroff and Dr. Finn, myself, were taking our time to really think about those questions, for which to be fair, we don't have full answers yet. However, we're not going to leave you a little bit and kind of what shall we do? Let's wrap up with some of the key clinical takeaways that we learned from this case in second line. A patient with disease progression after prior checkpoint inhibitor should surely receive a VEGF tyrosine kinase in the second-line setting as we just heard. At the same time, patient with disease progression after VEGF tyrosine kinase inhibitor should receive a regimen that includes immune checkpoint inhibition as we also heard. And interestingly, the unused first-line therapies in the first-line setting should not be ignored. They should still be considered. With this said, this brings us to the end of this case. Please see the other segments for further discussion about the latest data in hepatobiliary cancer or visit ascopost.com.
