Ghassan K. Abou-Alfa, MD: This is very important to bring up, and another discussion that’s important in regard to later lines of therapy will come into play now that you’ve brought up the different choices. We’ll discuss this case, and I have a key element that I will discuss with our colleagues. This is a 63-year-old gentleman with a history of hepatitis C, chronic; his diagnosis started 8 years ago, no radiographic features of cirrhosis. It’s the same case we just spoke about. The patient has abdominal pain, performance status is good, mass in the liver of 2.7 cm, 3 satellite lesions. A biopsy confirmed HCC [hepatocellular carcinoma], unresectable. He had transarterial chemoembolization [TACE] 3 times, excellent response, got atezo [atezolizumab] and bev [bevacizumab], as we know. As the case continued, the patient who had all those therapies and got atezolizumab and bevacizumab, ultimately progressed. Now we have progression of the disease, and the question is what to do from there. Before I discuss some of the second-line therapies, I would like to ask Dr Yarchoan a very specific question. With atezolizumab and bevacizumab as first line, would you jump onto whatever the choice is in second-line therapy, or would you still consider lenvatinib after atezolizumab with bevacizumab?

Mark Yarchoan, MD: Great question. One of the challenges is with the new frontline options, we have very little data for what to do after bevacizumab with atezolizumab. It’s a bit of a tangent, but sometimes you do see these cases where you have oligoprogression after bevacizumab with atezolizumab. That’s not this case, but I think it’s worth mentioning. It used to be that we were very regimented. Patients with Barcelona Clinic Liver Cancer stage B got locoregional therapy [LRT]; advanced stage patients got systemic therapy. I think more and more, there’s a role for systemic therapy in intermediate stage disease, and more and more, I think there’s a role for locoregional therapies in advanced stage disease, particularly in the setting of oligoprogression. There’s more of a back and forth, and I don’t know if Dr Salem wants to say something about that. For patients like this who have new lesions, who have multifocal progression after bevacizumab with atezolizumab, I think many of us are reaching for a TKI [tyrosine kinase inhibitor] of some kind. I think it’s reasonable to use a first-line TKI like lenvatinib or sorafenib, or consideration of a traditional second-line TKI like cabozantinib. I think both are very reasonable options in this case.

Ghassan K. Abou-Alfa, MD: Thanks so much, Mark; you made 2 beautiful points. I will first address one with Dr Salem, and then I’ll carry on with the second one. Dr Salem, am I right when I meet a patient in the clinic and they ask me, “Can I go back to Dr Salem to get an embolization?” I always say, in HCC, everything remains on the table. Am I right?

Riad Salem, MD, MBA: Yes, you’re absolutely right, Ghassan, and Mark brought up a great point, which is, yes, obviously with the LRTs, we think about the BCLCBs [Barcelona Clinic Liver Cancer stage B] and the advanced disease for systemic therapy. But more and more now, we are realizing that we should not function in a manner that is so regimented, and patients actually will fluctuate back and forth by stage. I do think that what Mark brings up is a very important point. There are many patients now, particularly with some of these therapies like lenvatinib and atezolizumab and bevacizumab, that give you very good responses, but for some reason at month 6, 9, 10, 12, 14, there’s only 1 small area that’s progressing. Rather than be regimented and change the entire therapy, you can think about a locoregional therapy. There’s a patient I just treated about 3 weeks ago who had massive bilobar metastatic disease, responded very well on systemic therapy, and had 1 small area that was clearly progressing on scans. We went in there and we radioembolized that small segment, and she stayed on her regimen. What we’re seeing is more options from a systemic standpoint, very well tolerated from a systemic standpoint, and again, because of the new locoregional therapies that give a good quality of life and are well tolerated, we can start to mix these things as part of clinical practice to make sure that we optimize all of the treatments for the patients.

Ghassan K. Abou-Alfa, MD: Absolutely, very well said. I’m very happy to see that I was right about assuring our patients that everything remains on the table. With this said, we’ll go back to the second point that Dr Yarchoan brought up in regard to the choices of therapy. These are the NCCN [National Comprehensive Cancer Network] guidelines. We have regorafenib, with required prior sorafenib exposure. We have cabozantinib, which ironically is the only drug that’s approved in second and third line; ramucirumab, with a requirement of AFP [alpha-fetoprotein] of over 400 ng/mL. I like what Dr Yarchoan mentioned; Mark, I agree with you that lenvatinib, sorafenib could still be remaining here. Dr Singal, when we used to meet in person at the meeting in Park City that happened every year with the transplant colleagues, we spoke about line-minus-1 therapy, ie, after atezolizumab and bevacizumab. We agree with Dr Yarchoan that you still consider a lenvatinib option, per se. Other recommended regimens are nivo/ipi [nivolumab and ipilimumab], we are still waiting for the final results, but it can be considered; pembro [pembrolizumab] is fully approved now; and nivolumab, as we discussed…with the FDA. I’m sure the NCCN guidelines will probably change at some point. And of course, there is the issue of the MSI [microsatellite instability]-high, but again, it’s extremely unlikely that we will address it in regard to HCC.

As we just heard from our colleagues, beyond second line we can consider still the therapies that were considered in first line, among which is lenvatinib. Here is a nice table of all the studies that occurred for regorafenib, cabozantinib, ramucirumab, nivolumab and ipilimumab, and pembrolizumab, plus placebo. All of those have either full approval, being regorafenib, cabozantinib, ramucirumab and pembrolizumab; and condition approval for nivolumab and ipilimumab. At least we have plenty of options in second-line therapy. You are right Mark, we’ve lived through this for a long while. It’s nice to see that after starting from nothing—20 years ago I used to tell patients to go home—look where we are now. These are incredible data that we should be all very proud of. I would say that discussions are appropriate to address the other therapies. I will ask it only as a challenging point, Dr Singal, is there any reason you can think of why, if a patient gets atezolizumab and bevacizumab, I would say no to lenvatinib and they should go, for example, to cabozantinib? Do you have any thoughts?

Amit Singal, MD: I think, Ghassan, this is a data-free zone, so I don’t think I can say definitively that one is right and the other is wrong. I have to say, from our center, we use that T-minus-1 approach that you referenced, where we use sorafenib or lenvatinib after atezolizumab and bevacizumab, and then we save the prior second-line therapies now for the third line. I think one of the things we’re trying to do in our center, for example, with this large intrahepatic tumor burden, earlier recognition of TACE or TARE [transarterial radioembolization] failure, getting people onto first-line therapy so you can then go through second-line therapy, potentially third-line therapy. I know it’s a bit tangential to the choice here, but I think the choice is honestly less relevant than maximizing lines of therapy. That’s the big one, but I don’t think I would say one is right and one is wrong. It’s a discussion with your patient.

Ghassan K. Abou-Alfa, MD: I love the way you said it, which is maximizing lines of therapy. Wow, what a great discussion, really engaging. I would like to summarize. No. 1, I will start by reiterating what Dr Salem said, which is this is a multidisciplinary team at best, and the first item is something we are proud of. We hope you all, as you listen to us and hear from us, engage in the same way with your colleagues from the different disciplines about what’s best for your patients. We spoke about the importance of having the biopsy to confirm the diagnosis because of the pathologic necessity for that, added to what else we can decipher from these data for therapies.

No. 2, we spoke about local therapy, and Dr Salem beautifully referred to radioembolization and chemoembolization as 2 options, which of course, need the multidisciplinary team to bring them up. Then we spoke about the choices of therapy in first-line treatment. We spoke specifically about lenvatinib in detail, and we said it’s an appropriate therapy and it could be the only therapy sometimes, in case you have contraindications for the atezolizumab plus bevacizumab that we just spoke about. We held off on discussing further details of durvalumab and tremelimumab from the HIMALAYA study because, to be fair, it’s not approved yet. We spoke about the line-minus-1 in regard to pressing on from atezolizumab and bevacizumab to lenvatinib as an option, as Dr Yarchoan mentioned. I liked very much how Dr Singal wrapped it up by saying that with the second-line therapies, it’s a matter of how we can enhance further options of treatments so we can help enhance survival.

I would like to thank all of my dear colleagues for their thoughtful, great presentations and informative discussion. For our viewing audience, thank you for joining us for this Targeted Oncology™ Virtual Tumor Board® presentation. We hope today’s discussion was a valuable use of your time and that you acquired practical knowledge that can help you in your clinical practice. Thank you very much for your time.

Transcript edited for clarity.