Ghassan K. Abou-Alfa, MD: On the other hand, when it comes to the subgroup analyses—and this is where I would like to bring in Dr Salem—because of other components that might play a role and help us define if it matters whom we are treating, prior treatments, no prior treatments, extent of disease, etc, we see that the data shows that everybody benefited. Dr Salem, would you have expected or anticipated any different perspective here, or are you happy to see what you are seeing in the subsets?

Riad Salem, MD, MBA: This is interesting. Obviously, when you look at subsets, they are, of course, hypothesis generating. They are interesting. The reality is in tumor board we look at them, we consider them, and that’s part of personalized decision-making. There was an effect pretty much across the entire spectrum of the patient population, and I think in the spirit of where we are these days, looking at the effect in the BCLC [Barcelona Clinic Liver Cancer] stage B patient population, it is particularly interesting. Is there a role for systemic therapy? Currently, a local regional therapy is the gold standard, so it just made it. The hazard ratio is 0.99 so it barely made it, but it appeared to have an effect on the BCLC stage B patient population. Now, more detail on who those Bs actually are, because as you can see from the new BCLC guidelines, there is a recognition that the BCLC stage B patient population is heterogeneous. It required further investigation. It is, in fact, as heterogeneous I think as some of the BCLC stage C patients, but what is the role of a systemic therapy? Clearly, as an interventional radiologist, I see that some BCLC stage Bs do well with a local therapy, and some do not. This is where the systemic therapy comes in and this provides us with a glimpse of the idea, let’s start investigating systemic therapy in this patient population. Is there a role and can we better define what that patient population is that will respond and do well with systemic therapy versus the one that should remain with a classic indication of a local regional therapy? That’s what we have here.

Ghassan K. Abou-Alfa, MD: I love what you said. I’m going to hold that thought because we’re going to come back to it. That promises a very good point that you bring in, in regard to the BCLC stage B and the systemic therapy. Independent of the prior therapy, independent of the different demographics being age, sex, region, performance status, body weight—which was a concern especially for 60 or less than 60 kilos—the benefit was, for both groups, independent of the AFP [α-fetoprotein] level, independent of the involvement of the vasculature and critically independent of the ideology. I know we’re tempted to think that some people will benefit more or less, but so far it has been the same. For the BCLC component, which I am finishing up in regard to what Dr Salem brought in, this is where I’m going to bring Dr Singal for the BCLC story. Amit, tell us about Dr Masatoshi Kudo, MD, PhD, who was the head of the REFLECT study [NCT01761266], in regard to the 7 criteria.

Amit Singal, MD: Ghassan, I think you’re referencing his study where he took patients with larger intrahepatic tumor burden and did a propensity match analysis where he compared this between lenvatinib and local regional therapy, most commonly TACE [transarterial chemoembolization] in that study. Interestingly, those patients with larger intrahepatic tumor burden had better outcomes and better survival than patients who were treated with lenvatinib up front rather than local regional therapy upfront. When you take a look at the exploratory analysis of why he showed increased degradation in the liver score in those patients who were treated with local regional therapy compared to those patients who went down to upfront systemic therapy. This is a small propensity score and match analysis, retrospective in nature, risks of residual confounding, so it’s not the answer, per se, but it’s hypothesis generating and very interesting, and makes us think about if there are patients who are not BCLC stage C, not advanced stage, who actually have intrahepatic tumor burden liver localized disease, but should be treated with an upfront systemic therapy, particularly as we’ve seen advances in systemic therapy options and outcomes. As you and many know, there are now trials specifically evaluating this question of large intrahepatic tumor burden taking a look at randomization to systemic therapy versus upfront local regional therapy. I think we’re going to have more answers on this as we move forward, but I think the idea that Dr Kudo put forward in that propensity score match analysis is one of the big things that I think could change how we manage these patients moving forward.

Ghassan K. Abou-Alfa, MD: Thanks so much for reiterating what Dr Salem brought into the discussion. It’s quite fascinating and this is why we give credit to my dear colleagues. Dr Salem is insisting and impressing on all of us the multispirit team approach where if a patient, as we just heard from Dr Singal, has a certain number of lesions in the liver, and at same time the size of the largest lesion if you add those 2 numbers—let’s say, for example, 4 lesions. Number 4 plus the largest lesion is 4 cm plus 4. Four plus 4 equals 8, it’s more than 7—this is where, ironically, the data has shown that patients can feel better with systemic therapy rather than with local therapy. I’m not implying that this should be happening, independently they are systematic, but it should be done within the context of the multispirit team approach that we are talking about. With this said, as we just summarized, sorafenib and lenvatinib showed noninferiority. Both show improvement to survival equally; No. 2 is PFS [progression-free survival], which was about 3 times higher for the Lenvatinib. At the same time, in the subgroup analysis, we see that lenvatinib faired very well for all of patients independent of their different variables or demographic components.

Now that we are into the era of second-line therapy, it will be nice to see, post study, what patients did. Understandably, for the patients who were on the lenvatinib arm, about a quarter of them did go to sorafenib because this was the only thing available at that time. For the sorafenib arm, because lenvatinib was not available, they went for some other form of therapy and some of them stayed on sorafenib which, by the way, is a practice that we’ve been practicing. At Memorial Sloan-Kettering, we started with the first study on sorafenib and, at the time, there was nothing else. We decided if there was no sorafenib when the short plan came out from the Barcelona group, we should keep patients on sorafenib because at least that maintains some control of the disease until better days. This is now evolving quite a bit. There was reported data that was presented, if I’m not mistaken, in January 2020 at GI [gastrointestinal] ASCO [American Society of Clinical Oncology] and it showed that the patients received sorafenib or lenvatinib on the REFLECT study. If you look at the survival after whatever they get as second-line therapy, it showed a critical improvement of outcome for lenvatinib, more than 26 months, which is the first we’ve seen as the highest, but of course within the context of the retrospective analysis nature of what we have seen.

Transcript edited for clarity.