Second-Line Options After IMbrave150 Regimen

Richard S. Finn, MD: The second-line setting has raised some issues for us because all the data we have from phase 3 studies were based on prior sorafenib. Here comes along progress, which we all love in the clinic: we have lenvatinib. There’s been no phase 3 study on drugs after lenvatinib. We then have IMbrave150 and atezolizumab/bevacizumab. Peter, how do you think about your second-line patients now if they’re getting atezolizumab/bevacizumab in the frontline setting?

Peter Galle, MD: This is a question that is frequently answered, and as there are no reliable data, it comes down to expert opinion and discussion. What is clear is that there are theoretical aspects to it. It might be an option to discuss a switch in mode of action. When having had an IO [immune-oncology] agent plus an antiangiogenic antibody, it somehow seems to be a good rationale to switch to a TKI [tyrosine kinase inhibitor], although this is just not based on evidence: it’s the theoretical option. With a pragmatic approach worldwide, it’s quite a matter of availability of the approval. If you take, for example, lenvatinib, in many countries, it is listed as first-line therapy.

What do you do now if you have had atezolizumab/bevacizumab in the first-line setting, and lenvatinib is used in the second-line setting? It’s not useful, but of course, it’s useful in theory. The good thing is that we have options. The problem here is we have to do lots of assessments. In real life, these will never mature as phase 3 trials with A against B against C. I believe what we should definitely try, and this is going back to our initial discussion when we start intermediate safe therapy, we should offer our patients systemic therapy, and we should try to offer them several lines of therapy.

In the past, this had already been demonstrated for the sequence sorafenib, regorafenib, and it was the same for lenvatinib. If you have more than 1 option, it is apparently better. In the old days, we were used to treatment beyond progression; in these days, it might be wise to reconsider the therapeutic strategy upon progression and to switch.

Richard S. Finn, MD: Yes, that’s an important point. When we had sorafenib, and we couldn’t offer patients anything after, if they weren’t going to qualify for a clinical study, it was pretty much continued until clinical progression. This raises the issue of following our patients closely, imaging them on a regular basis, and transitioning them to their next line of treatment on radiographic progression. Certainly 2 or 3 mm, I don’t think we would call that progression, but when there is continuous growth of a tumor or new lesions, that’s a sign to start to transition patients because the runway we’re dealing with here is their underlying liver disease as well.

Are we going to get to the point where we’re controlling patients’ tumors longer than the natural history of their liver disease? It’s an interesting thing to think about as we have all these new drugs available. Tony, a patient gets atezolizumab/bevacizumab in the frontline setting. I would say that there are several options that we know about. There is lenvatinib, which is a frontline TKI similar to sorafenib, but we then have phase 3 data with cabozantinib and regorafenib after prior sorafenib. Even with the cabozantinib data, we had 25% of patients who were in the third-line setting there. Can you review some of the data and explain how you think about incorporating these things and adverse effect profiles? What about cancer biology? How does the biology of these drugs come into play?

Tony Bekaii-Saab, MD: Add to the list the non-TKI, which is ramucirumab and the AFP [alpha-fetoprotein] level of more or equal to 400 ng/mL. At first glance, the landscape looks confusing. However, it’s gotten quite simplified. We often, as oncologists and physicians overall, try to complicate our lives, thinking about this more in terms of ACE [angiotensin-converting enzyme] inhibitors, and we have a million, how do you pick? My life has gotten easier. First of all, I think all TKIs are created equal until proven otherwise, yet no one has proved that any of these TKIs, including lenvatinib vs sorafenib, is better than the other. It’s choice, it does not matter as much. That’s 1 point. The second is the question of ramucirumab, to eliminate the non-TKI, it has become irrelevant. If you’re exposed to bevacizumab, I’m not going to waste your time on ramucirumab anymore. It’s a dud. It’s a dumb question.

Richard S. Finn, MD: Let me challenge you on that for a minute.

Tony Bekaii-Saab, MD: Well, you'll challenge me. You go with a VEGF monoclonal antibody, and you then go to another that hits the receptor. I’m not sure if you’re going to see much value out of it. It was barely active following a TKI. Yes, you get the floor.

Richard S. Finn, MD: There are 2 things, quickly, because I don’t want to get distracted. Isn’t there a precedent in colon cancer with ramucirumab after bevacizumab? Can you comment on that? You see a lot more colon cancer cases.

Tony Bekaii-Saab, MD: Yes, there is a precedent that shows that it’s barely meaningful when added to chemotherapy, not as a standalone treatment. That’s 1 point. But if you look at it, it doesn’t enhance response. It barely moves the survival by a notch. That’s not on its own; it has to work with something else, not on its own. The answer is maybe, but is it worth wasting the patient’s time on a little maybe?

Richard S. Finn, MD: I appreciate that point. Ramucirumab is well-tolerated, and for patients who have been on a TKI, it has a different adverse effect profile. I want to call out, and we’ll get back to the TKI discussion.

Tony Bekaii-Saab, MD: No, that’s different. Ramucirumab is…we’re looking at the landscape and the second-line setting.

Richard S. Finn, MD: Yes, well hold on.

Tony Bekaii-Saab, MD: The TKI….

Richard S. Finn, MD: I want to mention some data from ESMO [the European Society for Medical Oncology annual meeting] quickly. We [with the University of California, Los Angeles Health] presented a poster at ESMO where we’re looking at ramucirumab after drugs other than sorafenib. This is an expansion phase to the REACH-2 study, and it’s ongoing. We presented 24 patients, and many of them had atezolizumab/bevacizumab. There was a subset of patients who had atezolizumab/bevacizumab as well as IO, as well as lenvatinib. At least in the overall population, the PFS [progression-free survival] was fairly similar to that we saw in REACH, and the safety was certainly the same. I understand what you’re saying. We’re looking for a different mechanism, so that may be where the TKIs come in.

Tony Bekaii-Saab, MD: Alright. That question is not going to be settled anytime soon. Looking at the TKIs, most of these TKIs have similar activity across the board. However, here are the problems that I have with lenvatinib and sorafenib. In addition to what Peter was mentioning, they’re only being looked at in the first-line setting. With the data post-VEGF, assuming most of these agents hit some level of VEGF, the data for lenvatinib and sorafenib post other VEGF-directed therapy is lacking. We don’t know if they have much relevance in the second-line setting. In addition, we have 2 agents that have proven activity post-sorafenib in the second-line setting.

The patient has been somewhat exposed to a VEGF inhibitor plus other TKIs, and they have activity. That’s regorafenib and cabozantinib. Regorafenib and cabozantinib would be the natural choices because the data are there for them in the second-line setting. Albeit, it’s not post-atezolizumab/bevacizumab, but one can still argue that they at least have second-line data, post some semblance of a VEGF inhibitor in the first-line setting. The other thing I would say for cabozantinib, and I actually end up favoring cabozantinib based mostly on mechanism of action vs regorafenib, is because it hits MET and AXL, which are both known to be targets that rise in the resistance for VEGF inhibitors.

At least with bevacizumab in the first-line line setting, there is a bit of a theoretical rationale for cabozantinib. Frankly, if you pan out beyond HCC [hepatocellular carcinoma] and go to the world of RCC [renal cell carcinoma], that seems to be one of the mechanisms that supports the utilization of cabozantinib in this setting. In all frankness, they all are reasonable options. We’re sometimes wasting a lot of energy discussing which I want to do, even if it’s minus 1, or plus 1, or 0.

At the end of the day, we know that most of these patients, once they fail the first-line treatment, about half of them will not see the second-line treatment anyway. The argument stands for the second-line treatment, and for those who fail the second-line treatment, incredibly few will ever see the third-line setting. The discussion will focus on those 2 agents in my mind: cabozantinib and regorafenib. For the reasons I’ve stated, I favor cabozantinib post-atezolizumab/bevacizumab .

Richard S. Finn, MD: I have a different take, though there is obvious expert opinion here: it’s not right or wrong. I would approach it with atezolizumab/bevacizumab as maybe line 0, and we then have front-line TKIs sorafenib or lenvatinib. To your point, we then have second-line TKIs, cabozantinib or regorafenib. Pierre, could you give us what the survey says? What are your thoughts?

Pierre Gholam, MD: There are 2 rational approaches, as I understand them. There is the amnesia approach, which is to say that I give atezolizumab/bevacizumab. I hope for the best, and then I start sequencing from there onward as if that combination therapy did not exist. I start with first-line therapy, then a second-line set of approved therapies, etc. That seems to be a fairly popular approach. The other is to follow what Tony just mentioned, which is to say that there are drugs established in the first-line setting, and there are drugs that are established in the second-line setting, following sorafenib. I’m going to use those based on that prerogative.

That is honestly my favorite approach. I would use atezolizumab/bevacizumab as a first-line treatment, and I would use cabozantinib or regorafenib as the second-line therapy. Perhaps in a small select group of patients for whom I want to spare significant adverse events, I might use ramucirumab in the subset of patients with a high AFP, and I would take it from there. That would be my rational approach to this. I would definitely not use a sequence that includes IO followed by IO. I will preface this by saying that I’m not a medical oncologist, unlike this illustrious group of people here. My understanding is that IO followed by IO has not usually been a very fruitful approach. Please correct me if I’m wrong; I’m speaking out of my league here.

Richard S. Finn, MD: We’ll get to that. To wrap up, if we look at the data, all the TKIs have similar adverse effect profiles. We knew this from cabozantinib and the CELESTIAL study of cabozantinib vs placebo. We improved overall survival. We improved PFS with mostly single-digit response rates. Cabozantinib differentiates itself, as mentioned, because it hits not only VEGF but AXL and MET as well. Regorafenib was looked at in the second-line setting vs placebo after patients who had tolerated prior sorafenib. It has a significant hazard ratio in the 0.69 range for reduction in the risk of death as well as progression.

We did this with low objective responses, and we saw at ESMO recently some real-world data with regorafenib. That showed that its use in the real world from a registry study that the dosing, adverse effects, and disease control look similar to what was seen in the RESORCE trial.

Transcript edited for clarity.