Evolving HCC Treatment Landscape: Combination Therapy

Richard S. Finn, MD: Peter brought up a lot of interesting ideas about combinations, and I think combinations are thefuture. Katie, as long as we have your attention, the landscape in the next several years—and I’ll tell you I was asked this in 2007 or 2008—what is the future of liver cancer? We have sorafenib. I said, “It’s the golden age. We’re going to have all of these positive phase 3 studies.” I was off by about a decade. What’s your take?

Katie Kelley, MD: That’s a great question. It’s good to have more options. HCC [hepatocellular carcinoma] is such a heterogeneous patient population when you look at it from underlying organ function, degree of liver dysfunction, to etiology, the viral milieu may certainly impact the immune microenvironment in response to immunotherapy, to tumor factors. We obviously talked about PD-L1 and AFP [alpha-fetoprotein], but we don’t yet have other tumor genetic biomarkers to work with in HCC, with some early data for FGF19 and FGFR4 targets; that’s really preliminary so far. Having more drugs to choose from early on to tailor according to comorbidity and safety profile is one change in the landscape on the horizon that is a net benefit as patients are receiving more lines of therapy.

This is especially so as we start earlier with level 1 data into the intermediate space instead of waiting until patients are too advanced to receive more than 1 or 2 lines of therapy. Patients will receive more lines of therapy, and they will start earlier when they fail liver-directed therapy earlier. In terms of the combinations, we need to double down on biomarker efforts to try to understand both clinical biomarkers, like viral status, as well as tumor biomarkers. The big categories of combinations are going to be the CTLA-4 and PD-1 or PD-L1 vs the antiangiogenic combinations, and trying to discern which patients are best for which. That would be my answer.

Richard S. Finn, MD: At ASCO [the American Society of Clinical Oncology annual meeting], we saw some novel data of a triplet: nivolumab/ipilimumab/cabozantinib. My recollection of that data is that cabozantinib didn’t add that much. Is that how you rate that?

Katie Kelley, MD: Yes. It gets hard to flush out component contributions when you get into triplets like this, and there is certainly appreciable toxicity both from nivolumab/ipilimumab, which has a 50% immune-related toxicity requiring steroid rate, and with cabozantinib and PD-1 or PD-L1. You’re right that, in that small cohort, it didn’t show detrimental toxicity or benefit. In a small, approximately 30 patient cohort, it didn’t discriminate itself efficacy-wise beyond either doublet. It’ll be interesting to see how the COSMIC-312 data look with cabozantinib/atezolizumab because again, cabozantinib has a promising immunomodulatory mechanism, and the renal cell data support this as well. At first, we’ll start with the doublets. Before moving into triplets, it might behoove us to get more biomarker data to guide us. It will be hard to interpret those outcomes for triplets.

Richard S. Finn, MD: Peter, another combination that has only come about with mature data fairly recently is regorafenib/pembrolizumab. Regorafenib has been looking for a PD-1 partner for some time. Can you tell us how that data look compared to the other TKI [tyrosine kinase inhibitor] combinations?

Peter Galle, MD:The analysis is still a bit early and is not yet mature. We have investigated 35 patients so far. First of all, it does not have an unexpected toxicity, although the dosing is going toward a low dose. The maximum tolerated dose was not 160 mg, which would be a standard dose, but it was 120 mg. In fact, this combination will be developed at a lower dose, probably in the range of 90 mg per day. It is coming to the point that, in comparison to single-agent therapy where we have a tumor cyto-effect, here we talk about immunomodulation, and we need to recalculate our dosing. What we saw with respect to efficacy was a disease control rate of 90%, which is very promising. That needs to be developed further.

Richard S. Finn, MD: It’s an interesting idea, though, that maybe we don’t need the full dose of the TKIs to get the immunomodulatory effect. That might go for all the drugs, and we’ll have to continue to follow that story as we get the phase 3 data or mature data with that regimen.

Camrelizumab is a drug we didn’t talk about, but there were data at ESMO [the European Society for Medical Oncology Virtual Congress] in combination with apatinib. That looks again to Tony’s point about how many TKI/IO [immune-oncology] combinations do we need if they all look the same? The other thing though is that camrelizumab is being looked at in a phase 3 study that’s completed accrual vs sorafenib. This is an interesting study because it’s a noninferiority study. Unlike CheckMate 459, which was negative because it was a superiority trial, this might provide phase 3, level 1 evidence for use of single-agent IO in the frontline setting. This was a global study, and we’re waiting for the readout from that. This has been an amazing discussion.

There is a lot of interest in moving these combinations to earlier lines of treatment. There are a number of studies looking at these combinations with TACE [transarterial chemoembolization] after surgery. There is a study of cabozantinib and TACE. There is EMERALD-1, which is a phase 3 study of durvalumab, bevacizumab, and TACE, and there is the phase 3 LEAP-012 study, which is lenvatinib, pembrolizumab, and TACE. There’s EMERALD-2, which is durvalumab and bevacizumab after resection. There is a pembrolizumab after resection. There’s the CheckMate 9DX study, which is nivolumab after resection. There is truly an immense academic effort in liver cancer, and it’s exciting to see because this is not the rarest disease. It has a high morbidity and high mortality, and thanks to all of your efforts, we’re starting to see some light on the horizon for our patients.

It’s certainly an exciting time for our patients with liver cancer. Having been in the space for some time, it’s exciting to be able to sit down with a patient and tell them all the great options we have that are improving survival and that we can expect responses to their tumor. There is always a lot of exciting research to look forward to, not only in the frontline setting with all the combinations we talked about, but also moving these drugs to earlier lines of disease treatment.

With that in mind, I’d like to thank all 4 of you for your participation in this lively discussion. It was a great event, and I hope our audience found it very educational as well. Thank you very much for your attention.

Transcript edited for clarity.