Neoadjuvant Therapy to Downstage HCC

Reactions to treatment gaps in the neoadjuvant space for hepatocellular carcinoma and implications for incorporating data supporting newer, novel systemic therapies for appropriate patients.

Tanios S. Bekaii-Saab, MD, FACP: It makes quite a bit of sense. Transitioning to you, Mark, where do you see a lot of our more systemic modalities moving, more so in the early stage, maybe resectable disease, in HCC [hepatocellular carcinoma]? This pre-peri-operative approach, what are we looking at?

Mark Yarchoan, MD: In most prospective analyses that have been done, only about 20% of HCC is truly resectable at presentation. For patients who get resected, the majority of them end up recurring. Early stage HCC is an area where we need some progress. We need to increase the pool of patients who are considered curable, and then for patients who get resection, we need more effective strategies to increase the cure rates. That’s always the goal for the patients we see. There is no other tumor I can think of—we have systemic therapies now that produce response rates of 30% or more—where systemic therapy is not used to cure patients, because that always should be the goal. We presented a small study at ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium] that has been accepted now for publication, where we took tumors that were outside of normal criteria for resection. These are tumors either with major vessel involvement or multifocal disease, tumors where normally if they go to surgery, the outcomes are poor because they almost invariably recur. We treated these tumors with neoadjuvant, a combination of a TKI [tyrosine kinase inhibitor], in this case cabozantinib, with nivolumab. Bevacizumab plus atezolizumab would be our standard systemic therapy now, but bevacizumab has a long half-life, which can be problematic in the neoadjuvant setting.

Out of 15 patients, 12 of them ended up getting to resection, and we saw a high pathologic response rate of about 40% in the patients who got that therapy. The majority of patients who had pathologic responses, 4 out of 5 of those patients have not recurred now going on about 2 years. This is a proof of concept study, and there are other studies of neoadjuvant systemic therapy as well. There’s an ongoing study of nivolumab with or without ipilimumab from the University of Texas MD Anderson Cancer Center group that also has found a high pathologic response rate. We need more data, these are just hypothesis-generating studies, but eventually there may be a role for systemic therapy to expand the pool of patients who can go to surgery. At the same time, there are numerous phase 3 studies ongoing of adjuvant PD-1 to address the question, can we improve cure rates in this disease? I’m optimistic that we will.

Tanios S. Bekaii-Saab, MD, FACP: Mark, thank you. I want to go back to this, and I want to go to Rachna on this one, that [ipilimumab, nivolumab] data from MD Anderson, which is very interesting, but of course it was a highly selective single-arm study. I know your group under your leadership with SWOG [Cancer Research Network] has been building the next study. Perhaps you can touch upon what this looks like?

Rachna Shroff, MD: These were provocative and intriguing data. Being a single-arm phase 2 study, it was very logical for us to move this into a larger inner group kind of approach. To Mark’s point, the question is simply when you see a high path CR [pathologic complete response] rate, which is what [Ahmed] Kaseb, [MD]’s study from MD Anderson demonstrated. The question is, can [nivolumab, ipilimumab] be safely given, and can it improve outcomes in the preoperative setting? This study is going to be asking that question. SWOG is running the study, but it’s an NCI [National Cancer Institute]-sponsored study. It’s going to be a question of, should we be giving pre-operative [nivolumab, ipilimumab], and what does that do in terms of recurrence-free survival and outcomes? It’s gone through a couple of different iterations, but it’s now moving forward. We’re excited to be able to do this in a prospective randomized fashion. The important points are going to be simply having buy-in and support from our surgical colleagues. They really are excited about this. There’s a real interest in looking at the potential for neoadjuvant therapy. Given that there were intriguing single-arm data, initially the question was, should we be looking at things like path CR? At the end of the day, what we really care about is prospective recurrence-free survival, overall survival. Those are the really important end points we’re following.

Tanios S. Bekaii-Saab, MD, FACP: I’m looking forward to it, this is an exciting study. I want to go back to Ed. Can touch upon this LEGACY trial, which is a retrospective study, but led to the approval of TheraSphere essentially in patients with HCC. This study was a bit interesting as it included patients with BCLC-A [Barcelona Clinic Liver Cancer stage A] and BCLC-C. What is your perspective about the results of this study, and is it going to change anything in our practice?

Edward Kim, MD: I was pleasantly surprised that the FDA took the LEGACY study and approved the use of the glass microspheres for treatment of HCC. It’s the only therapy and interventional radiology that we have that has an on-label indication for treating HCC. It includes BCLC-A and BCLC-C; it excludes patients with vascular invasion extrahepatic spread.What it leaves is patients with an ECOG performance status of 1, which qualifies them for the advanced category. What it really does is, it takes the radiation segmentectomy, which is what we’re doing with radioembolization; it’s a surgical principle when surgeons do anatomic resection, so wedge resections. They remove that portion of the liver. This is focused on solitary HCC up to 8 cm in size. It had 88% objective response, 84% complete response rates. We’ve been using it for quite a while, but the on-label indication with the FDA helps practices around the country to treat these lesions either as a bridge to transplantation due to the longer wait times now instituted with the acuity circles, or as a curative intent therapy for unresectable patients. As Mark had mentioned, only 20% qualify for a curative resection. This gives the option for patients who have portal hypertension, low platelets, etc, to have potentially a curative intent procedure. We know that many lesions are beyond the ablation criteria of about 3 cm in size for curative intent, and so larger lesions can also now be treated with that type of mindset.

Tanios S. Bekaii-Saab, MD, FACP: We should have a quick word about how things have evolved in terms of planning and directing. There is a more directed approach with TheraSphere because the history of Y-90 [yttrium-90 radioembolization] hasn’t always been as focused and directed. It appears that we’re focusing more on these segmental or lobar foci. That’s an important message to bring, that this is a changing modality. The microspheres or the spheres themselves haven’t changed much, but how we use it in today’s world has changed and probably made it more effective and safer.

Edward Kim, MD: You sound like you were an interventional radiologist in your past life. It has been an iterative process, I would say over the last decade, where initially the radioisotopes were delivered in a lobar fashion. Potentially you had higher rates of nontarget damage that would accelerate fibrosis in the liver, especially in the nontumoral parenchyma. It’s changed in our techniques in the last several years to try to self-select just the tumor and the surrounding parenchyma, creating a margin so that you spare background parenchyma. This was shown in the LEGACY study as well, with a 5.6% SAE [serious adverse event rate]. It was shown to be quite safe, despite injecting high radiation doses, which is just internal radiation. It’s embedded into the spheres, and so wherever those spheres deposit, that’s where the radiation is. The radiation radius is only about 3 mm in range. Wherever it’s deposited, that’s where the radiation stays. It doesn’t travel outside of that, you don’t get huge rays of radiation that damage collateral surrounding the area, but wherever that’s deposited, that’s where the radiation is. That leads to safer procedures and also less nontarget damage, and it’s more focused on the target too.

Tanios S. Bekaii-Saab, MD, FACP: This is exciting and certainly moving us forward.

Transcript Edited for Clarity

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