 Anthony, here at ASCO [American Society of Clinical Oncology Annual Meeting], everything is about biomarkers. Every disease is moving into the biomarker space to select therapy, to select patients for the right therapy. What’s going on in HCC [hepatocellular carcinoma]?

 A lot in the research realm, but nothing that impacts clinical care. That’s the short answer.

 Are there any promising biomarkers that you would bet on? Is there 1 I want to integrate in my next-phase, randomized clinical trial?

 A lot of drug development in HCC is immunotherapy based. Finding predictive markers in immunotherapy has been a challenge across diseases in general. If we look at PD-1 and PD-L1 expression across recent studies in HCC, including phase 3, you notice that the responses are occurring despite PD-L1 being positive or negative, but the PD-L1–positive patients have a slightly higher chance of responding. It could be an enrichment strategy as part of an overall strategy, but it’s not a predictive marker. There are data evolving about CD8 and CD3 T-cell infiltration associated with outcome, like in other tumor types, if the right cells are in the tumor microenvironment.

 Correct. They tend to do better. There are some immune or inflammatory signatures picked up that consistently show association with multiple end points, including response and survival, including from CheckMate 459, the largest study to report biomarkers. Some of these immune signatures could be taken forward and validated a bit more and may become a part of selection strategy.

 We’re getting closer, but we’re not there yet.

 Closing this margin. Pierre, moving to the earlier stages, to screening and early detection, what’s happening? We keep hearing about platforms that are being looked at, with unmethylated and methylated DNA biomarkers. They look promising compared with other alpha-fetoproteins [AFPs]. What’s moving in that front?

 A lot of these platforms focus on finding suitable alternatives to our already-established screening methods. But in fact, the focus should be how we can augment our screening strategies to make screening more effective and higher yield. I hope the folks who already have products on the market are interested in expanding the use, and maybe take this to heart and start developing products that fill that bill. We don’t have any evidence, although studies—some of which we’re participating in—are ongoing.

These platforms seem to have a sensitivity and specificity that approach or slightly improve upon our established screening criteria for at-risk groups—basically, ultrasound imaging or in people who do this ultrasound combined with alpha-fetoprotein. There are limited studies looking at other markers, which over time have been used to enhance screening efficacy, including AFP-L3 [third electrophoretic form of lentil lectin-reactive AFP], DCP [des-γ-carboxy prothrombin], and things like that. It doesn’t look like that adds a tremendous amount in Western patients. In Eastern and Asian patients, for some reason these tend to be much higher yielding than in our Western patients, probably related to disease etiology and other factors.

 We’re not there, but there’s quite a bit of movement in that space.

 We need something. One paper about the underlying causes of HCC, and NAFLD [nonalcoholic fatty liver disease] was 1 of the fastest-growing reasons for HCC. For this population, we need a screening strategy. We see more patients with obesity and diabetes, which are difficult for ultrasound and to scan the liver completely. We need new screening tools that are low risk.

Videos

A brief review of predictive and prognostic biomarker needs in hepatocellular carcinoma, followed by discussion on screening and detection.

Management of HCC: Advances in Biomarkers and Screening

 Anthony, where are you seeing systemic therapy moving into the earlier stages, specifically the intermediate stages?

 I’d like to highlight that the intermediate stage is a very broad group of patients.

 You can go from 1 large lesion with 3 small ones to patients who are riddled with 10 or 15 small lesions in the liver across all lobes. These aren’t equivalent patients, and most staging systems are trying to differentiate these patients. There’s a subgroup of patients with liver-limited disease that’s still BCLC-B [Barcelona Clinic Liver Cancer stage B], who have extensive multifocal or infiltrative disease that’s high risk and should probably go straight to systemic therapy. This is 1 nuance being made in BCLC staging, but it’s in others as well.

Another point is combination therapies for the intermediate stage, which is something we’ve always been interested in doing. Everyone thinks, “We have 2 effective modalities, so why don’t we put them together?” In a nutshell, attempting this approach with TKIs [tyrosine kinase inhibitors] has largely failed. The largest body of data is with TACE [transarterial chemoembolization] or Y-90 [yittrium-90] with sorafenib, and these trials are largely negative. Now there are attempts to combine immunotherapy agents, whether single agent or in combination with TACE or radioembolization. The larger trials are ongoing. There are smaller reports of phase 1/2 studies showing the feasibility of this approach, showing some biomarker changes that validate proof of concept. That is an immune-modulatory effect of the liver-directed therapy. That’s nice and it’s evolving, but we must await the phase 3 data.

The last category compares liver-directed therapy with systemic therapy. This is the newest wave of trials, and it’s looking at patients with classic BCLC-B and asking if liver-directed therapy is still superior to systemic therapy.

 There’s quite a bit of activity. That’s the trend we’re seeing more as our systemic therapy becomes more effective. It makes sense to move it to earlier stages. For patients who aren’t suitable, if you think locoregional therapy may be their best option but unfortunately because of comorbidities, they may not be eligible, Arndt, what’s your standard? What do you do?

 We try to include these patients in clinical trials because we must redefine the intermediate stage and decide who’s a candidate for local and systemic therapies. In respect to this combination of local therapies with immunotherapies, we just presented our data from the IMMUTACE study, which combined TACE with nivolumab in 49 patients. It was a single-arm study with 15 centers in Germany looking at the safety and efficacy. Our primary end point was the overall response rate of 55%, which we counted as clinically meaningful, it was 72%. The largest tumor we treated was 18 cm with TACE. You’d think this isn’t a candidate for TACE, but with the combination with nivolumab, he almost had a complete response. That was remarkable in that case, but overall, the response rate looked very promising. Median overall survival is still early, but we are over 28 months, so that’s a signal that this combination could be meaningful. But I also fully acknowledge that we need to have the phase 3 studies to compare and to address the question of whether sequential therapy might not be the way to go and [that maybe we should] start with 1 treatment and then go to the next.

 Pierre, when we talk about combination, we’re talking mostly about the data with us now, which is single PD-1 or TKI. Now that we’re seeing combination immunotherapy—atezolizumab-bevacizumab, tremelimumab-durvalumab, ipilimumab-nivolumab—is this where we’re moving?

Panelists consider the role of systemic therapy in patients with intermediate-stage HCC who are ineligible for locoregional therapy.

Selection and Use of Systemic Therapy in Intermediate Stage HCC

Anthony El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses recent combination data in hepatocellular carcinoma (HCC).

There was a lot of discussion surrounding early trials in HCC during the 2018 International Liver Cancer Association Annual Conference, says El-Khoueiry. This includes some trials looking at combination therapy. Most of these trials are looking at anti—PD-1/PD-L1 agents with either tyrosine kinase inhibitors (TKIs) such as sorafenib (Nexavar) and lenvatinib (Lenvima), or with anti-VEGF agents.

One of the trials presented at the conference was the combination of atezolizumab (Tecentriq) with bevacizumab (Avastin). Although it showed a response rate of 60%, it was in a small number of patients, so El-Khoueiry says that this should be interpreted with caution. Further data is awaited. Nonetheless, there is excitement for the possibility for combinations of anti—PD-1/PD-L1 agents with anti-VEGF or TKIs in general, El-Khoueiry concludes.

Anthony El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses recent combination data in hepatocellular carcinoma.
 

Anthony El-Khoueiry, MD

Articles

Management of HCC: Advances in Biomarkers and Screening

Selection and Use of Systemic Therapy in Intermediate Stage HCC

Dr. El-Khoueiry Discusses Recent Combination Data in HCC