Emerging Treatment Considerations in HCC: An Expert Case-Based Discussion - Episode 5

Selection and Use of Systemic Therapy in Intermediate Stage HCC

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


Tanios Bekaii-Saab, MD: Anthony, where are you seeing systemic therapy moving into the earlier stages, specifically the intermediate stages?

Anthony El-Khoueiry, MD: I’d like to highlight that the intermediate stage is a very broad group of patients.

Tanios Bekaii-Saab, MD: Exactly.

Anthony El-Khoueiry, MD: 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.

Tanios Bekaii-Saab, MD: 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?

Arndt Vogel, MD: 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.

Tanios Bekaii-Saab, MD: 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?

Pierre Gholam, MD: That remains to be seen.

Transcript edited for clarity.