Novel Combinations Under Study for HCC


Richard S. Finn, MD: You touched on a few things. As patients are better compensated, getting started on systemic treatment at the right time, they are going to cycle through many drugs, outside of going on a clinical trial, which is always the best option. In practice, patients will get more drugs based on what we have available. The options probably include I/O [immuno-oncology], or immune checkpoint inhibitor combinations after prior I/O, in reality.

But you’ve commented on some interesting things that are in development. Ipilimumab-nivolumab, which got accelerated approval in the second-line setting, is now in the frontline setting. This is based on the CheckMate 9DW study, which explored the option vs sorafenib. At the same time, we saw the concept of CTLA4 and PD-1, PD-L1 inhibition based on the HIMALAYA study. That’s durvalumab and tremelimumab vs sorafenib, and single-agent durvalumab. This was a multiarm study. And there was data at ASCO [American Society of Clinical Oncology Annual Meeting] this year from Dr Robin Kate Kelley that showed response rates of the high 20% range with that regimen, similar to what we saw with nivolumab-ipilimumab in the second-line setting—with response rates of around 35%. These I/O–I/O combinations look very promising, and we’re waiting for phase 3 data.

At the same time, building on this idea of VEGF inhibition and PD-1 inhibition, we have lenvatinib and pembrolizumab. We published a phase 1b study in the Journal of Clinical Oncology in September of this year. This was a nearly 100-patient study that showed this combination had a response rate of about 36%, which is very similar to what was seen in the atezolizumab-bevacizumab single-arm phase 1b/2 study.

Many of these responses are very durable. The adverse-effect profile looks very similar to single-agent lenalidomide or single-agent pembrolizumab, with no new synergistic toxicities. The overall disease control rate, including stable disease, was around 88%. It was very high.

The LEAP-002 study has completed accrual. This is a placebo-controlled study of lenvatinib plus pembrolizumab, or lenvatinib alone. We’re waiting for the results of this study, just like we’re waiting for the results of HIMALAYA that also has completed accrual.

And then there’s the COSMIC-312 study, which looks at moving cabozantinib to the frontline setting. Here we see cabozantinib combined with atezolizumab vs cabozantinib alone. There haven’t been much data presented with this combination, but they’re building on the consistent theme of VEGF inhibition, or multikinase VEGF inhibition, in combination with immune checkpoint inhibition. This tells me that the landscape has a lot of potential to change in the coming year or so, depending on when these events read out. It’s a very exciting time.

With these studies ongoing, waiting for those readouts, Catherine, what do you see as an unmet need for our patients with advanced liver cancer?

Catherine Frenette, MD: One of the places we really need to have the data is when we consider moving these amazing systemic therapies into an earlier-stage patient. One of the discussions we always have at our tumor boards, as Michael pointed out, is, “Well, we can take that,” “We can do an ablation,” or “We can do a Y90.” Okay, but that also is going to take out some healthy liver. We certainly don’t want to decompensate someone with locoregional therapy over and over. Maybe we need to be moving to systemic therapy after 1 locoregional therapy if they didn’t get the response we wanted to see. Maybe we need to add these systemic therapies as adjuvant therapy after an ablation or resection. It would be amazing if we could decrease the recurrence rate after a resection and cure more of those patients, which would then encourage more patients to go to resection as opposed to going to transplant. We now know that they have a better chance of being cured compared with resection. Maybe 2 or 3 lesions should be resected, because the recurrence rate can be dropped down with these combinations? We have some really exciting opportunities to really change the whole way HCC [hepatocellular carcinoma] is treated.

Richard S. Finn, MD: Certainly, those studies are ongoing.

Transcript edited for clarity.

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